Severe Asthma (Fatal Asthma) 1 Bronchial Asthma Bronchial Asthma Second Edition D Behera MD (Medicine) FCCP FNCCP FICP FICA MNAMS (Medicine) Dip. NBE (Respiratory Medicine) Professor Department of Pulmonary Medicine Postgraduate Institute of Medical Education and Research Chandigarh (India) JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd EMCA House, 23/23B Ansari Road, Daryaganj New Delhi 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021, +91-11-23245672 Fax: +91-11-23276490, +91-11-23245683 e-mail:
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[email protected] Bronchial Asthma © 2005, D Behera All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only. First Edition: 2000 Second Edition: 2005 ISBN 81-8061-434-4 Typeset at JPBMP typesetting unit Printed at Gopsons Papers Ltd, A-14, Sector 60, Noida 201 301, India Dedicated to the loving memory of my distinguished teacher late Dr SK Malik VALLABHBHAI PATEL CHEST INSTITUTE UNIVERSITY OF DELHI, P.O. BOX NO. 2101 DELHI-110 007, INDIA Tel. (O) (R) Fax E-mail Dr. V.K. Vijayan MD (Med), Ph D (Med), D Sc, FAMS FCAI, FNCCP (I), FICC, FCCP (USA) Director : 91-11-7666180 : 91-11-7667027 : 91-11-7667420 :
[email protected] July 8, 2004 Date: ........................... Foreword The prevalence of bronchial asthma, a major public health problem is increasing worldwide. Several studies have demonstrated that there is an increase in morbidity and mortality from bronchial asthma. Over and under treatment of asthma may be responsible for high mortality rates. Until recently bronchospasm that results from hyperresponsiveness of the airways to multiplicity of stimuli has been regarded as the main cause of airway dysfunction in asthma. Bronchial asthma is now considered as a chronic inflammatory disease of the airways. This realization that inflammation is the key factor in the pathogenesis of asthma is reflected in the change in asthma therapy with emphasis on inhaled anti-inflammatory drugs. There are many controversies in the management of bronchial asthma especially the role of immunotherapy. Many new drugs are under development and yet there is no cure for asthma. In a country like India with different socio-cultural diversities and beliefs, the treatment of asthma varies and the existence of different systems of medicine in our country complicates the treatment issues. Prof D Behera, a renowned Pulmonologist of our country and Professor of Pulmonary Medicine at the Postgraduate Institute of Medical Education and Research, Chandigarh has taken up the challenge of bringing out the updated second edition of his book, “Bronchial asthma”. The tremendous response to the first edition of his book is a testimony to the academic excellence of this book. The second edition has 21 chapters including epidemiology, pathophysiology, clinical presentation, complications, management and various guidelines. This revised edition is a comprehensive review of bronchial asthma and provides practical information for Physicians and Pulmonologists who have to take appropriate diagnostic and therapeutic decisions in patients with bronchial asthma. I congratulate Dr Behera for his tireless efforts to bring out the second edition of this book. Dr VK Vijayan Director Accordingly the approach to management of asthma has also changed. Over the years our understanding about the disease has changed. the same is given for children. even in the same country at different parts. D Behera . although there is a wide variation in its prevalence in the world. but it will give a brief account of the same for the pulmonary physician. One of the major changes in our thinking about the pathophysiology of the disease is that the disease is inflammatory in nature rather than the earlier simplistic view of it being a simple bronchospastic disorder. A number of cytokines and mediators take part in its causation. Further. the references are updated with Vancouver style. This edition has brought out some of these changes. Although there is no guideline for adult Indian patients. The chapter on bronchial asthma in children is not complete in all aspects.Preface to the Second Edition Bronchial asthma is a common respiratory disorder affecting approximately 3-5 percent of the population. A number of guidelines have come up in recent years and there is a constant renewal in some of the concepts. have changed in recent years.Preface to the First Edition Bronchial asthma is a common disease affecting nearly 3 to 5 percent of the population. wherein it is proved that it is an inflammatory disease. A wide array of cells with a number of cytokines take active role in the pathophysiology of the disease. medications with anti-asthma drugs will be required for symptom-free life. In some cases life long. and in many cases most of the times. Although incidence. Earlier concepts about bronchial asthma. The idea of writing this book came to my mind while I was preparing for the second edition of my textbook entitled Pulmonary Medicine. the major difference is its recurring nature with periods of remissions and exacerbation. I thought a chapter on Bronchial Asthma in a textbook may not give sufficient justification to cover the explosion of recent knowledge acquired about the disease.and prevalence-wise the disease is not more common than tuberculosis in this country. particularly our understanding of its pathophysiology and approach to management. that it is a bronchospastic disease. This is a major contrast to tuberculosis where treatment for 6 to 9 months will cure the disease. D Behera . ......................................................... 208 14.... Alternate Treatments in Asthma .. 256 17............................................................................................... Prognosis of Bronchial Asthma ................................................................................... 117 9..................... 183 13................................................................. 176 12............................................... 293 20....................................................................................................... Pharmacologic Management of Asthma ..................................................... 127 10............ 235 15.............................................................................................................................................................. Inhalation Therapy ................................. 98 7..... Therapeutic Approach in Patients with Asthma II................................................................. 247 16............................ 40 4....................... Acute Severe Asthma (SA) ........ Diagnosis of Bronchial Asthma ........... 86 5.............................. New Treatment Modalities/Newer Drugs for Bronchial Asthma ......................................................................................................................... Pathology ...................................................................................................... Complications of Bronchial Asthma .. New Guidelines for Asthma Management (Pharmacological Management) ..................... 265 18. 306 21........... 134 11............... Chronic Bronchial Asthma . 92 6....................... Refractory Asthma) ............................................... New Guidelines for Asthma Management (Acute Asthma) .. 337 ........................................................... Clinical Presentation of Bronchial Asthma .............................. 1 2. 276 19................ Management of Asthma with Special Problems ............. Epidemiology .............. Therapeutic Approach in Patients with Asthma I................................. 14 3..... 114 8.......................................................................................................... Severe Asthma (Fatal Asthma..................... Asthma in Children ..................................................... Management of Bronchial Asthma ..................................................................Contents 1.... New Guidelines for Asthma Management (Non-pharmacological Management) ......... 314 Index ................................................................................ Pathophysiology of Bronchial Asthma ........... Aetiology ............................................ 6 Unfortunately. Questionnaires are the most practical tools to use in screening population for asthma. (ii) airway inflammation. immunologist.” PREVALENCE The prevalence of asthma is not exactly known. the meaning of which was panting. inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli. physiologist. Such questionnaires have been validated to assess the ability of individual questions and combination of questions to predict which individuals in the population have either clinical diagnoses of asthma or non-specific bronchial hyperreactivity to agents like methacholine or histamine. Earlier definitions were non-specific and therefore the condition was both under and over-diagnosed. . and (iii) airway hyperresponsiveness to a variety of stimuli”. Whereas the condition was previously considered as a bronchospastic disorder only. it is now recognised that asthma is primarily an inflammatory disease.3 However. and all these perspectives are difficult to merge into a comprehensive definition sufficiently specific to exclude other diseases. The Greeks had labelled this condition as “asthma”. This is because the precise way how to define asthma in population studies is defined differently.2. The clinician. A widely acceptable definition still remains elusive ever since it was first defined in 1959 by an expert study group during the CIBA Foundation Guest Symposium.1 The Global Initiative for Asthma (1995) defines asthma on the basis of its pathogenesis (vide infra). Obstruction is often reversible. during the past one-decade there have been major changes in the concepts of pathophysiology of asthma. The current definition incorporates both of these components and a generally agreed-on working definition of asthma is as follows:4 “Bronchial asthma is a disease characterised by (i) airway obstruction (airway narrowing) that is reversible (but not completely so in some patients) either spontaneously or with treatment. Bronchial asthma is difficult to define since it is not one homogenous condition and because there is no one objective measurement or series of measurements that can be used to make the diagnosis of asthma.1 Epidemiology DEFINITION Asthma is a disease whose presence dates back to at least the time of Hippocrates who noted a condition of ‘deep and heavy breathing’. either spontaneously or with treatment. the Consensus Report5 describes asthma as a “Chronic inflammatory disorder of the airways in susceptible individuals. Subsequently. and pathologist all have their own perspective of asthma. 33 Improved personal behaviour and medical care have a limited sustained impact on childhood asthma until basic environmental issues are modified. Wales.4 . the magnitude of the problem is evident from the fact that during a 10 years period from 1978 to 1987. and 150 paediatric deaths. France.1 million in 1984.7 per 1. the prevalence of asthma has increased in recent decades.87.6-8 To avoid these limitations.000 persons with much lower rates in persons younger than 45 years. In 1998.18 During the last decade.000 hospital admissions. About 15% (one out of seven) of children in United Kingdom wheeze and similar number suffers from the related disorders of atopic dermatitis. it seems that asthma remains under diagnosed especially during childhood. The effect of these disorders on children and adults is considerable in terms of morbidity and lost productivity resulting from the disease and its treatment . asthma prevalence rates increased 29% from 1980 to 1987. Nonetheless.5 million emergency department visits. UK and USA. studies from different countries keeping appropriate statistics have reported a significant rise in asthma morbidity and mortality. In general. West Germany.3 billion.000 hospitalisations and > 5000 deaths annually. the overall annual age-adjusted prevalence rate of self reported asthma increased 42% (from 34.35.18-28 In the United States.36 In addition. These questionnaires. and “having wheezing during the previous 12 months” have been the questions with best sensitivity and specificity for prediction of the flawed gold standards. England.16 Since the definition of asthma was varying. > 1. of course are being used most often in recent studies.000 deaths in USA.2 Bronchial Asthma physician-diagnosis of asthma and bronchial hyperreactivity are not particularly good “gold standards” for identifying asthma. 11 million missed school days.14 While asthma is one of the less common causes of death. Annually. There is some evidence that bronchial asthma is increasing in a number of countries particularly New Zealand.29 The overall 1988 asthma death rate was 1.37 From 1982 to 1992. the available statistics is viewed with some skepticism. questions about “ever having asthma”. approximately 17 million people have asthma (and asthma related symptoms) account for 10 million missed school days.6 million emergency department visits.6. many studies now use questionnaires.9-11 In general.9/100. asthma accounts for 12 million primary care visits. 200. an increase of 80%. the later is present in many people without asthma.15.31. The prevalence has risen over the past 30 years all over the world particularly in all Westernised societies perhaps as a result of the loss of childhood infections. “ever having asthma diagnosed by a physician”.13 The disease has reached epidemic proportions affecting 155 million individuals in the world. rising dramatically with increasing age.18-30 Asthma is the most common chronic disease of children in USA. approximately 500. However.17 An estimated 10 million persons in the USA had asthma. and Japan. despite the availability of effective drugs.15.000 people to 49.34 Various other statistics also prove that both asthma and allergic rhinitis have increased in recent years. 1. and the difference prevalence rates in different studies in the past can be explained in part due to these methodological difficulties. hospitalisation due to asthma and deaths attributed to asthma are increasing. Bronchial asthma is the most common chronic respiratory disorder among all age groups with a reported prevalence of 5 to 10%.12. In the general population. the direct and indirect expenditures for the treatment of asthma in the United States were approximately $11. Canada.32 About 6 million children in the United States have asthma compared to 3. earlier surveys will have flaws as mentioned. in many countries. there were 1. While the former can miss milder forms of asthma. Natural history of bronchial asthma in Australian children. (b) wheeze. The prevalence of bronchial hyperresponsiveness in those without asthma symptoms is 3%. however.08%. New Zealand children were also more likely than the Wales children to have a history of “wheeze ever” (27% vs.40 A survey of 12-year-old school children carried out in New Zealand and South Wales41 revealed a higher prevalence in the former (17%) than in the later (12%). Both current asthma symptoms and bronchial hyperresponsiveness are more common among females. Much of this increase appears real and not merely due to an improvement in the methods of diagnosis over these years. both morbidity and mortality from asthma in New Zealand are amongst the highest in the world.1. a continuous.38 One disadvantage with these statistics is that these are based on informations obtained by questionnaire and in most cases identical questions were not used at each survey. from available data. linear rise began.79% in 1989. The sex ratio of asthmatic and wheezy children was very similar in the two countries. The rise is 20 folds compared with that in 1961. 10.9 and 15% and “wheeze ever” between 9. 22%) and wheeze brought on by running (15% vs.1% in the age range of 13 to 18 years. bronchial hyperresponsiveness at 13. A simple flow diagram of the natural history of asthma17 based on the prevalence of childhood wheeze in Australia is shown in Figure 1.1:1. representing a six-fold increase.39 However. the overall annual age-adjusted death rate for asthma increased 40%.02 and 0.2 and 5%.4%. Fig. the prevalence increasing from 0. and atopy at 31. (c) and persistent wheeze .9%. Even more alarming is the observation that during this period. Between 1961 and 1966. A review of the available published figures for children in United Kingdom revealed prevalence for “wheeze in the previous year” of between 4.Epidemiology 3 per 1.29% in 1966 to 1. The top line indicates the group who are atopic and who wheeze while the bottom line represents those without evidence of (a) allergy. Figures for “asthma ever” varied between 1. The hatching represents the approximate percentages in each group who are atopic and who have bronchial hyperresponsiveness.7%.5%).9 and 24.000 people). Haahtela et al42 found that during 1926-1961 the prevalence was steady at between 0. that is. The overall prevalence of asthma is estimated at 13. In a study to determine the prevalence of asthma in cohorts of Finnish young men in the period 19261989. 8 to 12.52-55 The prevalence was reported to be 1. All the data collected on the basis of above informations indicate continuing extensive morbidity from asthma. although more effective treatment may be modifying this. The figure of “ever asthma” in 12 months is not strictly same as prevalence of asthma in adults. Whatever data is available. authentic information is not available regarding its prevalence or incidence. The same in urban males has been 4%.64 when there was a dramatic increase in asthma deaths in England and Wales.4% with an overall figure of 4. problems of sample size.58 The study from Greater Mumbai revealed a prevalence of 3. in recent years two studies from Mumbai and Northern India are available. This was most apparent in children 10-14 years.18 Adequate prevalence data from most developing countries is not available either for children or adults.8%. It is clear that the most dramatic increase in admission to hospitals has been in children. The overall prevalence of asthma in children of 10-18 years age at Chandigarh was 2%. apart from tuberculosis. A recent study from Delhi59 estimated the risk of asthma in children to be very high. MORTALITY Statistics for deaths from asthma yield widely variable mortality rates between countries.56 It was also reported by the same investigators that the prevalence in the morbidity surveys of government employees and their families in Delhi was 1. the number of children who have wheezed at sometime is around 25-30%.51 About 7% of the patients have persistent asthma as reported from Australia by Woolcock et al. but was also apparent for all age groups.6 and 3. Australia and New Zealand. In a survey of respiratory symptoms in India.76% in an urban population in the mid sixties.58 The true population prevalence was reported as 3.58.60. Other indices of morbidity such as days lost from work and restriction in lifestyle. the trends should be similar. This study showing natural history of asthma is based on the prevalence of atopy as measured by skin tests and the prevalence of childhood wheeze in Australia.15 Increasing asthma mortality was first highlighted in the early-mid 1960’s63.8 and 3. the prevalence of asthma has been reported to be 0.43-46 In addition. Although it is a general perception that bronchial asthma is a very common problem in India.57. at least partly. using the same methodology as in adults.59 Prevalence of asthma symptoms in children was determined in the International Study of Asthma and Allergies in Childhood (ISAAC) in the age groups of 6-7 and 13-14 years using a standardised sample survey.27% in both urban and rural females.5% by physician diagnosis and 17% using a very broad definition including those with asymptomatic bronchial reactivity.4% respectively). a validated questionnaire was used tested against physician—diagnosed asthma and the prevalence in the population was assessed.50.99% in rural males and 1. it lacks the uniformity of definition. .2% in rural and urban women respectively.4 Bronchial Asthma The Figure 1.2 to 6. In the North Indian survey. A number of studies from around the world show that the prevalence of atopy is between 3050% in children.94% in urban and 3.62 Since morbidity depends. nocturnal disturbances with symptoms and hospital admission rates confirm the trends and extent of problem due to asthma. the prevalence of asthma has been reported to be 1.47-49 Most children with persistent wheeze are atopic. Prevalence of asthma in Mumbai was similar in males and females (3.1 also shows the approximate number of people entering adult life with persistent wheeze.61 Prevalence of “ever asthma” varied from 1.5%.2% in adults in the western world. on prevalence. From different studies.56 However. and analytical methodology used. The range of such mortality between 1985-1987 in 20 different countries has been depicted in Figure 1. the mortality has increased more in female subjects than male subjects. and Germany has revealed a distinct rise in rates during the 20 years period prior to 1990. suggest a stabilisation of mortality rates due to asthma in United States.2% annually during the 1980’s and faster among subjects aged 5 to 14 years than those aged 15 to 34 years.66-72 In some countries.8 per 100.674 (0. The death rates for asthma among African Americans is three times higher than among White Americans. Most of the patients still died outside the hospital. The rate is per 100. this trend is less apparent in other countries. At the peak of the New Zealand epidemic in the 1970’s. Canada.000 population (1985-1987) . the rate has shown a declining trend since 1979. suggesting that the population genetic predisposition is not likely to be a risk factor for mortality. one epidemic in 1960’s in the UK and two in New Zealand. The trend in other countries is less apparent. there was a rise in deaths due to asthma in the USA from 1. Denmark.000) to 5. Among Whites. France. Two countries. the rates have doubled over the past 10 years. From 1977 to 1996. have experienced “epidemics” of asthma deaths.2. asthma mortality rate in Israel during the years 1980 to 1997 was low and stable.74 For example.667 (2. There was no difference in the asthma death rate and place of death between Jews and Arabs. however. 1. However.Epidemiology 5 particularly in 5-34 age group.1 per 100. Recent trends. New Zealand.2: Asthma mortality in 20 different countries of the world. the mortality rate for asthma was approximately 10 times the rate in the USA.000). the UK and New Zealand.73.15 The intriguing points about asthma mortality are that there are sizeable differences between countries and that death rates from asthma are gradually increasing in most western countries.75 Fig. However. one in the 1960’s and the other in the 1970’s. An analysis of asthma mortality rates in Western countries as well as developed nations such as the United States.65 The mortality rate increased by 6. 103 Lower socioeconomic status and African American race are strong risk factors for hospitalisation and mortality from asthma.97. There is clearly some misclassification of asthma deaths with over-reporting over age 50 and under-reporting in the younger age groups. Hospitalisation rates and episodes of asthma have increased in all age groups particularly in boys up to 4 years old. the term asthmatic bronchitis was coded as asthma rather than bronchitis.000.000 followed by Norway.101 Hospitalisation rates are twice as common in African Americans as White Americans. (iii) An increase in the prevalence and or severity of asthma.81-84 A number of reasons have been proposed including: (i) Partial contribution from the shift of International code of death (ICD-8 to ICD-9). from asthma has been reported.98 However. Netherlands. An estimated 15 million persons in the United States have bronchial asthma. particularly inhaled steroids.85-89 Other possible contributors are delay in care. some patients die before they can receive medical care. increased hospitalisation rates have been observed. The reasons for the trends in mortality due to asthma and for the sizeable differences between countries are not clear. (ii) Shifts in physician diagnosis patterns. USA. Due to this.93. air pollution. Although asthma is generally treated in an outpatient basis.80 In the last decade. the stabilisation of mortality. However. and even a decrease in mortality. and (v) Adverse drug effects. and Hong Kong reported asthma mortality rates less than 2/100. West Germany reported over 9 deaths per 100. though. many other causes have been advocated for the increase in asthma mortality and morbidity and they include allergen exposure.94 Race and socioeconomic status may influence the outcome of an asthma attack.96 Hospital admission rates for asthma are high and have increased in the last few decades. and the number is increasing.76-79 The increase in mortality in most countries cannot be primarily due to an increase in the prevalence of asthma as the rise in mortality is disproportionately greater than that of the prevalence. NATURAL HISTORY OF BRONCHIAL ASTHMA Over the last few decades the natural evolution of asthma from childhood to adulthood has been the subject of many reviews and studies and more than 50 such well-designed .102 Causes for the Increase in Asthma Mortality Besides the above mentioned reasons. environmental or social factors is not clear. increased incidence of viral infections. and physician management of asthma (Discussed subsequently). (iv) Increased diagnosis of asthma. and Sweden. inadequate access to health care. theophylline toxicity. The risk of death due to asthma appears to predominate in large urban areas with high rates of poverty.95. these postulates have not been confirmed. In the 60’s overuse of adrenaline in Europe and currently the use of fenoterol have been postulated to be contributory to the mortality due to asthma. New Zealand. poor compliance.6 Bronchial Asthma All statistics shown are derived from published population and mortality data available from the national statistics centres in each country.3 times greater in areas with a larger African American population. lack of access to health care.98-100 The exact proportion of deaths occurring outside the hospital and its association with genetic. as a possible factor.90-92 Most likely cause of the recent decline in asthma deaths is the more judicious use of prophylactic treatment. besides the overuse of β-agonists. especially from bronchitis to asthma in the 0-5 years age group and from COPD to asthma in smokers past middle life. medication use. Risk of hospitalisation for children with asthma is 8.4 times greater in areas with population of lower socioeconomic status and 5. 1.4% of children with severe or moderate bronchial hyperresponsiveness at the initial assessment had normal levels of bronchial responsiveness at the later assessment.110-116 No definite information is available about the progression of asthma through childhood and adolescence. some reports suggest that up to 80% of asthmatics may become asymptomatic during puberty.117 Martinez118 studied the natural history of wheezing in children aged 0-6 years and found that approximately half of the children experienced wheezing illness at sometime during the study period. Congenitally smaller airways may therefore predispose children to wheezing illness early in life. In some of them wheezing occurred early in life but resolved by the age of three years (transient early wheezing). Whether the decline in reported symptoms is real or the result of the children increasingly denying their illness as they reach puberty remains to be clarified. subjects may still have obstructive lung functions and increased bronchial hyperresponsiveness.104 It was long believed that the prognosis for asthma originating in infancy or childhood was good. there are varying reports about the persistence/disappearance of asthma symptoms in adolescence. and that in most patients the symptoms would resolve by the age of puberty. Different risk factors were associated with these results. some experienced wheezing illness between the ages of three and six years (late onset wheezing) and others had wheezing illness throughout the entire study period (persistent wheezing). Although epidemiological studies have shown a fair chance of either “remission” or a reduction in asthma symptoms between the ages of 10 and 20 years. as measured by functional residual capacity shortly after birth and before any lower respiratory tract illness had occurred. a review of literature shows that not all patients become asymptomatic in adulthood. the atopic status of the child. As against the above figures. the relapse rates after a symptom-free interval is also high. Most of the children who had a slight or mild degree of bronchial hyperresponsiveness at 8-10 years of age lost their increased response by the age of 12-14 years. asthma symptoms persist in 30-80% of adult patients. The risk was also increased in children whose mothers smoked during pregnancy. asthmatic mothers.109 It has also been shown that.123-126 This shows a significant number still will have asthma in adolescence.119. and their lung function decreased after the age of one till they are six years of age.120 In a cohort study of Australian school children121 tested initially at the age of 8-10 years and then again at 12-14 years of age. The reduced bronchial responsiveness may favour the hypothesis of a real reduction in the activity of the disease or higher doses of the provocative agents like histamine or methacholine may be needed to provoke hyperresponsiveness in larger airways of rapidly growing children. As discussed above.105-108 and most population based and clinical studies have also shown a reduction in asthma symptoms with age.Epidemiology 7 publications highlight the subject. even in the absence of asthma symptoms. the prevalence of bronchial asthma in adolescents in 4 different countries 122 varied from 2.8 to 38% at different ages and is summarised in Table 1. Children with late and persistent wheezing are more likely to be atopic as assessed by elevated serum IgE levels and skin test reactivity. Children with transient early wheezing had reduced pulmonary function. and parental history of bronchial asthma. the persistence of bronchial hyperresponsiveness at 12-14 years of age was found to be related to the severity of disease at 8-10 years of age. However. In fact. However. . Only 15.107. This study suggests the presence of two distinct wheezing illnesses up to the age of six years. and classification of chronic pulmonary emphysema and related conditions. 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Laplante JM et al. . 1975. Decrease in asthma mortality rate in Israel from 19991-1995: Is it related to increased use of inhaled corticosteroids? J allergy Clin Immunol 2000. 92. Suissa S. Beasley R. Chatkin J. 95. Stolley PD. 1908-1986. Changing asthma mortality. 87. J Epidemiol Community Health 1988. 89. Crane J. Stabilisation of asthma mortality. Sly RM. Am Rev Respir Dis. Tendencia da mortalidade por asthma bronnquica no Rio Grande do Sul. Bol Oficina Sanit Panam 1994. Reflections in the rise in asthma morbidity and mortality. Regional distribution of deaths from asthma. Poole C. J Pneumonol 1995. Causes of death in a population with asthma. Sly RM. 74. J Allergy Clin Immunol 1989. 78. Barmeir M. Rea HH. O’Donnell R.Gendler M et al. Campbell MJ. 73. Trends in asthma mortality in New Zealand. 90. 70. 80. Chest 1990. 94. Ann Allergy 1994. 1980-1993. Age. Vollmer WM. Hunt LW. Beasley R. Mair JE. Kolbe J. Sly RM. Results of an observational study. 84.84:421-34.97:507-08. Richards G et al. Prescribed fenoterol and death from asthma in New Zealand.264:1683-87. Lanes SF. Ann Allergy Asthma Immunol 1997. United States. National trends 1980 to 1997. Trends in asthma mortality in Mexico. Esdaile JM. 1979. Respiratory diseases disproportionately affecting minorities. 91. Sagura N. 71.124:1004-11. 76. Schwartz S et al.48:347-54.335:920. 81. Fenoterol and fatal asthma. Spitzer WO. Holgate ST et al. JAMA 19990. 83. Asthma mortality in Colombia. O’Donnell R.50:303-11. 1983-1995.345:41-44.62:347-54.147:543-49. Geneva. Lancet 1989. Bauman A.3:545-51. Arch Dis Child 1985. Changing patterns of asthma hospitalisation among children. Occult pulmonary abnormalities in asymptomatic asthmatic children.52:218-22. Pekham C. 119. Dick P.32:79-85. Bevegard S. Roorda RJ. 104.60:231-35. Blackhall M. A cohort study in childhood asthma admissions and readmissions. Woolcock AJ.19:299-306.79:206-11. Schechtman K et al. Thorax 1996. Friberg S. Burros B. 115. Patel S. Strachan DP. Reliability of a respiratory history questionnaire and effect of mode of administration on classification of asthma in children. Arch Dis Child 1970. J Asthma 2001. J Epidemiol Community Health 1986.101:624-29. Peat JK.98:191-95. Hallback I. Arch Dis Child 1986. Weiss KB. Gergen PJ. Stewart-Brown S. How reversible is asthma? Aust NZ J Med 1973. Remissions and relapse rates. Prognostic factors for the outcome of childhood asthma in adolescence. 98.102:153-57. Chest 1977. Kerrebijn J. von Mutius E. 116. Paediatrics 1996. Progression of allergy and asthma through childhood to adolescence. A follow-up study of 20 subjects with special reference to work capacity and pulmonary gas exchange. Thorax 1997. Martinez FD.61:642-46. 118. Halstead J. J Epidemiol Community Health 1978. Asthma and wheezing in the first six years of life. Balfour-Lynn. Toelle BG. 113. Biven RE et al. Longitudinal changes in bronchial hyperresponsiveness in asthmatic and previously normal children. Asthma from childhood to adulthood. Risk factors for asthma morbidity and mortality in a large metropolitan city.11(1):1-3. JAMA 1990. Natural history of allergic diseases in children.40:121-29. 1988-92.264:1688-92. Peckham C. N Engl J Med 1995. Ventilatory function in subjects with childhood asthma who have become symptom free. Bentham G. Carswell F. Health service accessibility and death from asthma in 401 local authority districts in England and Wales. 117.82:19-22.84:183-90. Cutz E. Golding J. Chest 1992.147:347 102. 109. Aberg N. A prospective study of the natural history of asthma. Peat JK. Vollmer et al. Capewell S.35:182-84. Ferguson AC. Osborne M. 114. Castro M. 108. The natural history of asthma in childhood. Anderson HR.12 Bronchial Asthma 96. 100. Cooper DM. Pulmonary function during clinical remission of asthma. Chest 1992. 103. Pre-school wheezing and prognosis at 10. Persisting airway obstruction in asymptomatic children with asthma with normal peak expiratory flow rates. Bland JM.90:480-84. Thorax 1996. Chest 1986. The continuing rise in emergency admissions. BMJ 1996. Lang D. J Royal Coll Gen Pract 1985. A prospective study of bronchial hyper responsiveness and respiratory symptoms in a population of Australian school children.332:133-38. Taussig LM et al. Wright AL.51(Suppl 1):S7-S12. Salome CM. J Allergy Clin Immunol 1989. Bronniman S. Sedgewick CS. Am Rev Respir Dis 1993. Park Es. Woolcock AJ.38:625-36. Engstrom I. Butler N. Graff-Lonnevig V. 106.312:991-992.78:333-36. Cade JF. Salome CM. 1979 to 1987. Pain MCF. 101.71:361-65.51(Suppl 1):S3-S6. Jones AP. 120. 111. Trends in US asthma mortality: Good news and bad news. Ann Allergy Asthma Immunol 1997.45:363-65. 107. Feldman W et al. 112. 105. Radford PG. Clinical asthma: Will NAEP guidelines help? Pulm Perspectives 1994. J Allergy Clin Immunol 1988. 110. 97. 121. To T. Acta Paediatr Scand 1990. . 99. Childhood asthma and puberty. The prevalence and natural history of wheezing in early childhood. Levison H. Clin Exp Allergy 1989. A national study of asthma in childhood. Hopp RJ. Lebowitz MD. 126. Woodman K.92:744-49. Martinez FD.94:831-35. Barbee RA.51(Suppl 1):S13-S17. Robson B. Bauman A. Findings before the diagnosis of asthma among the elderly in a longitudinal study of a general population sample. J Allergy Clin Immunol 1996. Fam Pract 1994. Forero R. Beissel E. Rimpela AH. Findings before the diagnosis of asthma in young adults. Larkin P. . Burrows B. 124. 125. Kolnaar B. Burrows B. Scand J Soc Med 1995. results from three community surveys.13:707-12. J Allergy Clin Immunol 1994. Rimpela MK. Burrows B. Early childhood respiratory symptoms and the subsequent diagnosis of asthma. Savonius B. Dodge R. 130. Dodge R. Dodge R. Lebowitz MD. Burrows B. Burgess C et al. Cline MG. J adolescent Health 1992.95:48-54.88:870-77. NZ Med J 1993. Asthma prevalence and management in Australian adolescents. Cline MG. Haahtela T. Asthma and allergic rhinitis among Finnish adolescents in 1977-1991. Issues in adolescent asthma: What are the needs? Thorax 1996. 127. Asthma in adolescents and young adults: Screening outcome versus diagnosis in general practice.106:239-41. Prevalence of asthma symptoms among adolescents in the Wellington region by area and ethnicity. Cline MG. Young L. Price JF.11:133-40.Epidemiology 13 122. 123. 128. Antecedent features of children in whom asthma develops during the second decade of life. Lebowitz MD. van-den-Bosch WJ et al.23:60-65. Lebowitz MD. J Allergy Clin Immunol 1991. Cline MG. J Allergy Clin Immunol 1993. 129. Population studies have clearly demonstrated the association between atopy and asthma. House dust mite allergens appear to be the most common one associated with asthma. Most people with asthma are atopic. atopy has been found to be the most important single risk factor. episodic symptoms continue. Unless the subject is removed from the source. This implies that allergens play a role in maintaining the disease. vi. It has been shown that subjects with apparently intrinsic asthma (normal skin tests). A brief account of each of these factors will be discussed. There is also a strong association between allergen exposure in early life and sensitisation to these allergens. sensitisation occurs and is followed by episodic wheeze. It has been shown that in Indonesian children. and with time become persistent. The stimulus is capable of increasing this for days and sometimes for weeks. who are exposed to these agents. In population studies and in clinical practice. v. iv. have higher levels of circulating IgE than the non-asthmatic population. iii. They are summarised below.14 Bronchial Asthma 2 Aetiology A number of factors are responsible either in the causation or exacerbation of bronchial asthma. there is less atopy and less asthma. Improvement in the symptomatology occurs on allergen withdrawal. There is a strong co-relation between allergic sensitisation to common aeroallergens and the subsequent development of asthma. in most population studies of asthma. Challenge with allergens in atopic asthmatics increases the severity of the disease. Occupational asthma occurs due to allergens and sensitisers. Similarly studies from France have reported a lower prevalence of asthma where mites are less in number. which can be measured by skin tests or with measurements of specific IgE. which proves the causal relationship between the two. i. There are at least 6 major evidences to prove that most asthma in young people is due to exposure to allergens or to sensitisers. although it has not been possible to demonstrate an association between allergen exposure and the development of asthma. ATOPY AND ALLERGY The association between asthma and allergy has long been recognised. In some healthy people. it is clear that majority of young people are atopic. ii.1 . It has been reported that 75-85% of patients with asthma have positive immediate skin reactions to common inhalant allergens. Furthermore. Another important factor is the way the allergen is handled.4 The proportion of “asthma-ever” attributable to atopy was 33%.7. making them more humid. and requirements of asthma medications. cockroaches and perhaps mites.12 There has also been spread of plants. The predominance of these allergens will of course depend upon various factors.Aetiology 15 Some studies. Even though not all asthmas are associated with or perpetuated by exposure to common airborne allergens. Houses tend to have less ventilation. grass pollens. A growing number of uncontrolled and controlled studies suggest that allergen eradication and avoidance measures lead to improvement in bronchial hyperresponsiveness. and concluded that the available data do not indicate that aeroallergen exposure is a major risk factor. bronchial hyperactivity is related to both atopy and measures of disease severity such as peak expiratory flow variability.9 Taken together these facts are strong evidence for the role of atopy in asthma.10 Outdoor allergens such as grass pollen. however. animal proteins. the proportion of cases attributable to atopy varied from 25 to 63%. and moulds. which in part may be responsible for the difference in the prevalence of asthma in various countries. Recent changes in housing styles in many western countries may have led to increased allergens levels. IgE antibody levels. Whereas house dust mite is the most important and common indoor allergen linked to asthma.11. The important association of atopy with childhood asthma is well recognised. reducing the patient’s exposure to allergens can help bring asthma symptoms under control. the climate of a particular area may favour the availability of various allergens. On the contrary.5 A review of studies relating atopy to asthma notes that in cross-sectional studies conducted exclusively or predominantly in children. Pollutions add to the allergenicity of aeroallergens. People now spend a substantial proportion of the time indoors.4 These findings are consistent with other studies. they reported that atopy attributes only 38% to the causation of asthma. soyabean dust and Alternaria alternate have been specifically linked to severe asthma exacerbations. severity of symptoms. Based on these findings.2 Pearce et al 3 reviewed the epidemiological evidence implicating aeroallergen exposure in the primary causation of asthma. exposure to these agents plays a major role. the process of IgE sensitisation begins right early in life while the immune response is still . recent studies suggest that among those reporting wheezing in the previous months have a stronger relationship with atopy for those reporting > 12 episodes of wheezing in the past 12 months compared to those reporting 1 to 3 episodes in the last 12 months.2 Some investigators have observed a weak and inconsistent association between atopy and asthma prevalence. Most of the responsible allergens are probably prevalent inside the houses since this is where human beings spend most of their lives.6 Relationship of atopy and severity of asthma is a well-known fact.13 Further.8 Conversely. it is suggested that atopy contributes more to the frequent or severe asthma than to mild or infrequent asthma.6 Atopy is also related to degree of bronchial hyperreactivity. Moreover. with a weighted mean of 38%. in patients having wheeze in the previous 12 months.14 Recent research suggests that for many allergic disorders associated with aeroallergens. while the proportion was 89% for those who were attending hospitals (indicating more severe form). In a further study. challenged the assumption that childhood asthma is largely of allergic etiology. and bronchial provocation have all helped establish the important role of allergens in many asthma exacerbations. Both indoor and outdoor allergen exposures have increased asthma morbidity. particularly local. Studies in asthmatics of allergen skin reactivity. and there has been widespread introduction of carpeted floors and pets living in the houses. The most important ones throughout the world appear to be the house dust mites. . However. Ragweed and grass pollination are definitely associated with asthma. Amarantus pollen is the most common offending allergen followed by Cassia siamea. cat or dog dander allergy may not be that important in this country. Brassica. Higher is the concentration of allergen earlier is the onset of disease. Aeroallergens are important in patients whose disease has started before the age of 30 years or who are exposed to occupational allergens. and fewer than 10% to food allergens. 10-15% to moulds. there are some plants. Some fungi sporulate on warm. Therefore. It is reported by several authors that severity of childhood asthma corelates with the number of positive immediate skin tests. etc. Imperata. allergens play a less important role than other ages and viral respiratory infections are the principal triggers.13 In contrast. Cassia occidentalis. Food allergies are not common triggers for asthma in adults. Lucknow.16 Bronchial Asthma developing. 10-20% to tree pollens. Mould spores exist primarily outdoors and tend to be seasonal. in Delhi. dry summer days and others prefer the rainy season. and peculiar habit of storage of food articles. Pollen Particles greater than 10 micron in diameter are usually cleared in the nose and mouth and do not penetrate the lower respiratory tract. which produce allergen-containing particles that are less than 10 microns. Therefore. The patient may have aspirin sensitivity. the density of allergen (per gram of dust) is an important factor in determining the age of onset of first symptoms. For example. and climate. Moreover.15 Prosopis is the commonest antigenic pollen in Bikaner. In infants. 50-75% of atopic asthmatics react to house dust mite. these might be an important allergen for people of India. lifestyle. 10-20% to dog dander. Mould Mould spores are generally smaller than pollen grains and are more likely to penetrate the lower respiratory tract.20 On the other hand Parthenium is the commonest offending agent in Kolhapur . Important outdoor allergens include pollens and moulds. Studies in children suggest that allergy influences the persistence and severity of asthma. Pollen allergy is usually season-related and is more closely linked to hay fever and allergic conjunctivitis. season. Cenchrus. Ricinus. and Varanasi. Children with multiple positive skin tests are more likely to have daily rather than intermittent symptoms of asthma. On the other hand because of tropical climates. However. Different Allergens (Figs 2. foods are not the common triggers. cockroaches grow plenty in this country.1a to 2. Prosopis. in adults the intensity of allergic skin tests does not appear to be associated with increased severity of asthma. The importance of allergy is different for different age groups. Although allergic reactions to food can occur in infants. did in fact develop allergy or asthma by the time they are 11 years of age.19. It has been shown that the level of dust mite allergen present in the home during the first year of life is a major factor in determining whether an infant born of an allergic mother who is genetically susceptible. Patient can also have allergy for the first time after the age of 30. 35-55% to cat dander.21 In the United kingdom. but it has no immunological basis. The predominant offending allergen will vary with locality. keeping cats as pets. similar number to grass pollens.16-18 Brassica is the commonest pollen in Bhopal and Kanpur. The important allergens in children after infancy appear to be inhalants. unlike in many western countries is not a common practice in India.1h) i. The species of the fungus vary with the geographic distribution according to climatic conditions. Allergenic pollens vary at different places. 1f: Perfumes . 2.1a: Dust during cleaning Fig.1e: House dust mite in the bedding Fig. 2. 2.Aetiology 17 Fig.1b: Pollen Fig. 2.1d: Domestic fuel Fig. 2.1c: Smoke Fig. 2. animal danders. Although house dust itself is not an allergen.1h: Mould in the wall ii. They occur in environments with sufficient humidity since they are quite dependent for survival on moisture from the atmosphere. This is the agent most widely implicated in the pathogenesis and provocation of allergic asthma. The principal allergen of the house dust mite is found in its faeces. The commonest mite is Dermatophagoides pteronyssinus. the food for the mite. These pellets are quite large and 10-40 microns in size. carpets. They are arachnoids distantly related to ticks and spiders. Live mites are equipped with suckers at the tips of their legs. similar to pollen grains and share some of the aerodynamic properties with them. pillows.000 faecal pellets. Loss of water from the mite body constrains their growth. They are ubiquitous.1g: Pets (Animal dander) Fig. bed covers. although it does not leave any immediately perceptible sting or bite. Other species may also exist in small numbers. House dust mite plays a major role in the causation of asthma. Mite antigen is found throughout the home. 2. which make them difficult to remove by vacuuming. they do not easily enter the lower respiratory tract and are rapidly cleared from the airway by . there are allergic components in it. The most important ones are mites. and soft toys. clothes. A gram of dust may contain 1. living in the house dust that provides both their shelter and food (scales of skin shed by humans). Like larger pollen grains.18 Bronchial Asthma Fig. 2. wherever human dander. upholstered furnitures.000 mites and 250. and cockroaches. but mites are capable of extracting water vapour even from air that is only 50% saturated. High levels are found in mattresses. is found. 32 Indoor moulds are prominent in environments with increased humidity. particularly in warmer climates and inner side of the house in cooler climates. and cat saliva and cat danders are potent allergens. It takes several months before the concentration of allergens in domestic dust falls after removal of the pet. Products made from feathers retain the allergens from bird. collectively designated as group I allergens or Der p I. Bla g 5 (glutathione – S-transferase). Some mite allergens may be smaller that may be in the respirable range for the lower respiratory tract.22-28 Animal allergens Dogs. Bla g 4 (calycin). and there are now tests available to quantitate this. The major cat allergen is Fel d I. cats. which is a protein secreted by the cat’s salivary.29-31 Cockroach allergen The cockroach appears to be important. and Per a 7 (tropomyosin). Cockroach allergy has been identified as an important cause of asthma. Bathrooms. furnishings. the Group I cross-reactive allergen Bla g 1 and Per a 1. and perspiration on pillows are .5 mm in diameter and flake-shaped. particles are less than 2. A study of children requiring hospitalisation for asthma found that the risk of re-admission was associated with continued exposure to high concentrations of mite allergen. Danders from these animals contribute greatly to the allergenic components of house dust. having perennial symptoms. and at the rate cats shed their fur and dander. The improvement of asthma in children residing in high altitude where low humidity constrains dust mite growth or in patients admitted to the relatively dust-free environment of a hospital14 indicates the contribution of the house dust mite to asthma exacerbation. The important domestic species are Blattella germanica and Periplaneta American. The protein is very stable and loses none of its antigenic potency for at least a month. A number of epidemiological studies suggest that close contact with a cat or dog in very early infancy reduces subsequent prevalence of allergy and asthma. Cockroaches produce several allergens. It is coated on to the fur by the usual grooming. kitchens. Mite antigen is readily demonstrated in the air during cleaning. Usually there is exposure to high levels of this allergen at homes. and high levels of IgE. All breeds of cats produce common allergens. The major allergens of house dust mites are probably digestive enzymes. sebaceous. Dogs also produce common allergens. which produce sensitisation.Aetiology 19 gravity. Although elimination of cockroaches totally is difficult. All warm-blooded pets can cause allergic reactions. and lacrimal glands. and other pet animals including rodents are commonly kept in homes. although minor breed differences may exist. including the birds and small rodents. This may be a consequence of high allergen exposure inducing tolerance. and other reservoirs of coated fur (the cat itself) are removed. development of cockroach allergens as recombinant proteins has led to better control of this form of asthma. Per a 3 (arylphorin). a reservoir of the antigen rapidly accumulates in household furnishings. In addition. basement areas. making them easily airborne and easily respirable. This form of asthma—“The cockroach asthma”—is a more severe form of the disease. little permanent reduction occurs unless carpets. While air filtration can remove some of the allergens. Kinds of Allergens The allergens are Bla g 2 (inactive aspartic protease). Fel d I. Bla g 6 (troponin). For several reasons cat allergen is more likely to cause sensitisation than that of dogs. Over 80% of acute asthma exacerbations in school children and about 60% in adults result from viral infections.40 There are some reports that regular consumption of oily fish is associated with a reduced risk for asthma in children.37 Risk Allergens: Responsible for Acute Attacks Threshold concentrations of allergens that can be regarded as risk factors for acute attacks include: • 10 μg/g dust of group I mite allergen • 8 μg/g dust of Fel d I. Apart from aggravating clinical asthma. Once the virus enters the epithelial cells. Cockroach sensitivity in children has been associated with greater symptom frequency and more emergency department visits due to asthma.41. In case of most rhinoviruses. The susceptibility of the asthmatic airway to viral inflammation is due to persistent allergic mast cell and eosinophil-derived inflammation stimulates the release of cytokines such as tumour necrosis factor-alpha. viral upper respiratory . although subsequent studies have not shown clinical benefits of supplemental ω3 fatty acids over a 6 months period.38 Impact of exclusive breastfeeding in children at 6 years of age has shown that the introduction of milk other than breast milk before the age of 4 months of age is a significant risk factor for increased likelihood of bronchial asthma.44 Recent experimental data showed a reduced risk with intake of lectins (wheat germ agglutinin from whole wheat products). food sensitivity is an important factor in the development of allergies. Breastfeeding has been advocated as a method of preventing allergy and asthma. mostly common cold viruses. which further enhance eosinophil and mast cell inflammation.33-36 Similar observations are made for elderly patients with asthma also. it has been hypothesised that decreased dietary antioxidant vitamin intake is associated with increased asthma.45 INFECTION It has long been recognised that viral respiratory infections provoke and alter asthmatic responses.20 Bronchial Asthma the common sites of mould growth. producing specific immunoglobulin IgE antibodies directed against respiratory viral antigens and enhancing mediator release. With breastfeeding there is a decreased risk (about 20%) for development of asthma. it replicates and generates a wide variety of proinflammatory cytokines. These observations have suggested that viral infections may be intimately involved in the development of asthma and allergy. particularly in asthmatic mothers and if the child is also atopic. another study has shown an increased risk of wheezing.39 However. The Viral respiratory illnesses may produce their effect by causing epithelial damage.42 Further. which cause an increase in the expression of receptors for human respiratory viruses on the airway lining epithelium. the major dog allergen • 8 μg/g dust of cockroach allergen FOOD ALLERGEN AND BREASTFEEDING In the first 1 or 2 years of life.43 Higher concentrations of vitamin intake are associated with a decreased serum levels if IgE and a significant decrease of atopy. the major cat allergen • 10 μg/g dust of Can f I. the receptor is an adhesion molecule (intracellular adhesion molecule-1). While viral infections can undoubtedly cause deterioration of established asthma. in recent years it is also observed that some infections are protective of bronchial asthma. it has been reported recently that H. parainfluenza virus. fears of germs and . These observations led to the “Hygiene hypothesis” of bronchial asthma.49 It is further proposed that modern vaccinations.47 The presence of this mediator may contribute to the bronchoconstriction and other effects of histamine that can accompany bronchial infection. Possibly they evoke a Th1-like protective response with the generation of IFN-gamma and IL-2. Pseudomonas infection in cystic fibrosis is responsible for a hyperreactivity reaction in these patients. the parasitic colonisation continued. or bronchiolitis is associated with greater airway responsiveness and more frequent history of wheezing.48 Interestingly. high concentrations of these Th1 cytokines could inhibit the release of Th2 cytokines.influenzae and other Gram-negative bacteria can synthesise histamine both in vivo and in vitro. Early hospitalisation for respiratory syncytial virus. but was accompanied by an increase in skin test reactivity to house dust mite. in the untreated children. viral or bacterial infections during the first three years of life may serve a protective function against the development of allergic diseases. Over the past century declining family size. thereby tuning the mucosal immune response away from allergen sensitisation. Venezuela showed that antihelminthic treatment causes a decrease in IgE level. croup. Similarly repeated vaccination with BCG exerted a protective effect against the development of allergy in young Japanese children. and rhinovirus. in part.Aetiology 21 infections increase airway responsiveness. Influenza virus is much more common in older children and adults. Another support of this protective infection comes from observations comes from the fact that the increase in asthma and allergy with movement to urban areas may be related to a decrease in early exposure to parasitic infections. transmitted by unhygienic contact with older siblings or acquired prenatally. Thus. It indirectly means that eradication of parasites or reduced opportunities for infection could. where children infected with measles during the first year of life had a 63% lesser chance of developing positive skin tests to common aeroallergens.49 Epidemiological studies comparing large populations who have or have not had such exposures support the hypothesis. Although bacterial infection i s no t a cause of such exacerbations. Both measles and BCG are potent stimulators of the Th1 cytokine response.50 The hygiene hypothesis explains that allergic diseases were prevented by infections in early childhood. which may persist for many weeks after the infection.46 Other microorganisms that can exacerbate bronchial asthma include Mycoplasma pneumoniae. IgE levels increased but the dust mite sensitisation fell. improved household amenities. A recent study in 101 nonsmoking severe asthmatics shows association between accelerated loss of lung function and seropositivity to Chlamydia pneumoniae. and higher standards of personal cleanliness may have resulted in more atopic diseases. explain the rural to urban differences in the prevalence of allergic diseases. This suggests that early exposure to microbial products will switch off allergic responses preventing allergic disorders like asthma. In contrast. This hypothesis is supported from observations from an African study. if multiple infections occur during the first few years of life. One study from slum are of Caracas. Provocateurs of Asthma The principal infection provocateurs of asthma in childhood during the first 2 years of life are respiratory syncytial virus (RSV). such as aspirin and nonsteroidal anti-inflammatory drugs. and aspirin sensitivity all increase in prevalence with increasing severity of asthma and they are not causally related. this study has the limitation of small sample size and early age limit of interpretation.e. A double blind placebo controlled trial using the probiotic. .59-61 Several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchial provocation tests. ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm. observed a reduced incidence of atopic eczema but no effect on IgE antibody sensitisation. Although analgesics not inhibiting this enzyme are generally considered to be safe. the most frequently employed alternative. and many patients with asthma and aspirin sensitivity have not been found to have nasal polyps.51 DRUGS About 5 to 20 per cent of adults with asthma will experience severe and even fatal exacerbations of bronchoconstriction after ingestion of aspirin or certain non-steroidal antiinflammatory drugs (NSAIDs). It is likely that sinusitis. Although the exact mechanism is not known. Eye drop preparations of this class of drugs also can induce asthma. However. propranolol and nadolol). Other drugs that are known to exacerbate asthma include beta-blocker drugs (i. The prevalence increases with increasing severity of asthma. has been reported to induce severe bronchospasm in mild asthma. inhaled verapamil. a calcium channel blocker.22 Bronchial Asthma obsession with hygiene are depriving the immune system of input on which it is dependent. These observations are derived from the fact that urinary LTE4 is two-folds to ten-folds higher in these patients than in aspirin tolerant patients. has been reported to cause asthma exacerbations in a few aspirin-sensitive patients. These drugs are as follows:52-58 • Aspirin • Ibuprofen • Indomethacin • Piroxicam • Sulindac • Tolmetin • Naproxen • Fenoprofen • Meclofanamate • Mefenamic acid • Diclofenac sodium The list is not complete and aspirin sensitivity implies cross-reactivity with other nonsteroidal medications. studies have demonstrated that leukotrienes play an important role in airway narrowing and other signs in these patients. it is nonimmunologic and probably depends on inhibition of cyclo-oxygenase. Lactobacillus CG. which may be accompanied by rhinitis and/or urticaria. An association between aspirin sensitivity in people with asthma and the presence of sinusitis and nasal polyps is often stressed. important for bronchial asthma. the arachidonic acid metabolism proceeds via the lipo-oxygenase pathway producing leukotrienes (see pathogenesis). Recent data suggest that exposure of young children to older children at home or to children at day-care protects against the development of asthma and frequent wheezing later in childhood.62-64 and improve respiratory function by expanding the airway in patients with aspirin induced asthma. nasal polyps. many patients with nasal polyps are not aspirin sensitive. acetaminophen. Although the exact pathogenesis of aspirin-induced asthma is unclear. Recently. Although there is a statistical relation. The inhibition of cyclo-oxygenase is a property common to all of the drugs producing this adverse reaction. In these individuals. Accordingly.65 An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to leukotrienes. In contrast to asthma in general. virtually all. many asthmatic athletes report that a warm-up period of sub-maximal exercise helps to minimise exercise-induced symptoms. this phase is uncommon (EIA is a nonimmunologic form of asthma) and not severe unlike the late phase of allergen-induced asthma. A rapid change to warm. Ambient air conditions during the post-exercise period also influence the degree of bronchoconstriction that develops. EIA diminishes or is completely abated during a refractory period that usually lasts 2 hours after an exercise challenge.75 During sustained exercise they are often able to “work through’ initial respiratory symptoms. How this airway cooling causes bronchoconstriction. the severity and impact is striking.70 The higher the minute ventilation during exercise and the colder and drier the inspired air.73 However. is not exactly clear.is appropriately intensified. moist air post-exercise tends to worsen the development of airflow obstruction. repetitive exercise periods.Aetiology 23 EXERCISE-INDUCED ASTHMA66-71 Exercise-induced asthma’ (EIA) is often used to describe the asthma of persons in whom exercise is the predominant or even the only identified trigger to airflow obstruction. and a rewarming-induced hyperaemia and oedema results in airway . the greater is the stimulus for bronchoconstriction. No available data support the concept that exercise-induced asthma represents a distinct pathologic or pathophysiologic entity. i. This is referred to as “refractory period”. Untreated EIA can limit and disrupt normal life. It is estimated that approximately 40 per cent of children with allergic rhinitis. exercise is the only trigger.e. For some asthmatics. will have other additional sensitivities that either can be found in the clinical history or will evolve over time.74 Some patients who engage in continuous. There are some reports now that a late phase of EIA exists. exercise-induced asthma is due mainly to smooth muscle contraction. Exercise-induced bronchoconstriction is one manifestation of the asthmatic diathesis. During short (few minutes) periods of exercise. Most.eucapnic voluntary hyperventilation. people with asthma have airway hyperirritability that leads to exercise-induced asthma if the provocative stimulus . from the lung during exercise resulting from hyperventilation of air that is cooler and dryer than that of the bronchial tree. experience resolution of initial symptoms despite continued exercise.72. It generally reaches its peak about 5-10 minutes after cessation of activity and usually resolves spontaneously in the next 30-90 minutes or within a few minutes of administration of an inhaled beta-adrenergic bronchodilator. but without clinical asthma. Therefore some investigators call this as airflow-induced bronchoconstriction (AIB) or exercise-induced bronchospasm (EIB). it is generally established that EIA is due to loss of heat or water or both. most patients in whom exercise is the predominant trigger. Airway narrowing develops within 2-3 minutes after cessation of exercise. The key aspects of the triggering stimulus are the level of ventilation during exercise and the temperature/water content of the inspired air. airways actually dilate. Exercise-induced asthma is the airway narrowing that occurs minutes after the onset of vigorous activity. Some investigators believe that airway cooling triggers bronchoconstriction in asthmatic subjects. It has been suggested that heat and water loss leads to changes in airway fluid osmolarity which initiates mediator release that cause constriction in the smooth muscle. which is characterised by both smooth muscle contraction and airway inflammation. this condition should be anticipated in all asthma patients. have EIA. This situation probably holds true for adults. Accordingly. In addition. Although the exact mechanism of asthma is debated. Because of this phenomenon. Although individual episodes of EIA are short lived. for all asthmatics. bakers. hypertonic aerosol.79 Environmental agents related to work place have been recognised as the causative agents for respiratory diseases for many centuries. . but it is also possible for persons outside the working area to develop disease after contamination of their environment by a point source industrial chemical irritant or allergen. It is speculated that cooling attenuates hypocapnia. It can also occur in more unrecognised ways like materials contaminating air conditioning system inlets from near by factories. regular exercise that improves cardiovascular fitness and thereby increased oxygen extraction from the blood by exercising muscle can help reduce exercise-induced bronchoconstriction by lowering the level of ventilation needed during any given exercise task.71 To reduce/avoid EIA. simple chemicals and organic compounds have been used more often with a consequent increase in new respiratory hazards. photography. Other inhaled irritants in the ambient air including high levels of air pollutants and smoke can also trigger asthma especially during exercise when larger than normal volumes of these irritants are inhaled. antibiotics and cosmetic manufacturing.79 It is now the commonest industrial lung disease in the developed world with over 400 causes.76-78 It may account for about 10% of adult onset asthma. Asthma can also result from massive pollution due to transportation accidents or gross contamination of the local environment by manufacturing industries. With increased industrialisation. sulphur workers. health-related industries. Effects of Exercise An athlete’s minute ventilation during exercise is determined in part by the workload undertaken as measured by oxygen consumption and in part by the degree of deconditioning as measured by minute ventilation. depth. dyeing. Thus. Bernardino Ramazzini had recognised the importance of occupation in the causation of asthma as early as 1713 particularly in grain workers. OCCUPATION AND ASTHMA Occupational asthma is the commonest industrial lung disease in the developed world with over 400 causes. particularly occupational asthma. Industries in which asthma occurs include plastics and paint manufacturing. and other occupations.and dry air-induced bronchospasm via a cold induced reduction in neuronal activity or mediator production and release. metal refining. forestry. Occupational asthma may account for about 10% of adult onset asthma. welding. and food processing. Rate.80-86 Agents causing occupational asthma are usually encountered in an industrial setting.24 Bronchial Asthma obstruction. Thus the strict definition of occupational asthma as reversible obstructive airways disease contracted in the work place may underestimate the real extent of the problem. electronics. and pattern (I:E ratio) of breathing at a given level of ventilation during eucapnic voluntary hyperventilation are not important determinants of bronchoconstriction. Swimming is the preferred exercise for persons with asthma because of this mechanism. millers. Another hypothesis put forth is that exercise-induced bronchoconstriction results from an imbalance between two opposing mechanisms: an excitatory pathway stimulated by airway drying and an inhibitory pathway initiated by airway cooling. or by contamination of workers or of their clothing. avoidance of a cold/ dry environment is preferable. gases. up to 60% of the workers become sensitised to Bacillus subtilis. and in the cotton industry the prevalence of byssinosis is 25-29% in workers exposed in the carding process and 10-29% in those exposed in the spinning process. amylase B.mahogany. pollen Laboratory workers/Veterinarians Food processing Detergent factory Poultry farmers Bakers Farmers Fish food manufacturing Silk workers Farmers Electric soldering Carpenters and Saw mill workers Shipping workers Cotton mill workers Granary workers 2. feathers Flour grain Storage mites. HDI) Antibiotics. methyl dopa Disinfectants Paraphenylene diamine Formaldehyde. piperazine. Platinum salts Nickel salts Cobalt salts Chromium salts Aluminium fluoride Persulphate Vanadium Stainless fumes Refining Plating Diamond polishing Stainless steel welding Manufacturing Beauty shop Refinery workers Welding . Bakers exposed to flour dust develop asthma at a rate of 10-30%. pancreatic enzymes papain. 6% of the animal handlers.1: Selective agents known to cause occupational asthma Agents Occupation 1. danders) Shellfish. oak. Animal proteins (urine. Coffee seeds bean Colophony Wood dusts (red cedar. MDI. 5% of the workers in plastics industry (volatile isocyanates). and 30-50% of those working in the metal industry using soluble platinum salts develop the disease. egg proteins. Inorganic chemicals. ragweed. droppings. Similarly 5% of the western red cedar workers. Organic chemicals. wheat Midges Silk-worm moths and larvae Castor beans. it is reported that between 5 to 15% of all cases of asthma in Japan are occupational. Natural organic environmental agents. insects. fungi. aerosols. and engineering factors. or particulate matters and can range from very low molecular weight inorganic chemicals to complex organic macromolecules. Isocyanates (TDI. industrial hygiene. Table 2. Agents capable of inducing occupational asthma can be vapours.1.Aetiology 25 Prevalence of Asthma in Workers Although the exact prevalence of occupational asthma is not known and will vary according to the setting in which it occurs. etc) Grain dust (moulds. ethylene diamine Furfuryl alcohol resin Dimethyl ethanolamine toluene di-isocyanate Plastic and foam Manufacturing Hospital workers Fur dyeing Rubber processing Foundry workers Automobile painting 3. and on working conditions. grain) Cotton dust Storage mites. on the industrial agent involved.subtilis enzymes Poultry mites. in washing powder industry. on the intensity of exposure. Some of these agents are shown in Table 2. soyabean. and injected local anaesthetics containing epinephrine. neuro-peptide release. in whom an immediate skin test reactivity can be demonstrated. particularly in restaurant salad bars in western countries.87 Sulphiting agents88-90 have been used to preserve foods and beverages since ancient times. However. all patients with asthma do not react adversely to sulphites.26 Bronchial Asthma Occupational asthma can be mediated by any of the several. . a number of reports appeared linking this agent with the occurrence of acute bronchoconstriction. They include. Some agents also act via alternative path way of complement activation through an antibody-independent mechanism. there are reports of positive challenge in up to 22% of unselected asthma patients and 25-50% of those with aspirin sensitivity. prevent browning. Sulphites are used to prevent oxidation of beta-adrenergic agonists. or by immunologic mechanisms. This may be due to varying extent of inhalation of liberated sulphur dioxide by different patients or there may be a subset of asthmatics. shrimp. However. It is not an inhibitor of cyclo-oxygenase. Although the exact prevalence is not known. the amount of injected solutions is inconsequential. Major sources of exposure to sulphites are processed potatoes. has been reported to be responsible for fatal attacks of asthma and its use has been banned in many countries. TARTRAZINE AND SULPHITE SENSITIVITY Tartrazine is a yellow dye commonly employed in food and medications. The levels released from food and beverages may be sufficient to account for the bronchoconstriction. beer and wine. For this purpose. They maintain the crisp and fresh appearance of the foods. mechanisms. and metabisulphite. injected epinephrine. dried fruits. direct pharmacological reaction by agents such as organic insecticides (parasympathetic agonists) and beta-adrenergic blocking agents. Except in vary rare individuals with true allergy to sulphites. the incidence of tartrazine-induced asthma is very low and perhaps is limited to those rare individuals who appear to have an immunologically mediated sensitivity to the dye. Beginning in 1958. These patients will be able to metabolise sulphites to harmless sulphates. Sulphur dioxide is a known irritant and asthmatics are particularly susceptible. The agents used include sulphur dioxide as well as the sodium and potassium salts of sulphite. sulphites are contained in some nebuliser solutions. the amount in the nebuliser solutions is sufficient to cause paradoxical bronchoconstriction or a blunted bronchodilator response in these subjects. and control microbial growth and spoilage. The reaction is particularly noted in those with aspirin sensitivity. Exposure to sulphites. Another source of sulphite exposure for patients with asthma is medication. A small number of asthma patients may have true allergy to sulphites. inflammatory bronchoconstriction secondary to toxic concentration of gases (nonspecific complement activation. However. reflex vagal bronchoconstriction in response to an irritant effect on specific receptors. All these agents release sulphur dioxide gas under suitable conditions of warmth and acidity. bisulphite. disrupted cell membrane releasing arachidonic acid products). or after drinking wine or beer. which have low levels of the enzyme sulphite oxidase. Sulphur dioxide released in the mouth and stomach from sulphites has been incriminated as the cause of precipitation of asthma in a vast majority of patients. 60% also had pulmonary symptoms. but not proven. It is also likely that nasal and sinus pathology can aggravate asthma. Traditional therapies originally indicated for allergic rhinitis and asthma are being reassessed to explore their potential utility in both these conditions. and a high proportion of new patients have coexisting upper and lower respiratory tract disease. During the past decade with increased understanding.98 The simultaneous occurrence of GER and asthma suggests a causal . Recently. and one disease’. and about 40 per cent have reflux oesophagitis. particularly if there is uncontrolled drainage of mucoid or mucopurulent material down the nasopharynx where it can contribute to cough and irritability of larynx. does this association represent an epiphenomenon? There is suggestive clinical evidence that sinusitis not only occurs in association with asthma but may also play some role in its pathogenesis. increased frequency of reflux episodes.94 The prevalence of asthma and allergic rhinitis is increasing in the general population. many studies have shown a high prevalence of GER among patients with asthma. As early as 1967. play a role in upper airway disease as well.95 Since then.96. independent of the use of bronchodilators. have acid gastro-oesophageal reflux.97 A recent report says that even asthmatics without having reflux symptoms have a high prevalence (62%) of abnormal results for 24-hours oesophageal tests. It is also possible.Aetiology 27 RHINITIS AND SINUSITIS A possible relation between sinusitis and activation of asthma has been postulated recently. However. Urschel and Paulson reported that of 636 patients scheduled for an operative treatment for GER. A high incidence of radiographic evidence of sinusitis on the order of 40 to 60 % has been demonstrated in asthmatic patients. it was believed that structurally and functionally there are differences within the respiratory tract which have been used as the basis for separating the airway into upper and lower respiratory tracts. that sinus infection may aggravate asthma through reflex mechanisms. Because its important role in the pathogenesis of both airways disease. it is now being appreciated that allergic rhinitis and bronchial asthma are considered as ‘one airway. there has been a renewed interest in the role that histamine plays in lower airway disease.91-93 Although historically. leukotriene receptor antagonists are recently have emerged as important therapeutic advances that have potential clinical utility in both asthma and allergic rhinitis. the question is. This material may also be aspirated into the lower respiratory tract. and interest in increasing in the theory that leukotrienes. or heart burn. especially during sleep. numerous investigators have reported on epidemiology. It is estimated that 60 to 70% of patients who have asthma have also coexisting allergic rhinitis. mechanisms and clinical trials in an effort to piece together the gastro-oesophageal reflux and asthma. current thinking is emerging that they should better be described as a continuum of inflammation involving one common airway. Since the late seventies. which are more potent inflammatory mediators than histamine. Epidemiological evidence for the association suggest that about three-fourth of the asthmatics. Studies of children and adults after medical or surgical therapy indicate that the asthmatic state may improve with proper management of the underlying sinusitis. GASTRO-OESOPHAGEAL REFLUX (GER) A number of reports are available in the medical literature on the relationship between gastrooesophageal reflux (GER) and pulmonary disease. The second proposed mechanism is micro-aspiration. This mechanism is supported by the findings that acid infusion of the oesophagus in asthmatic patients leads to increased airway resistance that rapidly reverses with antacids and infusion of acid into the lower oesophagus of asthmatic children during sleep induces bronchoconstriction.101-105 Prevalence of gastro-oesophageal reflux in asthmatics can be summarised as follows:106 • 57% of asthmatics have heartburn • 41% of asthmatics note reflux-associated respiratory symptoms • 82% of asthmatics have abnormal oesophageal acid contact times • 43% of asthmatics have oesophagitis • Heartburn is more prevalent in asthmatics over 65 years of age (35%) compared with asthmatics 18-34 years of age (23%) • Heartburn is associated with a higher rate of future asthma hospitalisation • Subjects reporting nocturnal GER have higher asthma prevalence rates and symptoms of obstructive sleep apnoea • Proximal oesophageal acid exposure is present in 48% of asthmatics • In children : abnormal oesophageal pH tests are present in 62% and GER is a risk factor for asthma (OR 1. consequently. other studies have not demonstrated such a beneficial effect. Reflex vagal bronchoconstriction occurs secondary to stimulation of sensory nerve fibres in the lower oesophagus. The partial narrowing or occlusion of the upper airway during sleep. and obstructive sleep apnoea syndrome. followed by an increase in intrathoracic pressure. such as shock. or excitement. However. particularly during sleep. respiratory symptoms. such factors are rarely the dominant cause of disease. Depression most often associated with asthma may be secondary to a chronic disease. Many patients with asthma acknowledge that exacerbations are provoked by psychological events. (b) a high prevalence rate of hiatus hernia and gastro-oesophageal reflux in patients with bronchial asthma and (c) an incidence of gastro-oesophageal reflux in 63 per cent of children with asthma.9). However. PSYCHOLOGICAL FACTORS There has been a great deal of controversy regarding the cause and effect relationship of asthma and psychological factors. Although the information linking depression and . patients commit suicide. to respiratory symptoms. In rare instances. The prevalence of gastro-oesophageal reflux is increased at least threefolds in both children and adults with bronchial asthma. Suggestion and hypnosis may have some beneficial effect in modifying the asthmatic reactions. The occurrence of GER after bedtime is strongly associated with asthma.99. might predispose the patient to nocturnal GER and. The evidence for the relationship also has gained support from the results of clinical trials. iii.99 Both medical treatment with antacids and postural therapy and surgical management of gastro-oesophageal reflux have resulted in improvement of asthma symptoms.100 i.99 Two separate mechanisms are involved in the gastro-oesophageal reflux and asthma relationship. bereavement.28 Bronchial Asthma relationship. ii. This is supported by the findings of (a) a large vagally mediated increase in airway resistance with minute quantities of hydrochloric acid infused into the trachea of cats. This entity is known as “TokyoYokohama asthma”. high sunlight and temperature inversions as in Los Angeles and Athens. and kerosene contain oxides of nitrogen and are responsible for increased respiratory symptoms as reported in some studies. A small increase in allergen exposure will make the airway more reactive. hopelessness. and other evidence of depression. The severe asthmatic attack is very frightening and such patients are understandably anxious. family disputes or marital disharmony may be major factors in the aetiology of intractable asthma. Occasionally. documented depression.114-116 Reports from the Tokyo-Yokohama area of Japan where USA soldiers were based. and noxious gases like ozone. recent unemployment. Donnora. UK.Aetiology 29 increased death from asthma is derived from clinical reports. biomass. In a review of cases in which children died suddenly and unexpectedly of asthma. act as respiratory irritants and can exacerbate asthma.113 Although recent studies have not established a direct causal relation of air pollution and bronchial asthma. there is now substantial evidence that air pollution can contribute significantly to asthma morbidity and mortality.123 Southern Ontario and Toranto124-126 have shown . recent family loss and disruption. Ambient levels of air pollutants exacerbate mucosal inflammation in asthmatic airways. and nitrous oxides may be important in the development in young children. London 1952) have identified a link between respiratory morbidity and mortality and high levels of sulphur dioxide and black smoke. and breathlessness associated with eosinophilia and positive skin prick tests. Similarly other atmospheric pollutants as in highly industrialised area containing sulphur dioxide and other smoke particulates can provoke asthma. morbidity and mortality of asthma globally. can affect lung function. there is clinical evidence that the children had expressed despair.122 Utah valley. and schizophrenia. wheeze. Belgium -1930. although these studies were not primarily focussed to study the association between asthma and air pollution. Ozone and other oxidants contained in photochemical smog which occurs in areas of high traffic density.121 Seattle. which will result in a large increase in severity and potential deaths.112 Air pollution is partly being incriminated as a possible contributing factor in the recent rise in the prevalence. revealed many cases of asthmatic bronchitis characterised by cough.111 Other environmental pollutants such as diesel particulates. Emissions from motor vehicles are a major source of these pollutants. sulphur dioxide. These individuals experienced relief of their symptoms when they moved out to less polluted areas. Other psychological problems that are documented as associated with those at increased risk of mortality include alcohol abuse. a wish to die. Japan. the association. Indoor air pollution due to cooking fuels such as gas. since the levels of pollutants were not measured. is striking. Similarly smokers have increased bronchial hyperreactivity to a variety of stimuli. Retrospective analysis of pollution episodes in the world history (Meuse Valley. this could not be attributed to any specific pollutant.117-119 Other studies from Yokkaichi. Pennsylvania-1948.120 Birmingham. This area experienced smog as it was highly industrialised and surrounded by hills. and potentiate inhaled response to aeroallergens.107-109 POLLUTION Pollution with particulate matter adds to the allergenicity of aeroallergens. however. psychological illness. Passive smoking is known to be a risk factor110 and there is evidence that diesel fumes are associated with increased allergic responses. However. ozone.138-146 It is. peak severity occurs at 29-36 weeks of gestation. a number of patients complain of exacerbation of their symptoms during or preceding menstruation. asthma becomes worse during pregnancy. smoking induces neutrophilic airway inflammation in asthma.148 This decreased steroid responsiveness is responsible for the faster decline in FEV1 seen in smoking asthmatics.30 Bronchial Asthma positive correlations between asthma exacerbations and SO2. if any. It is also reported that improvements in responsiveness are associated with improvements in clinical asthma severity.134-136 Increased bronchial responsiveness after birth occurs in infants exposed to maternal smoking.130. who in addition develop hyperthyroidism.132.137 Infants exposed to smoking are at increased risk of developing asthma later in life. have altered lung function. in the development of asthma. Asthmatics who develop . should either have a decreased requirements of bronchodilators or amelioration of their symptoms.130 Environmental tobacco smoke is important in the development of childhood asthma and in the worsening of asthma in children and adults. Asthma becomes less severe during the last 4 weeks of pregnancy. or whether it is the result of lung injury from exposure to cigarette smoke. in one-third. and sputum eosinophilia on treatment with steroid inhalation. ENDOCRINAL FACTORS Although the exact role of hormones in asthma has not been defined. however. therefore would expect that patients of bronchial asthma.147 Further. it remains unchanged. In women in whom asthma becomes worse during pregnancy.131 The earlier and the greater the degree of environmental tobacco smoke. fine particulate matter. However. It is also not clear whether the increased bronchial reactivity in these infants is purely genetic. In infants exposed to prenatal and postnatal cigarette smoking. airway hyperresponsiveness. progesterone alone did not appear to be the sole contributor to these improvements. However. Most patients return to a prepregnancy level of severity by 3 months of postpartum. and less maturity of lungs secondary to in utero lung growth retardation because of persistent exposure of lungs to nicotine.147 Asthmatic smokers have higher sputum total cell and neutrophil numbers and IL-8 concentrations compared to asthmatic nonsmokers. not clear whether increased bronchial reactivity after birth plays a role. the greater the likelihood of asthma developing in children. Asthmatic smokers have increased hyperresponsiveness to methacholine. Thus upon the eosinophils inflammation. sputum eosinophils and eosinophil-cationprotein levels are higher in nonsmoking than smoking asthmatics. it becomes better. and in one-third. It is also suggested that oestrogen plays a role in the pathophysiology of asthma and long-term use and/or high doses of postmenopausal hormone therapy increase subsequent risk of asthma. Retrospective studies suggest that in approximately one-third of women. smoking asthmatics show no improvement in lung function. The change in the severity of asthma during pregnancy is sometimes dramatic and tends to be consistent in subsequent pregnancies. the reverse has been observed.133 These limitations in lung functions may be secondary to smaller lung size.153 Several observations have been made on the influence of thyroid hormones on asthma.149-152 There may be an improvement in airway responsiveness during pregnancy that is greatest in those with the most hyperresponsive airway initially. Hyperthyroidism is accompanied by many manifestations suggesting over stimulation of the sympathetic system and this condition is a contraindication for use of β-2 agonists.127-129 Indoor air pollution is a contributory factor in exacerbation of bronchial asthma. and sulphates. In contrast. suggesting a normalising effect of smoking on the Th1/Th2 balance. One. a decrease in expression of genes that regulate INF-γ production.154 GENETICS AND ASTHMA Genetic factors play a contributing role in the pathogenesis of asthma. 12q. which provide the mechanism for antigen recognition and presentation to and by T and B lymphocytes. but in rare instances they become completely asymptomatic. HLA-DP. or a combination of both. do far worse than euthyroid asthmatics.9. 7.160 Many candidate genes and positional cloning have recently been identified. Suggestive evidences are also found for linkages and replication for loci on chromosomes 5q. recent family studies suggest that atopy is dominantly inherited. 6.13 and 16. These Th2like lymphocytes and their cytokines are over represented in tissue biopsy studies in patients with allergic diseases. It is established that there is a reciprocal relationship between Th2 and Th1 responses with IL-10 derived from Th2 cells inhibiting Th1 responses while INF-γ generated by Th1 cells inhibits Th2 responses. and 21q. 12 and 13.4. not only asthma improves.156-159 Cytokines are important components in the pathogenesis of asthma (see below). The concordance of asthma in monozygotic (MZ) twins is reported to be significantly greater than that in dizygotic (DZ) twins. This component operates through the human lymphocyte antigen (HLA. Linkages have been confirmed to chromosomes 4. Moreover. or MHC class II) molecules HLA-DR. which is a powerful suppressor of Th2 responses. Different linkages have been reported from different ethnic groups.160 The other genetic component that plays an important role is the ability of a susceptible individual to recognise an environmental allergen as foreign and starts an allergic immune response. Various mechanisms such as changes in beta adrenoceptor activity and altered prostaglandin metabolism have been proposed to explain these observations.11. . The genes for these cytokines are encoded in a small region in the long arm of chromosome 5 and a number of them are coordinately regulated.11q containing FcεR1-β.6 (near the major histocompatibility complex. HLA-DQ. The loci most consistently and robustly identified are on chromosomes 5. 13q and 16.13 and GM-CSF (granulocyte macrophage colony-stimulating factor). The chromosome 5 contains an IL-4 gene cluster which encodes the allergic cytokines IL-3. Further. T cells that differentiate along this route and preferentially release cytokines of the IL-4 gene cluster are called Th2-like. This gene is closely linked to inheritance of an increased IgE response and to increased bronchial hyperresponsiveness.155 There are several studies indicating familial aggregation of asthma. Molecular genetic linkage studies indicate that the “atopy” gene locus is on chromosome 11. in allergic diseases like asthma. It is a frequent clinical observation that asthma runs in families.161 The first genome-wide screen for linkages to asthma identifies linkages on chromosomes 4q.5. It is possible that. there is an increase in the expression of genes. Though the dosage of inhaled antigens and other factors influence the likelihood of clinical disease. 19q. other atopic conditions like allergic rhinitis and atopic dermatitis are common among the family members of the asthma patients. (MHC). which improves after euthyroid state is achieved. human genome studies have revealed that allergic diathesis is linked with a region on the long arm of chromosome 12 which contains the gene encoding interferon-γ) (INF-γ). In some hyperthyroid asthmatics following treatment of hyperthyroidism. which regulates Th2 cytokines.Aetiology 31 hyperthyroidism. Similar discrepancies have also been observed in hypothyroidism. Bronchodilator response is impaired in the presence of excess thyroid hormones. 2. SO2. NO2) Viral Respiratory syncytial virus Parainfluenza virus Human rhinovirus Bacterial Mycobacterium Chlamydia Mycoplasma Lactobacillus ω3 fatty acids Vitamins Antioxidants Lectins . Similarly polymorphisms in the 5-lipoxygenase gene and the leukotriene C4 synthase gene have been associated with response to medications that target leukotriene metabolism.2: Candidate genes for asthma Chromosome 1 5 6 11 12 13 14 16 Gene IL-10 IL-4 promoter IL-5 IL-9 IL-12B IL-13 GM-CSF CD 14 β2 adrenergic receptor TNF-α Human leukocyte antigens FcεR1-β.32 Bronchial Asthma Various candidate genes those have been implicated in atopy and asthma are summarised in Table 2. 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A population-based study of bronchial asthma in adult twin pairs. Genetics and lung disease.8:9-15. Nieminen MM.Aetiology 39 154. Pulmonary Perspectives 1997. Approaches to mapping genes for allergy and asthma. Dash RJ. 159.152:411-13. Jindal SK: Airway response to inhaled fenoterol in hyperthyroid patients before and after treatment. 156. 369-74. Cookson WOC. Lancet 1988. Hopkin JM. Dominant inheritance of atopic immunoglobulin-E responsiveness. 155. Am J Respir Crit Care Med 2000. Kaprio J. Hopkin J.121:7S-13S. The genetics of asthma: The important questions. Sandford AJ. Bleecker ER.302:1222. . Chest 1991. Am J Crit Care Med 1995. 160. Chest 2002. 163. Curr Opin Pulm Med 2002. 162. 158. Roy R. Br Med J 1991. Asthma genetics. Genotype predictors of response to asthma medications. 29:307. Meyers DA. Pare P. exudation of plasma. and mucus production. The LAR is also characterised by the release of inflammatory mediators into the same fluids. and • Inflammatory oedema and vasodilatation (hyperaemia). A further recovery occurs by 24 to 36 hours.1 These can be detected in the blood as they overflow into the circulation. bronchial challenge/inhalation of appropriate antigens will elicit an early response.40 Bronchial Asthma 3 Pathophysiology of Bronchial Asthma Bronchial asthma is a disease characterised by wide variation over short periods of time in the resistance to flow in the airways. This reaches its peak in about thirty minutes and resolves within 90-180 minutes. This early reaction is IgE dependent and is the result of IgE binding to mast cells by its Fc portion and to specific antigens by its F(ab) portion. When IgE-sensitised mast cells are exposed to antigen against which the IgE molecule is directed. This reaction can be prevented by pre-medication with sodium cromoglycate and nedocromil sodium and β-2 agonists. during this phase there is a striking infiltration of inflammatory . pre-formed and newly generated mediators are released. with varying contribution from each. and leukotriene C4 from airway mast cells. Three factors narrow airway caliber to limit the flow: • Airway smooth muscle contraction.2 This early response is due to the release of histamine. In this form. The cellular response in LAR in non-allergic asthma is similar. it is viewed as a sum of three features: the early asthmatic reaction (EAR). Most asthma is of allergic origin. in bronchoalveolar lavage fluid. • Gland and epithelial secretions and exudation into the airway lumen. Late Asthmatic Reaction (LAR) and Bronchial Hyperreactivity (BHR) The EAR is followed by a complete or partial recovery period over the next 1 to 2 hours and then by a further progressive fall in respiratory function. The hallmark of the disease is the airflow obstruction. and as metabolites in the urine and include histamine. but little is known of the underlying aetiology. prostaglandin D2.3 but not with steroids. which is maximum at 15 minutes and characterised by smooth muscle contraction. This response can only be partially reversed by β-2 agonist. Early Asthmatic Reaction (EAR) In atopic individuals. However. but pre-medication with cromolyn and corticosteroids inhibits this response. which is maximal between 6 to 12 hours. the late asthmatic reaction (LAR). and bronchial hyperresponsiveness. isolated late phase reactions in 6-14%. CD4+ T lymphocytes. and lymphocytes. the LAR is associated with histologic evidence of airway inflammation. mediators. macrophages.6 The BAL fluid from these subjects contains increased eosinophils. but there will be no late bronchoconstriction. Inhaled ozone and viral infections damage the bronchial epithelium. monocytes. The stimulus/stimuli in a susceptible host starts the ball rolling so that a number of cells with their products cause various changes that are characteristic of bronchial asthma.3. It is clear from studies in human and animals that the two phases of bronchoconstriction response to inhaled antigen have distinct characteristics. basophils.4 The BHR usually precedes the onset of LAR. is lessened by corticosteroids. cytokines from the cells in the airway mucosa in relation to allergen exposure with the subsequent effect of recruiting mature and precursor cells from the bone marrow and other sites of leucocyte sequestration. and neuropeptides in a coordinated manner are responsible for the ultimate airway obstruction.e. is sensitive to the effects of antiinflammatory drugs. In contrast. A number of cells and chemical by-products take part in the pathogenesis of bronchial asthma to bring about changes outlined above. A series of events including cellular elements.Pathophysiology of Bronchial Asthma 41 cells with activation of these cells which include eosinophils. neutrophils. i. The immediate response to antigen occurs before airway inflammation is established histologically. It is also known over the last few years that there is a close relationship . is relatively resistant to bronchodilator drugs. eosinophilic cationic protein.8 The results of skin testing of allergic subjects indicate that isolated immediate hypersensitivity reactions occur in about 20% of positive challenges. leading to an inflammatory response in the bronchial walls and bronchial hyperreactivity develops once airway inflammation become evident. Rabbit experiments showed that if they are depleted of neutrophils and then exposed to inhaled antigen. and is not associated with an increased bronchial hyperreactivity. All these support the hypothesis that inflammatory processes are important in the pathogenesis of bronchial hyperreactivity. is abolished or attenuated by prior bronchodilator drugs like β-2 adrenergic agonist. there will be an immediate bronchoconstrictor response. Thus. These findings suggest that airway inflammation underlines the bronchial hyperreactivity characteristic of LAR. This LAR is thought to be a primary mechanism responsible for airway (bronchial) hyperresponsiveness (BHR). Similarly neutropenic dogs do not develop hyperreactivity after exposure to ozone. and both reactions in 66 to 85%.7 Mucosal oedema and vasodilatation are the important components of airway obstruction during the LAR and contraction of airway smooth muscle contribute substantially to the EAR. Non-immunologic causes of airway inflammation are also associated with the development of bronchial reactivity. and neutrophils. it is apparent that both inflammation and bronchial hyperreactivity are important to bring about these changes. The BHR is an exaggerated bronchoconstriction of smooth muscles and airway narrowing on exposure to small quantity of non-allergic stimulant that usually does not provoke such a reaction in normal subjects. However. Bronchial asthma is now considered as a heterogeneous disorder with multiple triggers.6 The selective recruitment of these leucocytes into the airways during the LAR are probably due to the release of local and circulating messengers. neither they develop bronchial hyperreactivity. certain features are common to all asthmatics: Airway inflammation and hyperresponsiveness to a broad range of stimuli.5 This may last for several days or occasionally weeks. and is associated with bronchial hyperreactivity. The understanding and concept of pathogenesis of bronchial asthma has changed considerably over the past decade. and allergens are all associated with inflammation and these inflammatory stimuli are associated with airway hyperresponsiveness. presence of increased number of eosinophils in the sputum and peripheral blood of patients with bronchial asthma has been known for many years. mast cells. Most studies have shown that airway inflammation precedes hyperresponsiveness and may be a prerequisite for the development of hyperresponsiveness and clinical bronchospasm.21 These non-inflammatory cells may contribute to the inflammatory response and may also directly participate in the regulation of normal airway tone.1). Bronchoalveolar lavage studies from patients with bronchial asthma have shown increased number of eosinophils.e.22-31 INFLAMMATORY CELLS IN ASTHMA Mast Cells Mast cells have been recognised since a long time as the main effectors cells in early asthma reaction. IgE receptors are cross-linked with antigen.19 Further. Thus.34. viral infections.40 After immunological activation.39 are released from the mast cell during the allergic reaction when its high affinity. proteoglycans. epithelial damage.42 Bronchial Asthma between airway inflammation and hyperresponsiveness. and proteases. heparin. epithelial cells. primarily through the cyclooxygenase pathway to prostaglandin (PGD2). both preformed. and influx of inflammatory cells even in patients with mild asthma.16-18 Fresh biopsies from asthmatics of varying severity have shown epithelial changes.36 Based on the production of proteases. proteases38 and newly synthesised. airway inflammation as in purulent bronchitis may be present without hyperresponsiveness or bronchospasm.33 Normal human respiratory tract contains large numbers of mast cells beneath the bronchial epithelium and alveolar walls. On the other hand.9-15 Histopathological studies also have shown epithelial shedding and influx of eosinophils into the airway mucosa.20 Specific subtypes of lymphocytes (T-helpers2 [Th2]) may orchestrate a unique inflammatory response in the asthmatic lung and may significantly modulate the function not only of the inflammatory cells. a hallmark of bronchial asthma is of a specific nature that differs from other types of inflammation. and airway epithelial cells. i. airway inflammation.32. a number of subtypes of mast cells exist in human beings. whereas other populations of mast cells metabolize arachidonic acid primarily through the 5'-lipooxygenase pathway to LTB4 and LTC4 (Fig. and thromboxane A2. It is also reported subsequently that eosinophils and mast cells increase quantitatively during exacerbations of asthma. Bronchial asthma is now established as an inflammatory disease of the airways associated with inflammatory cell infiltration. some populations of mast cells metabolise arachidonic acid. and various humoral and chemical mediators of asthma. and subepithelial fibrosis. All mast cells have secretory granules that contain large amounts of histamine. chemicals. 3. Substantial data also support the role for both neutrophils and macrophages. These preformed substances are exocytosed from the cell after immunologic . Increased numbers of mast cells and histamine (a product of mast cells) have been found in the bronchoalveolar lavage fluid obtained from patients with bronchial asthma. platelets. histamine. pollutants.37 A large number of biologically active molecules. but also non-inflammatory cells which include endothelial cells. sensory nerves. deposition of collagens. The function of these cells can be modulated in asthmatics and they may produce mediators with effects on airway function. Exposure to oxidants.35 These calls are derived from CD34+ cells in the bone marrow. it is hypothesised that an imbalance between these inflammatory and anti-inflammatory substances will decide the final outcome. The tissue damaging properties of cationic protein mediators released from eosinophils (see later) are neutralised by the highly anionic heparin.1: Arachidonic acid metabolism and mediator release (LT. Thus. These substances are GM-CSF. JE. Through the release of cytokines similar to those released from TH2 lymphocytes. Although mast cells are primary cells in EAR through IgE dependent release of spasmogenic mediators. 3. it is possible that mast cells also play an important role in the development of LAR in addition to its primary role in EAR. this has not yet been proven. However. It has been suggested that mast cells also possess anti-inflammatory properties through release of heparin and related proteolysis. These cytokines are capable of recruiting. It has been shown recently in experimental animals that certain activated mast cells also release transiently a large number of cytokines affect the tissue microenvironment during inflammation. INF-γ. they also have an important role in LAR as they also produce . It has also been shown that heparin inhibits the increased vascular permeability induced by a wide range of agonists. IL-1. and M1P1. priming and activating other cells involved in inflammation.Pathophysiology of Bronchial Asthma 43 Fig. IL-3-6. can inhibit lymphocyte activation and trafficking and like glucocorticoids is capable of inhibiting delayed hypersensitivity responses. transforming growth factor. PAF.Leukotriene) activation. The granule is composed of a crystalloid core and a matrix. The IL-5 specifically stimulates eosinophil differentiation. as well as EPO in the presence of halide and hydrogen peroxidase. It has also been shown that MBP is deposited in the damaged areas in the epithelium.44 Bronchial Asthma GM-CSF. EDN and ECP are both ribonucleases. epithelial damage. blood and sputum eosinophilia in this disease.42. Eosinophil cationic protein (ECP) iii. damage bronchial epithelium. but also ECP and EPO alone. They have receptors for IgG. etc. All these mediators are released by activated eosinophils. Not only MBP. and recruitment and priming of other inflammatory cells. Biopsy studies both postmortem and during life have shown the presence of excess eosinophils in the bronchial mucosa of these patients. The genes of these proteins are cloned and the cDNA for MBP specifies the existence of a proMBP molecule that is composed of an acid-rich portion and a basic MBP portion. IgA.41 although some other reports indicate that they are less likely to be involved in the chronic inflammatory response. cytokines released from a number of cell types in the airways including activated T cells of the TH2 type. which has been termed as “chronic eosinophilic bronchitis”. and lactoperoxidase. particularly MBP applied to respiratory epithelium stimulates smooth muscle contraction and also can increase the sensitivity of the smooth . The release of these mediators results in bronchoconstriction. and IgE on their cell surface.43 Eosinophils44-47 The importance of eosinophils in the causation of bronchial asthma is evident in view of extensive tissue. ECP is a potent helminthotoxin. Eosinophil maturation and priming are under the control of IL-3. EPO is a member of the peroxidase multigene family that is composed of myeloperoxidase. thyroid peroxidase. Their development is dependent on T cell function. IL-5. and mast cells. Eosinophils have characteristic granules and granule proteins. In addition. The number of activated eosinophils is closely related to asthma severity and may be associated with epithelial shedding. Major basic protein (MBP) ii. and GM-CSF (Granulocyte macrophage-colony stimulating factor). Eosinophil peroxidase (EPO). interleukins. and their presence in the airways characterises the inflammation of asthma. The MBP is toxic to respiratory epithelium and is elevated in the sputum of patients with asthma. They also play a key role in asthma. Eosinophil-derived neurotoxin (EDN) and iv. Another molecule present in the eosinophils is the Charcot-Leydon crystal protein that possesses lysophospholipase activity. The above four proteins are present in the granules. These cells are able to produce many mediators that are responsible for the disordered airway function characteristic of asthma. IL-4. These substances include: • Platelet activating factor • LTB4 • LTC4 • PGE2 • 15-HETE • Oxygen radicals and • Four cytotoxic proteins48-51 i. Experimental studies have shown that eosinophil proteins. and activated (EG2+) eosinophils occurs in allergen-induced late phase reaction in atopic subjects.IL-5.55 IL-10 inhibits Th1 proliferation. and IL-10. Although CD8+ cells are not a part of this reaction. and IL-5. direct evidence of T cell involvement in bronchial asthma is acquired by the study of mucosal biopsy specimens from volunteers. vii.52. vi. IL-4. activated CD4+ cells are a feature of both active and chronic asthma. IL-6. T cells may be directly involved in eosinophil recruitment and activation by secreting various . which are characteristic of either the Th1 or Th2 subset. divided on the basis of lymphokines they secrete. the role of T lymphocytes in bronchial asthma had received little attention till recently. including IL-4 and INF-γ. and IL-3 and GM-CSF are secreted by both. While the Th1 cells secrete IL-2. T cells are attracted to the bronchial mucosal surface to the site of inflammation by specific receptors both on themselves and on the mucosal capillary and endothelial venules. iv. There are a number of evidences to prove that these cells play important roles in this disease. There is a significant increase in the number of IL-2R+ (CD25) cells both at the central and subsegmental airways. i. Corticosteroid resistant asthmatics have chronically activated circulating T cells (IL-2R and HLA-DR positive). IL-3. Patients with acute severe asthma have activated CD4+ lymphocytes in their blood. and IL-4 are important regulators of mast cell and basophil production. Lymphocytes52-70 Although production of IgE by B lymphocytes is well known. While IL-4 stimulates.54 They are Th1 and Th2. it has been found that substantial infiltration of CD4 IL-2R+ lymphocytes.56 Details of such interaction are being discussed above under genetics and asthma. that closely regulate IgE production by B lymphocytes. which is called Th0. the Th2 cells secrete IL-4. and IL-3. Recently it has been reported that a high percentage of these CD4+ cells are UCLH-1 or memory cells. another stable phenotype among T-helper clones has been recognised both in mouse and man. This subtype is characterised by an ability to generate a large variety of cytokines. interferonalpha and tumour necrosis factor-beta. These changes corelate well with the severity of disease. that respond to recall antigens. The elevation is associated with increased serum concentration of IL-2 soluble receptors and INF-γ. ii. the number of which returns to baseline value after successful treatment. and interferon-γ.53 Chronic asthma. represents a form of delayed-type hypersensitivity involving interactions between “activated” lymphocytes and eosinophils. Local accumulation of CD8+ cells in early phase reactions recovered in BAL fluid suggests that the subsequent late phase reaction may be in part. at least in part. iii. under the control of T cells. More recently. which suggests that eosinophil is an effector of the changes of bronchial hyperreactivity in vivo. v. and GM-CSF regulate eosinophil production. While INF-γ inhibits the development of Th2 cells. T lymphocytes secrete lymphokines.Pathophysiology of Bronchial Asthma 45 muscle to acetylcholine. more so for the later. and their presence is associated with actively secreting eosinophils. Therefore. More recently. It is now well established that there are two types of T cells. Electron microscopy has revealed elevated numbers of activated “irregular” lymphocytes in the bronchial mucosa. interferon-γ inhibits IgE synthesis. INF-γ diminishes cell processing necessary for IL-4 production. principally INF-γ. and the production of different cytokines. inhibit or antagonize Th2 effector function. it may be summarised that T cell participation is an important event in allergic diseases and asthma. by specific Vβ expressing T cell subsets. interferon and transforming growth factor-beta TGF-β. While IL-4 may act directly on the precursor T cell to induce Th2 differentiation. The first signal is triggered by the interaction between antigen-specific T cell receptor and peptide-major histocompatibility complex II complexes on APCs. IL-5 and GM-CSF with fewer Th1 cells whose cytokine profile includes IL-2 and interferon-γ. and.57-68 Two important cytokines . The role of transcription-factor NF-KB is emerging recently to play a key role in the pathogenesis of bronchial asthma. IL-4. costimulatory signals may fulfill a valuable role in T lymphocyte activation.70 Thus.78 CTLA-4 is a second co-stimulatory molecule and is a homologue of CD28.69 Thus. and increased airway responsiveness may be mediated. Type 1 T-helper (Th1) or Th2 cell differentiation. binds to accessory molecule B7. Corticosteroids are potent inhibitors of NF-KB and their antiinflammatory action is believed to be mediated through this mechanism. plays a major role in asthmatic airway inflammation. It is expressed only on activated T cells. The second signal or ‘co-stimulatory’ signal is triggered by CD80 (B7-1) and CD86 (B7-2) of the APC binding to the CD28 and cytotoxic T lymphocyte antigen (CTLA-4) of the T lymphocytes. Products of Th1 type cells. Th2 cells are more important by the way of production of various cytokines which are necessary for allergic responses.77 Thus.71 While T cell sensitisation is an important factor in the development of IgE production to a particular antigen and T cell subsets are important in establishing the process of airway hyperresponsiveness. immediate cutaneous hypersensitivity. which results in IL-5 secretion. or even eliminated. While the precise mechanisms by which inflammatory cells are recruited into the lungs are not fully understood. Such control establishes a model of how IgE can be tightly regulated in vitro. whether IgE will be produced in response to various allergic stimuli. There is a preferential expansion of type Th2 T cells secreting IL-3. interplay of these cytokines will decide whether IL-4 producing cells will be produced.73-76 In the absence of co-stimulatory signals. Experimental data have shown that the transfer of antigen-specific IgE. that are particularly important in bronchial asthma are IL-4 and NF-KB. The Th2 pathway is also involved in regulation of eosinophilia.69.46 Bronchial Asthma interleukins which favour the synthesis of IgE and activation of eosinophils and mast cells.72 CD4+ T cell activation leading to cytokine production and effector function requires two signals from the antigen-presenting cell (APC). It is postulated that inflammatory signals activate transcription factors such as NF-KB and this in turn will switch on the inflammatory genes. Lymphokines and various other cytokines that are relevant to airway inflammation in asthma are shown subsequently.70 IL-4 is essential for IgE production. and the preferential recruitment of eosinophils and mast cells. and INF-γ is a strong inhibitor of this process. Th1 cells are primarily responsible for classic delayed hypersensitivity. In contrast. thus. Such a mechanism would explain the peculiarities of allergic inflammation involving isotype switching to IgE synthesis. the T cell-dependent immune response is greatly diminished. IL-4 induces IgE synthesis. increasingly available evidence suggest that the activation of antigen-specific CD4+ T cells of the type 2 T-helper (Th2) subset in the lungs.79 and mediates T cell-dependent . which will lead on to the increased expression of inflammatory proteins. The differentiation into Th1 and Th2 cells are again regulated by cytokines. mast cell activity and IgE synthesis. depending on the antigen. macrophages are capable of releasing several potent neutrophil chemotaxins. prostaglandin (TxB2). The macrophage IgE receptors (IgE FcR) has a low affinity for IgE compared to that of the mast cell. atopy.82-86 The CTLA-4 promoter (-318 C/T) T allele may serve as a clinically useful marker of severe asthma.85 Monocytes and Macrophages Several findings favour a role for macrophages in bronchial asthma.96 Whereas in normal healthy humans.81 However. or bronchial hyperresponsiveness. macrophage function is altered by lymphokines. IL-8 is also chemotactic for lymphocytes. . This lower affinity binding suggests that IgE immune complexes may be more important in activation of these cells compared to mast cells and basophils that are sensitised by monomeric IgE. LTB4 and PAF are chemo attractants for eosinophils. with some studies79 the CTLA-4 might also deliver a positive signal to Th2 cell activation. could thus have effects on immune response. such as IL-4. Secondly. A significant association is found between severe asthma and bronchial hyperresponsiveness. but not with asthma. the role of CTLA-4 remains uncertain.95. may regulate the number of IgE FcRs on lung macrophages. Disruption of this delicate balance of immune regulation could lead to autoimmune diseases or atopic diseases. Fourthly. because of their greater strength of binding to this FcR. The production of LTB4 from macrophages is greater on a nanogram per cell basis than other cells. only 5 to 10% of the alveolar macrophages and 10-15% of the peripheral monocytes are IgE Fc positive. The percentage may be still higher in severe forms of asthma. such as INF-γ. They are also able to generate oxygen free radicals. neutral proteases. and β-glucuronidase after non-specific stimulation. Some of these studies also have shown that macrophages from asthmatics are hyperactive and release more lipid-derived mediators than those from the normal subjects. As many as 80% of the monocytes and up to 30% of the macrophages recovered from BAL fluid in mild asthmatics will be IgE receptor positive. and platelet-activating factor (PAF). Polymorphisms of the CLTA-4 gene. Thirdly.80. after in vivo and in vitro contact with specific allergen or non-specific stimulus. located on chromosome 2q33.Pathophysiology of Bronchial Asthma 47 immune response. This promoter polymorphism is associated with asthma severity. leukotrienes. these numbers increase dramatically in asthmatics. Therefore. Therefore it is possible that these cells interact with any inhaled allergen. It is reasonable to hypothesize that this lymphokine and/or others. Signalling through CTLA-4 may down regulate Th1 cell proliferation by inhibiting the production of IL-2 and IL-2 receptor expression. fibronectins. Three CTLA-4 genes are known at present.86-94 Firstly. it has been demonstrated that active macrophages are present at the air-surface interface of human airways as well as in alveoli. a subpopulation of peripheral blood monocytes and alveolar macrophages are IgE receptor positive. Macrophages produce histamine-releasing factor(s) that induce the release of histamine from basophils. CTLA-4 is considered to be important in the development of many of the immunologic and physiologic features of asthma. alveolar macrophages from asthmatics have been shown to release lysosomal enzymes. These include complement fragments. and LTB4. Fifthly. neutrophil attractant/activating protein1 (IL-8). which release histamine in the early phase reaction. . In addition. transudation of fluids and reduced clearance of inflammatory substances and respiratory secretions occur with disruption of epithelial mucociliary mechanisms. Epithelial Cells and Adhesion Molecules The infiltration of inflammatory cells into the airways is dependent on the expression of adhesion molecules on inflammatory cells and endothelial cells of the bronchial circulation. 12-and 15-hydroxy eicosatetraenoic acid. selectins (E-selectin like ELAM-1. GM-CSF. and leucocytes. L-selectin) and carbohydrates are important for lung inflammation. Neutrophils Although neutrophils are found in large proportions in the bronchial wall and bronchoalveolar lavage fluid in bronchial asthma.48 Bronchial Asthma Basophils Basophils are histamine releasing cells in the late phase reaction of asthma unlike mast cells. and inflammatory mediators. The bronchial hyperresponsiveness in asthma is attributed to the epithelial cell damage. This is effected by the interaction of various adhesion molecules expressed on endothelial cells. The epithelium also participates in mediator release and metabolism. Currently. P-selectin. Any or all of these cytokines could prime the basophils such that they become responsive to very low concentrations of stimuli or some could directly trigger basophil mediator release. immunoglobulin super gene family (intracellular adhesion molecule-ICAM. These structural changes in the epithelial barrier can lead to increased permeability to inhaled allergens. irritants. The spontaneous release of histamine is quite high by these activated basophils (20-40% of total). Various cytokines (IL-1. These include integrins. They also have ability to alter airway function. and histamine releasing factor) and PAF have an up regulatory/stimulatory effect on blood basophils. epithelial cells. PGF2α. The airway epithelial cells have a protective role against various tachykinins.102-109 Adhesion of various inflammatory cells to the bronchial vascular endothelium is a key step in the initiation and propagation of inflammation. and ECAM-1. although the specific mechanism is still under investigation. vascular cell adhesion molecule-VCAM. This release process has slow kinetics and is temperature dependent. Expression of various adhesion molecules is regulated by various mediators of inflammation. These finding suggest that neutrophils probably participate in inflammation of bronchial asthma.97 One consequence of inflammation is epithelial injury. platelet endothelial adhesion molecule-PCAM). it is not clear if they have any definite role to play in bronchial asthma. adhesion molecules are considered to be important in the causation of airway inflammation. such neutrophils in bronchial asthma show increased expression of membrane complement receptors and enhanced toxicity for complement coated antigens. These changes range from minor disruption of the epithelium with loss of ciliated cells to complete denudation of the epithelium. However. etc. These molecules are specific glycoproteins that are grouped into different families depending upon their molecular structure. platelets.98-101 They have the capacity to produce PGE2. IL-3. Morphological studies have shown that asthma is associated with epithelial injury. usually less than 80 KD in size. activation. microvascular leak. priming and chemotaxis. and many are glycosylated. the sulphidopeptide leukotrienes are of interest because they have the potential of involvement in both aspects of the asthma syndrome.e. maturation. mast cells eosinophils T cell. A detailed discussion on the role of different cytokines is given below. further recruitment and activation of various inflammatory cells. T cell growth. survival. T cells Neutrophil chemo-attractant and activator. growth factor (PDGF) Macrophages Fibrosis. and eosinophils survival. Increased expression of endothelial adhesion molecules Eosinophil activation Eosinophil and neutrophil differentiation.1: Various cytokines. their source and function in the pathogenesis of bronchial asthma110 Origin Function Various cells Th2-cells Th2 cell. fibroblasts inhibits IgE synthesis T cell Inhibition of Th1 cytokine. activation.117 The subsequent isolation and elucidation . it was distinguished from histamine on the basis that its effects were slow in onset and prolonged in duration. adhesion. and inflammation. LEUKOTRIENES Of the many mediators that have been implicated in the asthmatic response. stimulates monocytes production T cells NK cell and T cell growth. eosinophils. all essential changes in bronchial asthma. They are produced by different cell types. macrophages. mast cells Granulocyte differentiation. basophil differentiation and priming. endothelial adhesion Eosinophil differentiation. IgE synthesis inhibition T cells Critical regulator of allergic response T cells.1. Various cytokines and their function are shown in Table 3. epithelial cells T cells Eosinophil and macrophage activation T cell and macrophage activation. Cytokines IL-1 IL-2 IL-3 IL-4 IL-5 IL-6 IL-8 IL-10 Table 3. increased mucus secretion. eosinophil chemo-attractant Monocytes.111-116 They are generated by recruited cells and resident cells of the airways. eosinophils. i. mast cell T cell. IL-12 IL-13 GM-CSF chemotaxis IFN-γ Tumour necrosis factor Platelet derived Monocytes. The original discovery of a slow-reacting substance was that of smooth muscle contractile activity distinct from histamine. hyperresponsiveness. cofactor in IgE synthesis T cells T cell growth factor.Pathophysiology of Bronchial Asthma 49 CYTOKINES IN BRONCHIAL ASTHMA Cytokines are extracellular signalling proteins. These mediators cause contraction of airway smooth muscle. eosinophil chemotaxis IgE synthesis. mast cells. activation. Th2 cytokine inhibition INFLAMMATORY MEDIATORS IN ASTHMA From the foregoing paragraphs it is apparent that a number of mediators released by different cells are important for various changes observed in bronchial asthma. 130 and increased secretion of bronchial mucus from submucosal gland secretion. 3.2 arachidonic acid (AA) released from membrane phospholipids during cell activation may be oxidatively metabolised by the enzymes of the cyclooxygenase or lipooxygenase pathways. It is well established that the cysteinyl leukotrienes are formed when LTA4 exporting cells. and inflammatory conditions of bowel. The importance of leukotrienes has been suggested in a wide variety of disorders that include hepatorenal syndromes.2). As shown in Figure 3. the 5-lipooxygenase pathway generates 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) or is converted enzymatically to the unstable intermediate LTA4.123 These include severe airway obstruction. it is likely that the vascular endothelium will be exposed to cells capable of donating LTA4. such as polymorphonuclear leucocytes (neutrophils and eosinophils) provide LTA4 for effector cells such as vascular endothelial cells or platelets.122 besides their involvement principally in bronchial asthma.120 This FLAP is a cofactor resident in the nuclear membrane.e. skin and joints. since plasma leakage is prominent in more severe asthma. even in Pico molar concentrations. The leukotrienes have profound biochemical and physiologic effects. and LTE4) are potent spasmogens for non-vascular smooth muscle and comprise the activity previously known as slow-reacting substance of anaphylaxis (SRS-A). LTA4 is metabolised by an epoxide hydrolase to LTB4. LTE4) which are synthesised and exported into the microenvironment by a number of the above mentioned inflammatory cells. myocardial ischaemia. including mast cells and eosinophils.2: Synthesis of leukotrienes and their function .128 LTC4 is cleaved by glutamyl-transpeptidase to LTD4.131 The most Fig.129 oedema. 3.50 Bronchial Asthma of the structure of slow-reacting substance was identified as cysteinyl leukotrienes (LTC4. bronchoconstriction.109 Arachidonate is presented to the 5-lipooxygenase enzyme by 5-lipooxygenase-activating protein (FLAP). LTB4 is a potent chemo attractant for neutrophils.118-127 Furthermore. i. While cyclooxygenase pathway produces prostaglandins and thromboxane. LTD4. or by a glutathion-S-transferase (LTC4 synthase) to LTC4. and the sulphidopeptide leukotrienes (LTC4. which is converted by a peptidase to LTE4. LTD4. these enzymes being ubiquitous in the tissues and circulation (Fig. and leukotriene modifiers modulate antigeninduced asthma. However. in part.140 Pranleukast. The recent development and usefulness of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma further emphasizes the role of these leukotrienes in the pathogenesis of this condition. Leukotrienes participate in the pathogenesis of bronchial asthma besides the involvement eosinophilic airway inflammation. eosinophils. It is also now recognised that synthesis of leukotrienes in the lung may involve a single inflammatory cell type or an interaction between inflammatory and non-inflammatory cells termed “transcellular metabolism”. Some reports suggest that even transcellular metabolism may be the principal source of LTC4 in the lungs. a leukotriene inhibitor suppresses the increased values of sputum eosinophil count and eosinophil cationic protein during house dust mite-induced asthma are suppressed by further. Sulphidopeptide leukotrienes have been detected in the plasma during asthma attacks. Inhalation of LTE4at doses that induce a small but significant contractile response enhances the response to subsequent administration of inhaled histamine.139 Overproduction of leukotrienes not only occurs in house dust mite provoked asthma. LT4 is also a potent bronchoconstrictor although 30-100 times less potent than the above two. Leukotriene B4 (LTB4) is a potent chemotactic factor and is responsible. While in the former the overproduction occurs with an antigen-antibody reaction. subsequent enzymes like LTA4 hydrolase. Larger quantities of these substances have been recovered from the urine of asthma patients during acute spontaneous attacks than found in normal subjects. but not in normal subjects. LTC4 and LTD4 are approximately 3000 times more potent in contracting the airway compared to histamine in normal subjects.133. This enhancement is on the order of a four-fold shift in the histamine dose-response curve with the effect lasting approximately 24 hours with small effects persisting for up to a week. LTE4 induces a state of enhanced airway responsiveness in asthmatics. Significantly larger quantities are also recovered from the BAL fluid from subjects with symptomatic asthma. although the mechanisms of such overproduction are different. Their role in the smooth muscle contraction is controversial.Pathophysiology of Bronchial Asthma 51 prominent effect is their ability to mediate airway narrowing in normal subjects as well as in subjects with asthma. The airway obstruction is prolonged compared to that induced by histamine.132 The cells producing leukotrienes are only macrophages. airway epithelial cells and in the lung lining fluids. Thus a state of airway hyperresponsiveness is maintained. this drug increases FEV1 that falls during such provocation. but also in aspirin induced bronchial asthma.141-143 .135-138 Leukotrienes are important in asthma. This can also modulate the immune response by inhibiting the capacity to mount a delayed hypersensitivity response. and LTC4 synthase are more broadly distributed including non-inflammatory cells. for the recruitment of inflammatory cells to the airway and stimulation of secretion of inflammatory products.140 The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway narrowing and other signs in these patients are associated with 2-10 fold higher values of LTE4 in the urine of these patients compared to aspirin tolerant patients. although some studies suggest that they may increase airway smooth muscle responsiveness to subsequent stimulation. and mast cells that can synthesise them from the substrate arachidonic acid.134 These leukotrienes are recovered from nasal lavage fluid after inhalation challenge. neutrophils. the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade. in aspirin-induced asthma. which consist of serine proteases.153 Both these prostaglandins also potentiates the bronchoconstricting activity of histamine and methacholine. 166. It also releases tachykinins from airway sensory nerves. another mast cell product has a well-established role in the pathogenesis of asthma. and platelet aggregator. and increases cholinergic reflex.152 Prostaglandins PGD2 and PGF2. increases vascular and epithelial permeability.147-149 Histamine. Histamine induces bronchoconstriction.52 Bronchial Asthma Further. has vasodilator activity. It induces bronchospasm.163 It is an important mediator involved in the bronchial hyperresponsiveness in addition to having action of bronchoconstriction. activates C-fibre nerve endings. several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144. and chymase. and increased airway secretions and epithelial permeability.162. increases vascular permeability.151. PGE1 and PGE2 has bronchodilating effect.146 Mast Cell Proteases As much as 70% of the weight of a mast cell consists of proteases that are enzymatically active at neutral pH.A are very potent bronchoconstrictor agents. stimulation of eosinophil and eosinophil accumulation in the airway. smooth muscle contraction. vasodilator and prevents platelet aggregation. induction of airway microvascular leakage and oedema. tryptases.164 and the levels are found to be high in bronchoalveolar lavage fluid from these patients165 The substance causes bronchoconstriction. enhances neuropeptide release from sensory nerves. increases epithelial and vascular permeability. These enzymes regulate neuropeptide regulation in the airways. While Thromboxane A2 (TXA2) is a bronchoconstrictor. and increases the mucous glycoprotein secretion. and increases the secretion of mucus glycoproteins. vasoconstrictor.158-161 Recovery of this substance from bronchoaveolar lavage fluid in antigen exposed individuals supports such a role.156 On the other hand. PGI2 is a bronchodilator. and submucosal gland secretion. Bradykinin Bradykinin is another important inflammatory mediator in asthma and asthmatics have increased responsiveness to bradykinin. increases mucus secretion.150 Histamine The role of histamine in the pathogenesis of bronchial asthma is well established for a long time. the levels of histamine are increased in blood and bronchoalveolar lavage fluid.157 Platelet-activating Factor (PAF) PAF has attracted attention as an important mediator of bronchial asthma. These cells express a complex array of proteases.166 although the effects on airways are primarily mediated via BK2 receptors. .164.150 In patients of bronchial asthma. The former has greater bronchoconstrictor activity compared to that of the later or histamine.156.145 and improve respiratory function by bronchodilatation.167 Bradykinin mediates its effects through BK1 and BK2 receptors.155. IL-12 (inhibitors) Cytokines of eosinophil chemo-attraction and activation IL-2. IL-12R. IFN-γ. IL-4.3. PDGFR. The effects of cytokines are summarised in Table 3. TNFR-1(p55). IL-6R. IL-3R α-and β-chains. IL-11. IL-13 Cytokines involved in T cell chemo-attraction IL-16. IL-6R. gp130. FGFR Interferon receptor super family IFN-α/β receptor. and are mediated by binding to cell surface high-affinity receptors usually present in low numbers. IL-13. MCP-4 Th2 cytokines IL-4. TNFα/β Anti-inflammatory cytokines IL-10. having an effect on closely adjacent cells. which can be up regulated with cell activation. IL-6. They may also act at a distance (endocrine) and may have effects on the cell of origin (autocrine). They are produced by different cell types involved in cell-to-cell interactions. IL-4. FGF. TNF-α. IL-10. IL-13 (promoters). M-CSFR Protein kinase receptor super family PDGFR. Cytokines themselves may induce the expression of receptors which may change the responsiveness of both source and target cells. eotaxin. IL-3. soluble forms by alternative splicing (e.Pathophysiology of Bronchial Asthma 53 Cytokines Cytokines are extracellular signalling proteins. The receptors for many cytokines have been regrouped into super families based on the presence of common homology regions (Table 3. SCF Cytokine receptors Cytokine receptor super family IL-2Rβ-and γ-chains. Table 3. TNFR-II(p75) Seven-transmembrane G-protein coupled receptor super family Chemokine receptors The effects of an individual cytokine may be influenced by other cytokines released simultaneously from the same cell or from target cells following activation by the cytokine. MIP-1α/β Cytokines of neutrophil chemo-attraction and activation IL-8. IL-4R. EGFR. IL-1α/β.g. EGF. GM-CSFR. RANTES. IL-4R) Immunoglobulin super family IL-1R. resulting in an increase in its effects. RANTES. TNFα/β. Some cytokines may stimulate their own production in an autocrine manner. IFN-γ Cytokines involved in atopy IL-4. A classification according to function is proposed in Table 3. IL-12. GM-CSF. usually less than 80 kD in size and many are glycosylated.2: Classification of cytokines and cytokine receptors Cytokines Pro-inflammatory cytokines IL-1α/β. IL-1ra Growth factors PDGF. TGF-β. and therefore function in a predominantly paracrine fashion.168 . where as others stimulate the synthesis of difference cytokines that have a feedback stimulatory effect on the first cytokine. IL-5 α-and β-chains. IL-5. IFN-γ receptor and IL-10 receptor Never growth factor super family NGFR.2. IL-5. MCP-3.3). T cell and epithelial activation • BHR • Activation epithelium. antigen-presenting cells. monocytes/macrophages • BHR • ↑ IL-8 from epithelial cells • ↑ MMPs from macrophages • T cell growth factor • B cell growth factor • ↑ IgE • ↑ Activated T cells and IgE from B cells • ↑ Mast cell growth and differentiation • ↑ Mucin expression and goblet cells • Causes eosinophilic inflammation and BHR • B cell growth factor • Activates fibroblast • BHR • Eosinophil apoptosis and activation. endothelium. fibroblasts • ↑ adhesion to vascular endothelium... ↓ Th1 ↑ IgE ↑ Mucin expression and goblet cells eosinophil maturation ↓ Apoptosis ↓ Th2 cells BHR Activates eosinophils ↓ apoptosis ↑ IgE ↑ mucin expression and goblet cells As for IL-2 Growth and differentiation of T cells Eosinophil migration Growth factor and chemotaxis of T cells (CD4+) T cell proliferation Activates epithelia.54 Bronchial Asthma Table 3. cosinophil accumulation in vivo • Growth factor for Th2 cells • B cell growth factor. neutrophil chemo-attractant.3: Summary of effects of cytokines Cytokines Lymphokines IL-2 IL-3 IL-4 IL-5 IL-13 IL-15 IL-16 IL-17 Pro. endothelial cells. . induces release of leukotrienes Contd.inflammatory IL-1 TNF-α IL-6 IL-9 IL-11 GM-CSF Important cellular and mediator effects • • • • • • • • • • • • • • • • • • • • • • Eosinophilia in vivo Growth and differentiation of T cells Eosinophilia in vivo Pluripotent haematopoietic factor ↑ Eosinophil growth ↑ Th2. and sometimes neutrophils. ↑ mast cell growth ↓ BHR ↓ Th2 proliferation ↓ BHR ↓ Eosinophil influx after allergen ↓ Th2 cells Activates endothelial cell. monocytes ↓ IgE Fibroblast and airway smooth muscle proliferation Release of collagen ↓ T cell proliferation Blocks IL-2 effects Fibroblast proliferation Chemo-attractant for monocytes. endothelial cell migration • BHR • ↑ VCAM-1 on eosinophils • Growth factor for mast cells Inhibitory cytokines IL-10 • • • • IL-1ra • • IFN-g • • • • • IL-18 • • • • Growth factors PDGF • • TGF-β • • • • • ↓ Eosinophil survival ↓ Th1 and Th2 ↓ Monocyte/macrophage activation. such as histamine and cysteinyl-leukotrienes.3). from eosinophils and mast cells to induce bronchoconstriction. more myofibroblasts with an increase in collagen deposition in the lamina reticularis. mast cells ↓ Airway smooth muscle proliferation Inflammation and Cytokines in Asthma Asthmatic Inflammation The chronic airway inflammation of asthma is characterised by an infiltration of T lymphocytes. An acute or chronic inflammation may be observed with acute exacerbations. Cytokines SCF Important cellular and mediator effects • Proliferation and maturation of haematopoietic cells. such as an increase in the thickness of the airway smooth muscle with hypertrophy and hyperplasia. Cytokines play an integral role in the coordination and persistence of the inflammatory process in the chronic inflammation of the airways (Table 3. .. with an increase in eosinophils and neutrophils in the airway submucosa and release of mediators. airway oedema and mucus secretion..Pathophysiology of Bronchial Asthma 55 Contd. more vessels and an increase in goblet cell numbers in the airway epithelium. eosinophils. macrophages/monocytes and mast cells. epithelial cells. Changes in the resident cells are also observed. alveolar macrophages/monocytes ↓ IgE ↓ BHR ↓ Via IFN-γ release Releases IFN-γ from Th1 cells Activates NK cells. ↑ B cell. fibroblasts. It is predominantly produced by activated macrophages and synthesised with IL-12 to induce (IFN).182 Cytokines also play an important role in recruiting inflammatory cells to the airways. The primary signals that activate Th2 cells may be related to the presentation of a restricted panel of antigens in the presence of appropriate cytokines. Dendritic cells are ideally suited to being the primary contact between the immune system and external allergens. which may be released on exposure to inhaled allergens via FcεRI receptors. including GM-CSF. IL5. IL-4. migration and pathobiological effects of eosinophils may occur through the effects of GM-CSF. These cytokines. TNF-α and IL-6. 3.175 IL-1 is important in activating T lymphocytes and is an important co-stimulator of the expansion of Th2 cells after antigen presentation. This inherently low levels of IL18 may be associated with pathogenesis of asthmatic airway inflammation. which themselves may release multiple cytokines.172 IL-4 drives the differentiation of CD4+ Th precursors to Th2. in particular B7.56 Bronchial Asthma Th2-associated Cytokines CD4+ T lymphocytes of the asthmatic airways express Th2 cytokines including IL-3.176 Airway macrophages may be an important source of first-wave cytokines.171 IL-4 also increases the expression of an inducible form of the low-affinity receptor for IgE (FcεRII or CD23) on B lymphocytes and macrophages.169 With the expression of IL-4.γ synthesis from T lymphocytes. Bronchoalveolar mast cells from asthmatics show enhanced release of mediators such as histamine. but in asthma there is reduced suppression after exposure to allergen.174 Both GM-CSF and IFN-γ increase the ability of macrophages to present allergen and express HLA-DR. IL-8 and RANTES which then leads to influx of secondary cells.like cells. Mast cells also elaborate IL-4 and IL-5. IL-10. IL-5 and certain chemokines such as eotaxin. IL-13 and GM-CSF. The maturation and expansion of mast cells from bone marrow cells involve growth factors and cytokines such as SCF and IL-3 derived from structural cells.177. such as IL-1. IL-3. both on endothelial cells of the bronchial circulation and on airway epithelial cells. promoting differentiation of T cells to the Th1 subsets. IL-18 is a cytokine with potent interferon (IFN).173 Antigen presentation Cytokines may play an important role in antigen presentation (Fig.179 Mature eosinophils may show increase survival in bronchial tissue. The IL-18 levels are low in the BAL fluid of patients with bronchial asthma.180 Eosinophils themselves may also generate other cytokines such as IL-3.3).170 IgE produced in asthmatic airways binds to FcεRI receptors (high-affinity IgE receptors) on mast cells priming them for activation by antigen. synthesis of IgE by B lymphocytes on immunoglobulin isotype switching occurs. . Airway macrophages are usually poor at antigen presentation and suppress T cell proliferative responses (possible via release of cytokines such as IL-1 receptor antagonist). Eosinophil-associated cytokines The differentiation.178 IL-5 and eotaxin also induce the mobilisation of eosinophils and eosinophil precursors into the circulation. may then act on epithelial cells to release a second wave of cytokines.181 Cytokines such as IL-4 may also exert an important regulatory effect on the expression of adhesion molecules such as VCAM-1. IL-1 and TNF-α increase the expression of ICAM-1 in both vascular endothelium and airway epithelium. may lead to proliferation of Th2 cells.2/ CD28 interaction. such as eosinophils.γ-inducing activity. IL-5 and GM-CSF. Co-stimulatory molecules on the surface of antigen-presenting cells. 3: Cytokines and cell interaction in bronchial asthma Airway wall remodelling cytokines Proliferation of myofibroblasts and the hyperplasia of airway smooth muscle may occur through the action of several growth factors such as PDGF and TGF-β. They are produced by neutrophils. eosinophils. . such as TNF-α and FGF may also play an important role in angiogenesis of chronic asthma. Oxygen Radicals Oxygen radicals have been indirectly implicated in the development of hyperresponsiveness. but also by structural cells. Epithelial cells may release growth factors. The relative importance of these substances in bronchial asthma is poorly defined. such as airway epithelium. since collagen deposition occurs underneath the basement membrane of the airway epithelium. Cytokines. 3. such as macrophages and eosinophils.Pathophysiology of Bronchial Asthma 57 Fig. endothelial cells and fibroblasts. PDGF and EGF are potent stimulants of human airway smooth muscle proliferation184 and these effects are mediated via activation of tyrosine kinase and protein kinase C. These growth factors may stimulate fibrogenesis by recruiting and activating fibroblasts or transforming myofibroblasts. They may be released from inflammatory cells in the airways. and macrophages in the lungs.183 Growth factors may also stimulate the proliferation and growth of airway smooth muscle cells. Proteolytic enzymes . They may also influence the function of non-neuronal cell types. growth. OH– Proteolytic enzymes Basement membrane thickening O–2. epithelial cells.190 The role of different mediators is summarised in Table 3. proliferation. compared with normal subjects. and eosinophils. LTD4. accumulation. The cellular sources of neurotrophins include mast cells.) in their expired air. LTD4. H2O2. including immune cells.188 Taken together.189 Neurotrophins The neurotrophins are a family of peptides that promote survival. and differentiation of neurons. but the exact role that the neurotrophins play is unclear. Table 3. LTE4 Prostaglandin E Bradykinin Platelet activating factor Cellular infiltration Eosinophil chemotactic factor (airway hyperreactivity) Neutrophil chemotactic factor HETEs LTB4 Mucus secretion Histamine (H1response) LTC4. LTE4 Prostaglandins generating Factor of anaphylaxis Prostaglandins HETEs Acetylcholin Macrophage mucus secretagauge Desquamation O–2. LTE4 Prostaglandins and TXA2 Bradykinin Platelet activating factor Acetylcholin Mucosal oedema Histamine (H1response) LTC4. The development and maintenance of asthma are thought to involve nervous system and the immune system. NOS. and increased reactivity in the airways. lymphocytes. and activation of immune cells. These neuropeptides may be released from the central terminals of airway afferent neurons. The action of neurotrophin receptors like Trk (tyrosine kinase) acts possibly act in concert with known immune regulating factors to modulate the maturation.58 Bronchial Asthma Nitric Oxide Although it is now well established that normal subjects have measurable concentrations of nitric oxide (NO. in patients with bronchial asthma the peak or mixed expired NO are about 50% higher. LTD4. these findings have led to the speculation that expired concentrations of NO reflect the inflammatory microenvironment of the asthmatic airway wall.4: Role of mediators causing pathological changes in asthma Pathological changes Mediator implicated Bronchospasm Histamine (H1response) LTC4.4. smooth muscle cells. the airways of patients with asthma have up regulated expression of type II nitric oxide synthase.185-187 Furthermore. macrophages. which leads to increased autonomic reflex activity. Neurotrophins also can modulate afferent nerve function by stimulating the production of neuropeptides within airway afferent neurons. Once released these peptides act as either neurotransmitters. mucous secretion. The later innervate airway smooth muscle. Upon their discovery subsequently in brains. localised to. prostaglandins. neuropeptides were first termed “gut hormones”. and inflammatory cells. now it is established that these peptides are present throughout the body and may be produced by. Neuroendocrine cells are granulated epithelial cells found throughout the conducting airways. vascular tone. or mediators. and vascular permeability.198. They modulate airway caliber. prostaglandins. They are also capable of affecting inflammatory cell function by modulating mediator release and chemotactic responses. and bombesin. blood flow. Acetylcholin normally binds to the cholinergic receptor and causes release of cyclic 3'. Originally described in the gastrointestinal tract. Adrenergic .199 Neuropeptides are small amino acid components that are localised to neurons. It is suggested that M2 autoreceptors are dysfunctional in bronchial asthma. There are three types of pharmacologically defined muscarinic receptors. neuroendocrine cells.Pathophysiology of Bronchial Asthma 59 NEUROPEPTIDES IN ASTHMA There is increasing evidence that abnormal neurogenic mechanisms and neuropeptides contributing in the pathophysiology of bronchial asthma. they are located in neurons. They contain a number of peptides. and tachykinins enhance Acetylcholine release from the postganglionic nerves in the airways. The M2 receptor functions as an autoreceptor in airway tissue.201 The sympathetic nervous system in the bronchial tree is inhibitory because of its prominent airway relaxant effect. and cold air stimulate afferent receptors causing reflex bronchoconstriction. and the nonadrenergic noncholinergic (NANC) pathways. vascular permeability. hormones. The M1 receptor is located in the parasympathetic ganglia and facilitates vagal transmission. CGRP (calcitonin gene-related peptide). they were termed as “gut-brain hormones”. Neuropeptides such as VIP (vasoactive intestinal peptide) has been identified in various inflammatory cells including eosinophils. acting as a feedback-inhibitory receptor to reduce neurotransmission. mucus secretion. histamine. cells other than cells of the nervous system. In the respiratory tract. The neural control of the airways is mediated by three pathways: cholinergic (parasympathetic). Their wide spread distribution and different physiological effects make neuropeptides excellent candidates to play important roles in asthma. Acetylcholin is the cholinergic messenger.200 Neurotransmitters like TxA2. and migration and release of inflammatory cells. adrenergic (sympathetic). mast cells. This causes bronchoconstriction. Inflammatory mediators like histamine.191 The cholinergic nervous system is considered excitatory in nature because it plays an important role in maintaining bronchial smooth muscle tone and in mediating acute bronchospastic responses. The system consists of vagal afferent fibres in and around the airway lumen that travels to the central nervous system and then terminate in efferent fibres.5'-guanosine monophosphate (cyclicGMP). PGD2. The M3 receptors are present in large airways and in some peripheral airways and are largely responsible for smooth muscle contraction. and bradykinin stimulate irritant receptors and C-fibre endings in the airway leading to a reflex bronchoconstriction.191-197 Autonomic nerves regulate airways smooth muscle tone. katacalcin. Cholinergic nerves are the dominant neural bronchoconstrictor pathways for human lungs. However. Triggers like sulphur dioxide. which are important in regulating the smooth muscle tone. This is mediated by β-receptor stimulation and by cAMP. including calcitonin. and mononuclear and polymorphonuclear leucocytes. 3. Functional deficiencies of the system can result from blockade of nonadrenergic pathways at the level of ganglia or nerve endings. subjects with asthma have now been revealed to potentially have changes in their nonadrenergic inhibitory and noncholinergic excitatory nervous system. These changes will lead to an imbalance in the autonomic nervous system and predispose subjects with asthma towards bronchospasm (Fig. However. and thus the nerves are “peptidergic”. irritant gases. or from enhanced breakdown of neuropeptides by peptidases released from inflammatory cells in the asthmatic airway.203 They also decrease mucus secretion and manifest anti-inflammatory actions. Cigarette smoke. Although there is little or no direct sympathetic innervations of human airways. in addition to the proposed changes in the cholinergic and adrenergic nervous systems. The neurotransmitters for the NANC nervous system were initially thought to be purine nucleotides. and prostaglandins. and inflammatory cell function. there are reports that there are more substance P immunoreactive nerves in the lungs of patients with asthma compared to that in normal subjects. In addition. Deficiency of this system has been postulated to contribute to the development of bronchial hyperreactivity. only VIP. neuromodulin L) and calcitonin gene-related peptide (CGRP) are believed to be neurotransmitters of the noncholinergic excitatory system and thus act as endogenous bronchoconstrictors. and inhalation of industrial pollutant toluene diisocyanate inhibit NEP and exaggerate neurogenic inflammation.4). plasma extravasations. Earlier it was believed the imbalance between cGMP and cAMP production was the underlying mechanism of bronchial asthma. Angiotensin converting enzyme (ACE) also helps in the degradation of these neuropeptides. It has been demonstrated recently that there is a loss of VIP from pulmonary nerve fibres in asthmatics. neurokinin A (substance K. from deficiency of airway VIP or PHM receptors.202. Immunoreactive VIP is observed within nerves in more than 90% of lung sections from normal subjects but is not identified in any lung sections from patients with asthma. there are many αand β-adrenergic receptors that are important in regulating bronchomotor tone. a decrease in the normal degradation process of substance P occurs by NEP or ACE.60 Bronchial Asthma fibres represent only a minor component of the total nerve fibres in human airways. peptide histidine methionine (PHM). (Yin-Yang hypothesis). smooth muscle contraction. and nitric oxide may be the neurotransmitters of the nonadrenergic inhibitory nervous system and thus are important endogenous bronchodilators. pulmonary vasomotor tone. Thus neurogenic inflammatory responses are normally mild and probably protective in nature.210-215 An enzyme neutral endopeptidase (NEP) exists on the surfaces of all lung cells. . These neuropeptides have the remarkable ability to affect multiple cells in the airways and to provoke many responses including cough. including histamine. This series of effects is termed as “neurogenic inflammation”. bradykinin. Other peptides such as substance P. such as adenosine and adenosine triphosphate and accordingly the NANC nerves were termed “purinergic”. respiratory viral infections. it is not clear whether it is a primary or secondary event. mucus secretion. Although a number of neurotransmitters have been identified. It is proposed that in asthma. and neutrophil adhesion. mucosal permeability. A number of substances are known to release neuropeptides from these nerves include capsaicin (most potent). antigen. but peptides.204-209 These peptides also play a role in regulating mucus production. Therefore. The enzyme inactivates the neuropeptides limiting their concentration. and various inflammatory mediators. However. now it is believed that the neurotransmitters are not purines. 5-fold. LTC4. The airways of asthmatic subjects are 14-fold.112 Further.to 1000-fold when measured in terms of FEV1 but they were only 15fold differences in V30. Such stimuli actually induce an asthmatic state or heighten the vulnerability of asthmatics. and LTE4 respectively in a direct comparison of the potencies of these substances in six asthmatics and six controls. the bronchial epithelium. LTD4. cumulative data suggest that hyperresponsiveness to the leukotrienes may be more marked in the central rather than the peripheral airways of asthmatic subjects.Pathophysiology of Bronchial Asthma 61 Fig.216 Similarly Smith et al reported a 30% fall in V30 in response to LTD4 . methacholine.4: Autonomic imbalance postulated for bronchial asthma It is suggested that abnormal control of the airway is the underlying mechanism of bronchial hyperreactivity. Depending upon the inciting stimulus. the relative differences in potencies between asthmatic and controls were 100. Various components of the tracheobronchial tree might contribute to this phenomenon. Bisgard reported that the airways of 8 asthmatic subjects were more responsive to LTD4 than were those of 9 nonasthmatic controls. and 194-fold more responsive than were the airways of normal subjects to histamine. such as smooth muscle. 3. making them more prone to overt attacks in response to minor stimuli that would be ordinarily tolerated. Bronchial Hyperreactivity Airway hyperresponsiveness to a large number of stimuli is a characteristic feature of asthma in humans. The level of airway responsiveness usually correlates with the clinical severity of asthma and medication requirement. The degree of responsiveness can be further increased by a series of stimuli associated with inflammation in the periphery of the lung. various neurohumoral mechanisms and the mechanical linkage between the lung parenchyma and the airways including the baseline airflow obstruction. with a preponderance of excitatory (cholinergic and α-adrenergic) or a deficiency of inhibitory (α-adrenergic) control. different cells and mediators may be playing a role in producing and perpetuating the inflammatory state and producing further increases in responsiveness. 15-fold. 9-fold. which results in activation of adenyl cyclase and increases in intracellular cAMP. 34 and 164. which may be the basis of a more severe form of the disease or the basis of the heterogeneity of receptor expression and response to betaagonists observed clinically. submucosal glands. smooth muscle of bronchi and bronchioles. to a lesser extent dopamine) as agonists. Although a number of studies have addressed whether β2 AR are dysfunctional in asthma. four of which result in changes in amino acid residues 16.220 Some of the important molecular domains that have been found to be important for receptor function have also been identified. respectively. and lymphocytes. The β2 AR is expressed to some extent in virtually every tissue in the body. eosinophils. a 30% fall in V was accompanied by a 17% fall in FEV1 in asthmatic subjects and a 3% fall in FEV1 in normal controls.223 Bronchial or tracheal smooth muscle obtained at either autopsy or surgery from asthmatic patients show a deficit in β-adrenoceptor function. Administration of β2-adrenoceptor agonists increases airway tone and responsiveness in patients with asthma. β AR) and Asthma Beta-adrenergic Receptors (β β ARs belong to the family of adrenergic receptors that use the endogenous catecholamines epinephrine and norepinephrine (and. Recent genetic polymorphisms of the β2 AR have been identified in the population. immune cells including mast cells. Perhaps this occurs as a secondary phenomenon in asthma either because of the drugs used and thus acquired or there may be a receptor mutation or polymorphism. β3) and they couple to the stimulatory G-protein.221 It seems that beta-receptor dysfunction may not be the primary lesion in asthma.62 Bronchial Asthma was accompanied by a 60% fall in sGaw in asthmatic subjects but only a 30% fall in sGaw in normal controls.218 While FEV1 represents the central airway function. cells transferred with β2-adrenoceptor complimentary DNA containing the mutations at amino acid positions 27 or 164 showed altered β-adrenoceptor function. 27. alveolar walls. Gs. Nine different adrenergic receptor subtypes have been cloned. Studies on the distribution of Ban I polymorphisms in South African asthmatics showed the presence of both these alleles in this group.230 Moreover. but the genotypes were found with similar frequencies in . But when the same individuals inhaled LTE4. There are reports that β3AR also regulates bronchial smooth muscle tone in pharmacological in vivo studies. V30 represents small or peripheral airways function.217 In another study Davidson et al reported a 30% fall in V30 induced by inhaled histamine was accompanied by a 10 and 13% fall in FEV1 in asthmatic and normal subjects.224-227 A large number of polymorphisms or point mutations have been described in the human β2-adrenoceptor gene. macrophages. A restriction fragment length polymorphism (RFLP) of this gene has been reported using the restriction enzyme Ban I.228 Another biallelic polymorphism is reported using the restriction enzyme Fnu4HI.5. The interaction of various factors and the pathophysiology of bronchial asthma is summarised in Figure 3. there appears to be no consensus in this matter.222 Several lines of evidence suggest that the β2-adrenoceptor may be abnormal in asthma.219 There are three β AR subtypes (β1. this is present in epithelium. neutrophils. β2. β2 AR has been studied extensively and thought to have important therapeutic implications. making the β2-adrenoceptor gene an attractive candidate gene in this disease. In the lung. the endothelium and smooth muscle of pulmonary arteries. Szentivanyi proposed in 1968 that asthma may be due to an inherited or acquired deficit in β-adrenoceptor function.229 while subsequent investigations reported nine different point mutations within the coding region. Pathophysiology of Bronchial Asthma 63 Fig.231 Subsequent . Further studies on sequencing of the β2-adrenoceptor gene identified nine separate point mutations or polymorphisms.5: Interaction of various factors in the causation of asthma allergic and nonallergic subjects. but the findings were not sufficient to exclude genetic linkage to either methacholine responsiveness or allergy.230 Japanese investigation on family members of asthmatics found a higher prevalence of asthma in family members who lacked the 3. 3. but there was no significant difference in the frequency of alleles between the asthmatic and nonasthmatic patients.1 kb Ban I RFLP. features. elevated NO may result in elevated NO reaction products. However. NO is higher in the expired air of asthmatics. Two forms of NO is known. While the former is induced by TNF-alpha and beta. etc. In addition. Presentation of allergen peptides to the T cell usually occurs in local lymphoid tissue along with the essential engagement of co-stimulatory molecules (B7 and CD28) and results in the differentiation of the naive T cell to one that generates a range of cytokines which upregulate cells and antibodies involved in the allergic response. and leukotrienes.221 Nitric oxide is present in the expired air of healthy individuals. and eosinophil recruitment. indicated that these are not linked to a dominant β2-adrenoceptor gene with strong effect in families with an inherited pattern of asthma. mast cell activation. recent advances in the understanding of its pathophysiology indicate that it is a heterogenous disorder with multiple triggers. such as those that cause bronchoconstriction or inflammation. however. Thus its level should be reduced in bronchial asthma.235 and epithelial NOS is higher in the epithelial cells in them. iNOS (independent of Ca++) and cNOS (Ca++/calmodiulin-dependent.234 It is a known bronchial smooth muscle relaxant. called dendritic cells.236 This implies that NO may increase in asthma as a compensatory response to other factors. interferon gamma. endotoxins. and methacholine airway hyperresponsiveness.64 Bronchial Asthma studies also showed that distribution of these alleles was not different between asthmatics and nonasthmatics. at mucosal surfaces.232 although it was not possible to exclude an association. These processes are orchestrated by T lymphocytes.233 Nitric Oxide (NO) and Bronchial Asthma185-188 Nitric oxide is synthesised from L-arginine by the enzyme NO synthase (NOS). PAF. Thus. it is obvious that NO has the potential to affect a number of cells critical for normal lung function and NO possibly plays a key role in the pathogenesis of asthma and its inhibitors may be useful therapeutically to treat asthma. interleukin-1 and other cytokines. particularly peroxynitrite. fungi. In a more recent study to exclude genetic linkage between the β2-adrenoceptor gene and asthma. which are virtually common to all asthmatics. pollen. T lymphocytes receive an allergen-specific signal from highly specialised antigen presenting cells. stimulation of the later occurs through mediators like bradykinin. house dust mites.185. constitutive form). These include airways inflammation and hyperreactivity to a broad range of stimuli. elevated NO might exacerbate bronchial obstruction because NO relaxes vascular smooth muscle and thus. viral infection. by the dendritic cells . histamine. Further. The chronic allergic response is a continuous process of IgE generation. it is not clear whether elevated NO is part of the primary pathologic process in asthma or is a compensatory response.6. such as superoxides. allergy. which may cause airway damage if excess. There are. In atopic individuals. CD4+ lymphocytes of the Th2-type are activated and clonally expand after capture and processing of inhaled allergens like cigarette smoke.237 Although the terms “intrinsic” and “extrinsic” no longer adequately reflect our knowledge of the clinical syndrome of asthma. acetylcholine. SUMMARY OF EVENTS LEADING TO AIRWAYS INFLAMMATION The pathogenesis of bronchial asthma is more clearly understood in extrinsic or allergic asthma and is summarised in Figure 3. But on the contrary. vascular engorgement which is an important pathogenetic mechanism. A number of Th2-derived cytokines are involved in mast cell. and eosinophil recruitment and maturation. basophil. 3. The genes for these cytokines are encoded in a small region on the long arm of chromosome 5 and a number of them (IL-4.238 A number of cytokines are then released.237.Pathophysiology of Bronchial Asthma 65 Fig.6: Pathogenesis of bronchial asthma which migrate to the regional lymph nodes and present allergens. to lymphocytes. together with major histocompatibility antigen II. Th1 lymphocytes are involved in cell-mediated immunity. IL-4 and IL-3 play a particularly important role in this arm of the immune process by interacting with B lymphocytes. and GMCSF) are coordinately regulated. While Th2 lymphocytes produce these cytokines. IL-5. they change the immunoglobulin isotope being secreted from the shortterm protective antibody IgM to the allergic antibody IgE. As with dendritic T cell interactions. effective signalling to β cells requires an interaction with the Th2 cell and . The wall is also thickened and obstructed due to the engorgement of the bronchial blood vessels. a beta chain. Antigen-specific IgE binds to effector cells via specific IgE receptors. Allergen specific IgE binds to IgE receptors on several inflammatory cell types such as eosinophils. antigens. CD40L). The relationship between airway inflammation and the development of airway hyperresponsiveness and clinical asthma has been well established during the last decade. High affinity IgE receptors are an important link between the presence of specific antigen in the microenvironment and activation of mast cells and other cells. and macrophages. allergen-specific IgE is generated. it is thought that the gamma chains are the units that initiates intracellular signal transduction. which accentuates airways’ inflammation including the release of 5-lipooxygenase products and proteases. when antigen binds an adequate number of these receptors to initiate receptor clustering. The presence of intraluminal fluids including mucosubstances further obstruct airways and could make it more difficult for individuals to clear secretions from their airways. Although smooth muscle constriction can lead to airways obstruction. signal transduction occurs. only non-specific IgE is generated. The second component of the gene involves the genes responsible for cytokine response.66 Bronchial Asthma involves antigen presentation and engagement of a second set of co-stimulatory molecules (CD40 and its ligand. The importance of airway wall remodelling with thickening of the airway wall due to infiltration with inflammatory cells and alteration in the amount and type of collagen deposited in the airway is reflected in the enhanced degree of obstruction that is observed for a given level of smooth muscle activation in the remodelled wall. While the alpha chain binds IgE. IL-4 or IL-13. and two gamma chains. some chemicals. A strong genetic component plays important role in the form of an ability of a susceptible individual to recognise an environmental allergen as foreign and mounts an allergic immune response through the human lymphocyte antigen (HLA or MHC class II) molecules. Exposure to oxidant pollutants. IL-4 produced by Th2 lymphocytes ‘fuels’ the inflammatory reactions in the airways and leads to production of further Th2 lymphocytes and to differentiation and maturation of IgE producing B lymphocytes. mast cells. and viral respiratory tract infections are all associated with inflammatory cell infiltration into the airway and these inflammatory stimuli are also associated with the development of airway hyperresponsiveness. Thus IgE has the important role of linking allergen recognition to cell signalling in a variety of cells. however. but cell-cell contact does not occur. If IL-4 or IL-3 is present. the specific mechanisms of transduction are not established. it is now understood that nonmuscular airway obstruction is not less important. Most studies have shown that airway inflammation precedes the development of hyperresponsiveness . and co-stimulatory molecules. which release a range of active mediators. Neutral endopeptidase (NEP) is a major enzyme of importance in limiting the biologic activity of small peptide mediators such as substance P or neurokinin A. The beta-adrenergic receptor and nitric oxide represent two effector mechanisms that are important in modifying the biology of an asthmatic response. Such engorgement could account for a significant component of asthmatic airway narrowing under certain circumstances. If T and B cell interact in the presence of antigen. The inflammatory cells then release various inflammatory mediators outlined above. Mast cell proteases are also important players in the inflammatory process. Leukotrienes along with other products cause bronchoconstriction and other changes characteristic of bronchial asthma. The molecular nature of the IgE receptor has now been clearly defined.221 it is composed of four chains: an alpha chain. nasal congestion.247 in nasal lavage. These Fig.239 a different type of observation has been noted in children with wheezing in their bronchoalveolar lavage fluid. While the pathogenesis of occupational asthma. Aspirin Induced Asthma Patients with bronchial asthma and sensitivity to aspirin (ASA) and other nonsteroidal antiinflammatory drugs are often corticosteroid-dependent and have the accompanying symptoms of rhinosinusitis.240-244 In contrast. Eosinophilia and elevated IgE levels have also been found in infants who subsequently develop asthma.7: Interaction of various factors . Although. BAL eosinophilia is a common finding in adults with asthma. loss of taste.245 Upon challenge with aspirin or other cyclooxygenase inhibitors these patients have increased cysteinyl leukotriene release as detected in urine.Pathophysiology of Bronchial Asthma 67 and may be the prerequisite feature necessary for the development of both hyperresponsiveness and clinical bronchospasm.246. approximately one-half of the children with wheezing in infancy and young childhood will no longer be wheezing at 6 years of age. It is possible that neutrophil-induced inflammation is important in the early stages of wheezing in infants. intrinsic asthma and other forms of asthma is less clearly understood.8. anosmia. these conditions are thought to involve a cytokine “cascade” similar to that involved in extrinsic or allergic asthma. Increased numbers of cells and increased neutrophils in BAL samples have been reported in children having wheezing. bronchial hyperreactivity and airway obstruction in asthma is shown in Figure 3.237 The mechanisms of allergy in causing episodic and chronic asthma are shown in Figure 3. The relationship between airway inflammation. and recurrent severe nasal polyposis.248. rhinorrhoea.249 and in bronchial lavage fluids.7. It is also possible that this neutrophil response may be a response to an unrecognised infection.250 in contrast to aspirin-tolerant subjects. 3. Further. 3. Ag-.140 The role of leukotrienes in the pathogenesis of aspirin-induced asthma comes from the fact that airway . the overproduction occurs with an antigen-antibody reaction. in aspirin-induced asthma. While in the former. the percentage of cells that immunostained for lipooxygenase and that are identified as eosinophils and mast cells are significantly increased in aspirin-sensitive patients. this drug increases FEV1 that falls during such provocation.112 The recent development and usefulness of leukotriene receptor antagonists and synthesis inhibitors in bronchial asthma including that of aspirin-induced asthma further emphasizes the role of these leukotrienes in the pathogenesis of this condition. although the mechanisms of such overproduction are different. Leukotrienes participate in the pathogenesis of bronchial asthma besides the involvement eosinophilic airway inflammation. and leukotriene modifiers modulate antigen-induced asthma. The mechanism of AIA is due to the inhibition of cyclooxygenase and bronchospasm is because of an increased generation of spasmogenic leukotrienes via lipooxygenase pathway. (TH-:T-lymphocyte. Majority of these subjects can be desensitised by the administration of aspirin orally. which may lead to an improvement in the severity of asthma and of rhinitis. MC-.139 Overproduction of leukotrienes not only occurs in house dust mite provoked asthma.68 Bronchial Asthma Fig.251 Furthermore. but also in aspirin induced bronchial asthma. An additional hypothesis for the mechanism of aspirin sensitivity suggests that there is increased target organ sensitivity to leukotrienes. the overproduction is due to a shift to the 5-lipooxygenase series of the arachidonate cascade. In patients with AIA. ingestion of aspirin is followed within 1 to 2 hours by the onset of bronchospasm.8: Mechanisms of episodic and chronic asthma.135-138 Leukotrienes are important in asthma. which may be accompanied by rhinitis and/or urticaria. inflammatory cell population in bronchial biopsies from aspirin-sensitive asthmatic patients demonstrates significantly greater numbers of mast cells and eosinophils per square millimetre of tissue than do similar biopsies from asthmatic subjects without aspirin sensitivity. Mast cell .140 Pranleukast a leukotriene inhibitor suppresses the increased values of sputum eosinophil count and eosinophil cationic protein during house dust mite-induced asthma are suppressed by further. Antigen) observations conclude that cysteinyl leukotrienes are involved in aspirin-induced asthma (AIA). This may occur by amplification of the response to cigarette smoke. It is also possible that patients with EIA may have hyperplastic capillary bed that develop exaggerated hyperaemia and airway oedema leading on to bronchial obstruction.146 Virus-induced Asthma Viral infections have been considered to play a significant role in the development and consolidation of obstructive airway disease. γ-interferon can augment basophil mediator release.252 enhanced sensitisation to inhaled allergens due to increased permeability and recruitment of dendritic cells.Pathophysiology of Bronchial Asthma 69 narrowing and other signs in these patients are associated with 2-10 fold higher values of LTE4 in the urine of these patients compared to aspirin tolerant patients. i. but in few this EAR will be followed by a LAR several hours after the initial response subsides.145 and improve respiratory function by bronchodilatation. Thus.256.264 Further. like γ -interferon.257 Enhanced airway responsiveness and the late allergic reaction persist for weeks beyond the viral infection. the event precipitates bronchoconstriction. Obstruction to airflow begins soon after cessation of exercise and peaks in 5-10 minutes. The EIA is a consequence of thermodynamic events that occur within the tracheobronchial tree during or after hyperventilation that is associated with exercise. . lymphocyte activation by virus may provide a very different cytokine profile and in this manner selectively enhances inflammation. The other mechanism of EIA may be as a result of water loss from mucosal surface and resulting increase in osmolarity of the fluid interface of the mucosal surface in the airways.260. The magnitude of bronchospasm is directly proportional to the heat loss from the respiratory tract required to bring the inspired air to alveolar conditions.261 Two major hypotheses have been put forward to explain the mechanism whereby water and heat loss by hyperventilation with exercise causes airway narrowing.262 ii. induction of steroid resistance. Lymphocytes are activated during incubation with rhinovirus and secrete cytokines.253 or reactivation of latent but persistent virus due to insufficient T-helper-1-type immune response and/or administration of corticosteroids.262 Because of this hyperventilation during exercise. during re-warming of the airways by reactive hyperaemia of the bronchial circulation with subsequent airway oedema of the bronchial wall during the post-exercise period. Thus. there is a fall in the airway temperature and respiratory water loss.259 Most patients will recover completely in the next 30-60 minutes.e.142-144 Further.263 Mouth breathing to meet increased demand of oxygen further aggravates this factor because air bypasses the nasal air-conditioning mechanism.258 Exercise-induced Asthma (EIA) Exercise-induced asthma is a temporary increase in the airway resistance following vigorous physical activity.255 Rhinovirus increases airway responsiveness and also promotes the likelihood of a late allergic reaction to allergen.71.254 Viral respiratory infections increase symptoms of bronchial asthma in many patients. evaporation causes cooling. i. several leukotriene modifiers inhibit the asthma response in oral or inhaled bronchoprovocation by aspirin and other non-steroidal anti-inflammatory agents144. it does affect eosinophil function.265 Oedema due to hyperaemia of microcirculation may be the cause of bronchial obstruction developing after exercise. including promotion of survival. Furthermore. Although γ-interferon does not have any proinflammatory activity like those of Il-4 and 5. that co-relates with the severity of exercise-induced bronchoconstriction in asthmatics.269-273 During exercise.276. a potent bronchoconstrictor. a phenomenon that is supported by comparative studies of diverse sporting activities. but also airway oedema.278. Exerciseinduced bronchospasm is. a feature of 70-80% of asthmatics. This conclusion is arrived from observations made in antileukotriene drug studies in EIA. An isolated late asthma reaction occurs 4-6 hours after the challenge. to a larger extent. due to bronchial microvascular phenomena such as vascular engorgement and plasma leakage that could thicken the mucosa and thereby narrow airway diameters. eucapnic voluntary hyperventilation manoeuvres designed to simulate exerciseinduced bronchoconstriction in the laboratory. Various reports give conflicting results concerning the role of inflammation in EIA. some believe that EIA. Assessment of albumin flux in airway lining fluid stimulated by hypertonic saline solution is a sensitive predictor of the severity of this phenomenon.281-284 It is also demonstrated that the release of histamine.267 Recently another hypothesis suggests that increased excessive production of nitric oxide during exercise289.274.267 Exercise-induced bronchoconstriction. it is possible that both of these hypotheses are related to the airway narrowing following exercise in asthmatics.279 Similarly antileukotrienes are helpful in cold air-induced bronchial asthma280 highlighting the role of cold air in causing EIA.293 An early reaction occurs within a few minutes after an inhalation challenge. (ii) isolated late. reaches maximal intensity within 8-10 hours.70 Bronchial Asthma which may lead to mast cell and basophil degranulation and precipitating EIA. (iii) biphasic.292 Specific inhalation challenge tests may induce any of the five types of reactions: (i) isolated early. at least in part. such as histamine and leukotrienes.286-288 These findings underline the bronchoconstrictor potential of airway dehydration. It is also been recommended swimming as the exercise least troublesome to asthmatic patients because of the humidity of the inspired air. Presence of thermally sensitive neural receptors in the airways of patients susceptible to EIA may be responsible for bronchoconstriction in response to cold air.291 Occupational Asthma Bronchial hyperreactivity is a characteristic feature of occupational asthma. and ends within 60-90 minutes.275 Since mast cell-derived mediators. or (v) atypical asthmatic reactions.266. reaches maximal intensity within 30 minutes.277 However. and airway dehydration occurs with subsequent exercise-induced bronchoconstriction.285 from mast cells and other airway cells under hyperosmolar conditions. Leukotrienes seem to play a particularly important role in this response. may cause not only airway smooth-muscle contraction. is mediated through the release of bronchoconstrictor substances from inflammatory cells in the airway wall. including cysteinyl-leukotrienes. and thus the respiratory tract needs to condition much larger volumes of air over a much shorter time during exercise compared with rest.290 increases airway vascular permeability.268 is triggered by drying of the bronchial epithelium due to airway water loss from the tracheobronchial tree. Further. The findings that269 inhaling fully humidified air at body conditions could prevent exercise-induced bronchoconstriction demonstrated the importance of water loss from the airway. and ends after . which could in turn amplify the effects of airway smooth muscle contraction. the ventilation rate increases. and other pro-inflammatory bronchoconstrictor mediators. demonstrate that airway fluid-loss has a similar bronchoconstrictor effect to histamine. (iv) continuous. subepithelial fibrosis. Some low-molecular-weight molecules (<5000 daltons) like acid anhydrides and platinum salts act as haptens and induce specific IgE antibodies by combining with a body protein. glycoproteins and polysaccharides are usually complete antigens. Atypical reactions usually start 2 hours after a challenge and last for a few hours. immunoglobulins of the IgG class. for many low-molecular-weight molecules. such as isocyanates. Both preformed and newly formed inflammatory mediators are released. oedema. This form of asthma is associated with the workplace. . IgE-dependent agents induce isolated early reactions or biphasic reactions.299-301 An increase in the activated eosinophils and T lymphocytes has been found in the mucosa and sub-mucosa. so that continued low-level exposure to the causative agent can be tolerated without problem. Bronchial biopsy studies in these individuals have shown bronchial epithelial cell injury with desquamation. but most often the condition improves. In a continuous type of asthma reaction there will be no remission between the early and late reactions. hypertrophy of smooth muscle.302 Animal models for pathogenic and immunologic mechanisms of bronchial asthma have also confirmed these observations. and IgE-independent agents will induce isolated late. neuropeptide release.298 Pathologic airway changes are similar to those in patients with other forms asthma. biphasic or atypical asthma reactions. and bronchial wall inflammation. but not eosinophils. but may be the markers of exposure . (i) reflex vagal bronchoconstriction in response to an irritant-effect on specific receptors. and they orchestrate the inflammatory events already outlined above. and mast cells increase in the epithelium.Pathophysiology of Bronchial Asthma 71 24-48 hours. with infiltration of plasma cells and lymphocytes. (iv) or immunologic mechanism leading to allergic tissue injury.306307 The diagnosis is made by the presence of non-specific responsiveness and a compatible history. The prognosis varies. in which wheezing illness starts within 24 hours or less of a single large exposure to an irritant. perturbation of cell membrane releasing arachidonic acid products). and exudation of fluid and mucus. specific IgE antibodies have not been identified or are found only in a small proportion of cases. The specific reaction between antigen and IgE gives rise to a cascade of events that is responsible for the activation of inflammatory cells.295 Most high-molecular-weight compounds (5000 or more daltons) induce asthma by producing specific IgE antibodies. The condition is inflammatory. (ii) inflammatory bronchoconstriction secondary to toxic concentrations of gases (nonspecific complement activation. mostly eosinophils. but does not involve immunological recognition of the irritant. A biphasic reaction is an early reaction with spontaneous recovery followed by a late asthma reaction. may be involved in immediate-type reaction. Occupational asthma induced by IgE-dependent agents is similar to allergic asthma.297 In addition to IgE-mediated reactions.303 Some other mechanisms that are responsible for occupational asthma are as follows. Some of them include accumulation of inflammatory cells.304 Irritant induced occupational asthma (Reactive airways dysfunction syndrome. However. (iii) a direct pharmacological reactions by agents like organic insecticides with anticholinergic activity (parasympathetic agonists) and beta-adrenergic blocking agents. which develops after acute inhalation of a respiratory irritant in toxic concentrations. possibly IgG4. T lymphocytes may be directly involved in the inflammatory process.297. RADS) is persistent asthma and airway hyperresponsiveness.305 The onset of respiratory symptoms and the presence of airway hyperresponsiveness within a few hours of exposure to an identifiable irritant distinguish this entity from hypersensitivity induced occupational asthma.296 Presence of these antibodies does not necessarily mean the cause of the disease. These molecules such as proteins.294 Generally. Elevated bronchoalveolar lavage fluid histamine levels in allergic asthmatics are associated with methacholine bronchial hyperresponsiveness. Madison JM. and beclomethasone dipropionate on allergen-induced early asthmatic response. Seminar Respir Med 1991. Inflammatory mediators in asthma. Finnerty JP. Comparative effects of inhaled salbutamol. 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Expired nitric oxide (NO) concentrations are elevated in patients with reactive airway disease.143: 1025-29. Am J Respir Crit Care Med 1999. 232. 242. Nucleic Acids Res 1988. Berretinni WH. Emala CW. Le Bourgeots M. Hirshman CA et al. Sladek K. Am J Respir Crit Care Med 2001.132:312-18. Thorax 1995.89(Suppl 2):A317. 245. Holt PG. Urinary leukotriene E4 concentrations increase after aspirin challenge in aspirin-sensitive asthmatic subjects.147:A515. Wei Chu H et al. XV International Congress of Allergology and Clinical Immunology (abstract). Hizawa M. Stamler JS. Am J Respir Cell Biol 1993. Ohe M. Endogenous nitric oxide is present in the exhaled air of rabbits. Am Rev Respir Dis 1990.1:87-92. Bai TR. Fitzgerald GA.121:722-31. Gustafsson LE.50:353-59. Westcott JY. Munakata M. Ann Intern Med 1968. A biallelic DNA polymorphism of the human β2-adrenergic receptor detected by Ban I-Adrbr-2. jouen-Boedes F. Asthma. Am Rev Respir Dis 1993. Krawiee ME. Persson MG. Persistent wheezing in very young children is associated with lowered respiratory inflammation. 243. Drazen J. 5 years old with severe recurrent wheezing. Gaston B. Martinez FD. 226. 246. 134:57-61. 234. Abnormalities in airway smooth muscle in fatal asthma.181:852-57. Chest 2002. Ohe M. Dean TP et al. 308:1502-05. McFadden ER Jr.Pathophysiology of Bronchial Asthma 83 248. McFadden ER Jr. Gypear D.59:106-12. 249. Spiegelberg ML. Christie PE. 269. Lemanske RF. J Clin Invest 1989. Anderson SD. 260. 261. Bronchial challenge by exercise or hypertension. prostaglandins and histamine into nasal secretions of aspirin-sensitive asthmatics during reaction to aspirin. Swenson CA. Philadelphia. Exercise-induced asthma. Eur Respir J 2002. Respiration 1977. Gilbert IA.58:564-70. 256. Jr. Silverman M. Sousa AR.144:1267-73. Godfrey S.149:940-46. et al. Godfrey S et al. Stevenson AD. Exercise-induced late asthmatic reaction with neutrophil chemotactic activity. Role of latent viral infections in chronic obstructive pulmonary disease and asthma. Soja J. 252. Eur Respir J 2002. Huftel MA. 1988. Howland WC. Chen WY. Dworksi R. Pichurko B. 250. Dick EA. Lancet 1990. 262. Am Rev Respir Dis 1988. et al. Exercise-induced asthma – a review. Futura Publishing Co. Busse WW. Am J Respir Crit Care Med 1996. Swenson CA. background and methodology. The effect of T cell depletion on enhanced basophil histamine release after in vitro incubation with live influenza A virus.13:745-68. Borcherding WR et al. 268. Folco GC et al. Eicosanids in bronchoalveolar lavage fluid of aspirin-tolerant patients with asthma after aspirin challenge. 267.76:763-72. 258. Horton DJ. et al. . Issues in exercise-induced asthma. Experimental rhinovirus-16 infection potentiates histamine release after antigen bronchoprovocation in allergic subjects. 253. 365-94. 255. Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions. Sladek K. J Allergy Clint Immune 1985. In: spector Sl. Heat and water loss from the airways and exercise-induced asthma. 251. 265. Papageoriou N et al. McFadden ER. Heat and water flux in the intrathoracic airways and exercise-induced asthma. Lee TH. Hypothesis: exercise-induced asthma as a vascular phenomenon.335:880-82. Am Rev Respir Dis 1991.597-606. 254. Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae.153:90-96.. 264.7:434-40. Perlmanlman DS.9:199-201. Br J Dis Chest 1975. Belcher NG. ven HL. Study of mediators of anaphylaxis in nasal wash fluids after aspirin and sodium meta-bisulphite nasal provocation in intolerant rhinitic patients.73:660-65.83: 1-10. 1989.69:1-39.19:341-49. Fontana A. NER Allergy Proc 1988. Respiratory viral infections as promoters of allergic sensitisation and asthma in animal models. Am J Respir Crit Care Med 2001. Anderson SD. Mirone C. Nagacura T. Gelfand EW. 257. Calhoune WJ.34:305-13. Arm JP et al. Vrtis TF. Immunol Allergy Clin North Am 1993. Busse WW. WB Saunders Co.137:847-54. Ed: provocative challenge procedures. Thermal mapping of the airways in humans.. Am J Respir Cell Mol Biol 1992. Hogg JC. Release of leukotrienes. J Appl Physiol 1985. Ann Allergy 1987. Bowman HF et al. Nasser SMS. O’Hickey S. Role of virus infection in asthma. Schwarze J. Anderson SD. Am J Respir Crit Care Med 1994. 259.164:S71-S75. Inflammatory cell populations in bronchial biopsies from aspirin sensitive asthmatic subjects. Is there a unifying hypothesis for exercise induced asthma? J Allergy Clint Immune 1984. J Appl Physiol 1987. 266. N Engl J Med 1983.631:681-91. Pathogenic mechanisms of exercise-induced asthma and the refractory period. Swenson CA. New York. Pfister R. Ferreri NR.19:546-56. Dick EC. Godfrey S. Ortolani C. Fouke JM. In: Bierman CW. Ed: Allergic Disease from infancy to adulthood. 263. Asai K. Simplified eucapnic voluntary hyperventilation challenge. Deviskas E. 288. Ingram RH Jr et al. Gilbert IA. Silber G. 280. Eggleston PA. Anderson SD. Influence of heat and humidity on the airway obstruction induced by exercise in asthma. Barnes PJ. Effect of the inhaled LTD4 receptor antagonist. Airway dehydration: A therapeutic target in asthma? Chest 2002. J Allergy Clin Immunol 1994. 289. Anderson SD. Allergy Proc 1989. MK-0476. Heimer D. 279. Scharf SM.61:433-40. Kanazawa H. Rajagopal KR et al. Follet R et al. Rosenthal RR. Hutcheroft BJ.147:1419-24. Chan-Yeung M.26:117-21. Inbar O. McFadden ER. 294. Update on exercise-induced asthma. Perrin B.219 against exercise-induced asthma. Glass M. McFadden ER Jr. Sensitivity to heat and water loss at rest and during exercise in asthmatic patients. 290. Bronchial challenge with room temperature isocapnic hyperventilation: a comparison with histamine challenge. Hogan T et al.48:1034-43. Eliasson AH. Binks SM. Am Rev Respir Dis 1993. Bronsky E.10:215-16. 277. 281.71:571-77. J Allergy Clin Immunol 1984. Thorax 1993. Strauss RH. Belvisi MG. J Allergy Clin Immunol 1991. 282. Am J Respir Crit Care Med 1995. 293. Hendeles L et al. J Asthma 1989.73:676-79. 278. Chest 2002. Bronchial provocation tests in etiologic diagnosis and analysis of asthma.. Israel E.330:1362-67. The effects of swimming on asthmatic children. Strauss RH. Yoshikawa J. Vascular involvement in exercise-induced airway narrowing in patients with bronchial asthma.122:166-70. 275. Exercise-induced asthma: a difference in opinion regarding the stimulus. Holgate ST. Chest 1992.219. Sports Med 1992. Reiss TF. Walters M. In vivo release of inflammatory mediators by hyperosmolar solutions.137:606-12.. Am Rev Respir Dis 1993. Peppys J. a potent leukotriene (LT)D4 antagonist.135:1043-48.106:1081-87. Cartier A.63:459-71. Veiga R. J Clin Invest 1978.84 Bronchial Asthma 270. Exercise-induced asthma. Sensitivity and specificity of bronchial provocation testing: an evaluation of 4 techniques in exercise-induced bronchospasm.147:1413-18. 292. Reassessment of the temporal patterns of bronchial obstruction after exposure to occupational sensitizing agents.297:743-47. Am Rev Respir Dis 1987. Hirata K.14:397405. Huang SW. Rayburn DB et al. Lichtenstein LM. . Deal EC Jr. Chest 1985.88:586-93. Ingram RH Jr et al. Phillips YY. McFadden ER Jr. Enhancement of exercise-induced asthma by cold air. Warner J et al. J Allergy Clin Immunol 2000. J Allergy Clin Immunol 1979. Bar-Or O.(abstract). inhibits exercise-induced bronchoconstriction in asthmatics at the end of a once daily dosing schedule (abstract). Eur J Respir Dis 1982. Spector SL. Proud D. Ghezzo H et al. Kagey-Sobotka A. Snadder LA. 274.112:829-59. Yoshikawa J. 291. Thomson HW. Wong R. Makkar HK. J Appl Physiol 1979. on cold-air-induced bronchoconstriction in patients with asthma. Am Rev Respir Dis 1988. Kanazawa H.121:1806-11. Schoefield RE. ICI-204. 287. N Engl J Med 1994.63:28-34. Sila U et al. Nonspecific bronchial reactivity in occupational asthma. 276.102:347-55.87:630-39. Phillips YY. 272. Am Rev Respir Dis 1975. Smith CM.46:476-83. A comparison of the osmotic activation of basophils and human lung mast cells. 283. Ann Allergy 1993. 284. Ingram RH Jr et al.151:A377. participants in a swimming program in the city of Baltimore.93:295A. The protective effect of inhaled leukotriene D4 receptor antagonist ICi 204. 286. Water loss without heat flux in exercise-induced bronchospasm. 285. O’Sullivan S. Argyros GJ. 273. Nitric oxide and lung disease. McFadden ER Jr. Hirata K.. 271. New Engl J Med 1977. Lau LC. Hyperapnea and heat flux: initial reaction sequence in exercise-induced asthma. Lam S. Swimming and asthma: Benefits and deleterious effects. Moloney E. Role of endogenous nitric oxide in exercise-induced airway narrowing in patients with bronchial asthma. Chan-Yeung M. Chan H. Soto-Aguilar MC. Thorax 1996. Chest 1985. Ed.27:155-63.85 (Suppl 1B):2.145:160-68. Martin RJ. Martin RJ. Deaths from asthma in Victoria. Frew AJ. A 12-months survey. In: Lemmer B. Seminars Respir Med 1991. Dollery C.6:136-47.4:523S. Corrigan CJ. Ballard RD.1:808-11. Eur Respir J 1994. Occupational asthma due to isocyanate.Pathophysiology of Bronchial Asthma 85 295. Circadian basis of the late asthmatic response. Robertson CF. Asthma: A nocturnal disease. Occupational asthma. Taylor AJN. The role of cellular immunology in asthma. Gautrin D.45:94-96. 304. J Allergy Clin Immunol 1992.81. 312. 310. Med J Austr 1990.. Boschetto P. Phillips D. Proceedings of a symposium. 301. Weiss MA. Mohiuddin AA. van Aalderen WMC. Asthma: Analysis of sudden deaths and ventilatory arrests in hospital. Oosterhoff Y. Am Rev Respir Dis 1992. histamine and cortisol. Malo JL. Smith HR et al. Cicutto LC. Cellular and protein changes in bronchial lavage fluid after late asthmatic reaction in patients with red cedar asthma. Branthwaite MA. 320. Barnes P. Cicutoo LC. Kusaka Y. 308. Postgrad Med J 1991. Clin Pharmacol 1996.13:105s-112s. Maestrelli P et al. behera D: Pattern of airflow obstruction in Bronchial Asthma—An observation on Home-Monitoring of Peak Expiratory Flow Rate. Shah A. Is reactive airway dysfunction syndrome a variant of occupational asthma? J Allergy Clin Immunol 1994.67(Suppl 4):S20. Animal models of occupational asthma. Huller H. Am Rev Respir Dis 1990. Lam S. 316. Chan-Yeung M. Shirakawa Y. Chest 1982. Martin RJ. N Engl J Med 1980. Nocturnal asthma: Mechanisms and the role of theophylline in treatment. Fabbri LM.1:273-79. Boulat M et al. 297. Chai H. Bronchial asthma and sleep disturbances. 296. Bowes G.152:511-17. Chen WY. Fitzgerald G.80:44-50.143:351-57. Saetta M. Airway cooling and nocturnal asthma.303:263-67. Frew AJ.51:541-45. Activated T lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma. Persistent asthma syndrome after high level irritant exposure. J Ass Phy India 1997. Eur Respir J 1991. 305. Maestrelli P. 302. Weersink EJM. Karol MH. Lam S. Maestrelli P. Chan-Yeung M. Ind J Chest Dis All Sc 1997. J Allergy Clin Immunol 1993. Boulat LP. Steinijsnd VW. LeRiche J. 318. 315.89:821-29. 306.85:6-8. Morrimoto K. 311.675-800. Airways inflammation in nocturnal asthma. 317. Gerritsen J. Am Rev Respir Dis 1990.142:1153-57.141:33-38. Nocturnal dyspnoea: Prevalence in asthmatic children. Postma DS. Meijer GG. Eur Respir J 1988. 298. Br Med J 1977. Lymphocyte transformation with cobalt in hard metal asthma. Clark TJH. 303. 300. Staudinger HW. Am J Med 1988. 309. Bentley AM. Nakano Y. Reactive airways dysfunction syndrome (RADS). Respiratory irritants encountered at work. Bush RK.92:466-78.7:555-68. 307. Eur Respir J 1991. Mapp CE.333-107-12. Airway mucosal inflammation in occupational asthma induced by toluene diisocyanate. .93:12-22. J allergy Clin Immunol 1987. Ind Health 1989. Brooks SM. 319. Brown M. Turner-Warwick M. Di Stefano A.12:185-95. Factors related to the nocturnal worsening of asthma. 314. Kay AB. Theophylline steady-state pharmacokinetics: Recent concepts and their application in the chrono-therapy of bronchial asthma. Immunologic aspects of occupational asthma. Rubinfeld AR. Am J Med 1988. 321. Epidemiology of nocturnal asthma. 299. Hetzel MR. Saetta M et al. Clinical chronopharmacology. Salari H. Dryden P. Nocturnal asthma and changes in circulatory epinephrine. Immunologic studies of the mechanisms of occupational asthma caused by western red cedar. Am Rev Respir Dis 1991. Salvaggio JE.39:77-79.88:376-84. Gupta ML. Bernstein IL. New Engl J Med 1995. 313. Dal Vecchio L. However.7-9 Although the basement membrane is of normal thickness. Biopsies taken from mild asthmatics requiring only occasional bronchodilators.2 Large segments of the airway from the major bronchi to the periphery are occluded with a mixture of tenacious secretion containing serum protein mixed with mucus and cellular debris. and mononuclear cells were present in increased numbers in the postcapillary venules. Crystalline material consisting largely of major basic protein derived from eosinophil granules (Charcot-Leyden crystals) may be present. However. Eosinophils. or with mild disease. dense eosinophilic infiltration. There is oedema.86 Bronchial Asthma 4 Pathology The earlier descriptions of histological changes in bronchial asthma relied on postmortem specimens taken from people dying in status asthmaticus. Most of the eosinophils revealed the ultrastructural features of activation and degranulation. neutrophils. .1. The existence of severe inflammatory changes is well known from necropsy studies on patients died of bronchial asthma. and were frequently in close contact with the vascular endothelium. showed them to be always abnormal compared to that from nonatopic normal individuals. peribronchial smooth muscle hypertrophy and apparent basement membrane thickening. and epithelial denudation in the bronchial wall. The strips of epithelial cells are called Curschmann’s spirals. Airway samples obtained at open lung biopsy show goblet cell hyperplasia. fresh biopsies were taken from eight asthmatics.1a-c) Fibreoptic bronchoscopy has helped in sampling the bronchial mucosa as well as the submucosa from the subcarinal levels in asthmatics at various stages of their disease. The most important observation was that epithelial changes and influx of inflammatory cells also existed in the two untreated patients who had mild disease both clinically and functionally. epithelial shedding and influx of eosinophils into the airway mucosa have been associated with bronchial asthma. Another important observation was the presence of apparent thickening of the subepithelial basement membrane. three having moderate and three with severe asthma. with two of them having mild asthma. This was in contrast to perfectly intact epithelium found in a control subject. In 1985. Clumps of cells (Creola bodies) or isolate metaplastic cells are common. no detailed pathological changes were available in milder forms of asthma before the use of fibreoptic bronchoscope (Fig 4. Further evidence of epithelial shedding in asthmatics is provided by the findings of clumps of epithelial cells in the sputum of such patients during acute attacks.4-6 These bronchial mucosal biopsy findings resulted in surprising results. significant inflammation is also present in early asthma in patients with only a short duration of symptoms. and a wide spread infiltration of eosinophils.3 All of them showed virtual destruction and shedding of epithelium at the three airway levels studied. Such changes included the presence of mast cells at various stages of degranulation. Since the 1960s. 4. 4.1a: Normal airway Fig. 4.Pathology 87 Fig.1b: Airway during an attack of bronchial asthma Fig.1c: Schematic representation of the airway in patients with bronchial asthma . Recent data further revealed an expanded network of subepithelial myofibroblasts with both contractile and collagen secreting properties. Eosinophils are present in some cases. cause the epithelium to be in a chronic state of . the myofibroblasts. Although the factor(s) controlling the proliferation and collagen-secreting activities of the myofibroblasts is not known. together with fibronectin but not laminin. This remodelling process is mainly caused by a complex interaction of inflammatory cells that are central to the pathogenesis of asthma with structural tissue cells. mediators. and smooth muscle. Remodelling of the airways in asthma involves structural changes in the epithelium. these structural changes may underlie the progressive and irreversible airflow obstruction that is seen in patients with poorly controlled asthma over a period of time. The number of myofibroblasts correlates with the degree of subepithelial thickening. and extracellular matrix including the basement membrane. Extensive collagen deposition within the bronchial mucosa might influence the mechanical properties of the airways and contribute towards bronchial hyperresponsiveness and irreversible airflow obstruction. Epithelial injury plays an important role in asthma airway remodelling. suggesting a repair response secondary to chronic inflammation. There is submucosal infiltration with degranulating mast cells and lymphocytes. Thus. suggested that anti-inflammatory treatment with inhaled steroids should be started in the early stage of bronchial asthma to prevent structural changes from occurring in the airway wall. play important effector role through the release of a number of cytokines. mast cells and macrophages together with structural tissue cells. This suggests the fibroblastic origin of the band. T cells. The remodelling of airways in bronchial asthma involves structural changes in the epithelium. Using immunostaining this collagen is identified as predominantly types III and V. and smooth muscle. The inflammatory cells such as eosinophils. This remodelling process is mainly orchestrated by a complex interaction of inflammatory cells that are central in the pathogenesis of asthma with structural tissue cells. but not type IV (basement membrane)13 collagen. the myofibroblasts and extracellular matrix including basement membrane. including hypertrophy and hyperplasia of airway smooth muscle and thickening of the reticular layer of basement membrane. Bronchial biopsy specimens from children show thickening and hyalinization of the basement membrane. The thickness of the reticular basement is increased even in mild asthma and is correlated with airway obstruction and hyperresponsiveness.11 AIRWAY REMODELLING Chronic inflammation in the airways leads to structural changes.88 Bronchial Asthma the subepithelial band consists of dense cross-linked collagen fibrils. It is therefore.10 Similar changes have been described in the asthmatic airway in childhood. and chemokines. This later thickening is due to the deposition of collagen from activated myofibroblasts in response to cytokines and growth factors released during the inflammatory response. The ciliated epithelial cells showed loss of cilia in some cases. the increased subepithelial collagen in asthma does not represent a thickening of the true basement membrane but rather collagen laid down by fibroblasts with the lamina propria.12 There is extensive deposition of collagen beneath the true basement membrane. Overactive fibroblasts are constant findings. Monoclonal antibody studies suggest that the sub-basement membrane band consists of types III and V collagen.14 An intrinsically aberrant epithelium when injured by toxic mediators. 29 Recent studies have shown that eosinophils.99 L for a man of the same age and height who smoked and had asthma. levels off around 25-35 years of age.05 L. and lower lung function as well as accelerated loss of FEV1. ongoing active airway inflammation will have substantial impact on the risk of relapse later in life. and increased stored mucin in the airway epithelium. mast cells.Pathology 89 increased injury and repair.30 These results indicate ongoing airway inflammation and airway remodelling in adolescents in clinical remission of atopic asthma. Generally. it could at least partly account for the functional abnormalities including bronchial hyperreactivity observed during remission. and bronchial response to adenosine-5’-monophosphate correlated significantly with the quantity of tissue eosinophils. persistent asthma and following airway challenge. On this logic a 175 cm tall. Subclinical airway inflammation may well determine the risk of an asthma relapse later in life. Airway inflammation and remodelling contribute significantly to the decline in lung function in bronchial asthma. Blood eosinophil cell counts. T cells. exhaled nitric oxide (eNO) levels. and smooth muscle fibres.18 Further. Airway Pathology during Asthma Remission Spirometric abnormalities and bronchial hyperresponsiveness to methacholine or cold air challenge during clinical remission of asthma are often observed.20 It is unclear whether these functional abnormalities reflect persistent activity of the airways inflammatory process or merely indicates structural changes of the airways as a consequence of childhood asthma. These structural changes (airway remodelling) are probably early events in the course of the disease that appear to progress. potentially life-threatening. and IL-5 are significantly elevated in the airway mucosa of subjects with bronchial asthma in remission compared with control subjects. there may be a subset of nonsmoking asthmatics those have an excess overall decline in lung function. The process of remodelling leads to thickening of the airway wall. irreversible airway obstruction without the presence of emphysema. This interaction is called the epithelial mesenchymal trophic unit. This may lead to severe. Therefore. nonsmoker.25 If airway wall thickening is present in subjects in clinical remission of asthma. Significant airway remodelling was found in subjects in clinical remission. subjects with subclinical airway inflammation could benefit from anti-inflammatory treatment.16 Similar observations are made for adult asthmatics that may also have increased decline in lung function during their life.13 Also blood eosinophil cell counts were higher in subjects with clinical remission. Further. in asthmatic children the observation is different. Patients of asthma have increased goblet cell hyperplasia. lung function increases during childhood. Pro-fibrotic stimuli cause subsequent subepithelial basement membrane and submucosal alterations of collagen. ongoing inflammation results in more severe airway hyperreactivity.26-28 Elevated exhaled nitric oxide (eNO) levels and bronchial hyperreactivity during clinical remission have been demonstrated recently implying ongoing inflammation. On the other hand.17 This enhanced decline in lung function is present in both sexes and is further enhanced by smoking. However. compared with the FEV1 of 1.21-24 The exact physiologic consequences of airway wall thickening are not completely understood. and declines after the age of 35 years.19. A girl developing asthma at age of 7 years would have 5% reduction in FEV1 by age of 10 years and a 7% deficit by age of 15 years compared with children without asthma.15. elastin. Matrix metalloproteinase-9 concentrations are increased in severe. . nonasthmatic man had an average FEV1 of 3. Effect of asthma on pulmonary function in children. 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Tenascin in airway basement membrane of asthmatics and decreased by an inhaled steroid. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. .105:514-17. Fahy JV. sinusitis. although may be continuous or continuous with acute exacerbations. as well as within each patient.4 These nocturnal attacks wake the patient in early hours of morning and the patient feel the need to get out of bed and want to open the window for air. documented pneumonia. The precipitating event (discussed above under etiology) may or may not be evident from history.5 Many other risk factors discussed above like domestic dust mite. who have asthma have coexisting allergic rhinitis.e. The sputum is usually white or clear. chest tightness. airborne irritants. itching. are also capable of aggravating asthma and are known as asthma triggers as they can provoke . and the patient may sometimes notice more solid or greenish streaks in it. allergic rhinitis has been recognised as a risk factor for asthma and between 20-38% of patients who have allergic rhinitis have coexisting asthma. pollens. Viral infection of the upper airways is another important preceding event in many patients. tobacco smoke. It is estimated that about 10% of the population. sneezing. increase in severity over a minute or two and wane over about half an hour. shortness of breath. and modest degree of sputum production. Dry cough may be the only manifestation of asthma in some (cough variant asthma). falling into every age group from infancy to old age. The symptomatology is generally episodic. Most patients will complain of the onset of an attack of bronchial asthma following allergic pharyngitis. The usual symptoms include cough. or atopic dermatitis.3 The pattern of symptoms may be perennial.1 Conditions known to be associated with bronchial asthma include rhinitis. viral bronchiolitis. atopic dermatitis. history of pulmonary infiltrates. or perennial with seasonal exacerbations. mould. may occur after several minutes of usually unaccustomed exertion. Exacerbation of symptoms.2 Further. in the form of sore throat. running nose or a blocked nose. furred animals. and the spectrum of signs and symptoms varies in degree of severity from patient to patient. The incidence of IgE mediated allergy (allergic rhinitis. double the number having overt asthma symptoms experience asthma-like symptoms. over time. recurrent croup.92 Bronchial Asthma 5 Clinical Presentation of Bronchial Asthma The clinical presentations of bronchial asthma are heterogeneous. nasal polyposis. symptoms of gastro-oesophageal reflux and passive exposure to smoking) may be rewarding. Between 60-78% of patients. hay fever) and bronchial asthma in close relatives is very high. There is usually a circadian variation with more nocturnal symptoms. Detailed clinical history taking is very important in the clinical diagnosis of bronchial asthma. wheezing. The detailed medical history of the patient including other allergic disorders and in children history of early life injury to airways (bronchopulmonary dysplasia. seasonal. i. pain in the throat. foreign body aspiration. However. The symptoms are generally severe. neither its presence nor its absence will confirm or exclude bronchial asthma. The skin test for allergens is usually negative and the serum IgE level is often normal. The difficulty arises because of the lack of appreciation of the difference between truly late onset asthma and asthma that is recognised late. and nasal polyps. Physical examination of chronic asthma (for acute attacks see later) should focus on the upper respiratory tract. there will be evidence of hyperinflation of the lungs with use of accessory muscles and appearance of hunched shoulders and “pigeon chest”. extreme emotional expressions (laughing or crying hard). It is often said that “all that wheezes is not asthma”. Other triggers include smoke from domestic cooking fuels. cold air or weather changes. the skin and the chest. bronchial stenosis.Clinical Presentation of Bronchial Asthma 93 asthma attacks. postnasal drip. pale nasal mucosa. to which the response is dramatic. Asthma associated with polyarteritis nodosa and aspirin-sensitive bronchial asthma are usually of intrinsic type.7 This is important because the missed asthmatic patient with long-standing under treated asthma is more likely to develop irreversible airflow obstruction. People with asthma may have one or more triggers. CLASSIFICATION Intrinsic and Extrinsic Asthma Some investigators try to classify bronchial asthma into the intrinsic and extrinsic types. history of allergy or the responsible allergen is not easy to find out always. they do not respond well to conventional therapy and a greater likelihood that the patient will need maintenance oral steroids. In children. assuming a 5% prevalence of asthma overall. Asthma perhaps occurs more frequently in the elderly than is usually appreciated and . The intrinsic asthma usually has late onset with no history of atopy or allergy and is nonseasonal. many do not agree with this classification in view of the recent understanding of the underlying pathogenesis of asthma. upper airway obstruction. and drugs like aspirin. The findings may reveal the presence of rhinitis and/or sinusitis in the form of purulent nasal discharge. Presence of rhonchi is a characteristic finding in asthma and will be present in most patients. cold drinks. Crepitations are not the findings of asthma unless there is secondary infection or a complication like allergic bronchopulmonary mycosis. Moreover. Although there is no agreeable definition of this entity. a reasonable definition would be “asthma with onset of symptoms in adult life in a patient with no pre-existing. pulmonary oedema. and different individuals have different triggers. Late Onset Asthma Late onset asthma is a much used but poorly defined term.6. The intensity of the breath sounds in symptomatic asthma will be reduced and the expiratory phase is prolonged. wheezing is not a reliable sign of severity. persistent respiratory symptoms”. However. etc. Flexural eczema may indicate the presence of atopic dermatitis. physical activity (running and other exercises). Rhonchi may be heard in many other conditions including chronic bronchitis. A great majority of these patients have auto-antibodies to smooth muscle and among women. Moreover. aspiration pneumonia and pulmonary embolism. food additives. True onset of asthma is perhaps more common than it was appreciated and may affect one in 50 of the adult population. thyroid and gastric antibodies and antinuclear factor. Occupational Asthma Occupational asthma is the most common occupational lung disease in developed world and accounts for 26-52% of all occupational lung diseases in UK. There is usually a latent period between the first exposure to the offending agent and the onset of asthma. Occupational asthma may develop in a person with preexisting asthma or concurrent asthma after workplace exposure. The patient usually complains of chest symptoms after working hours. Women. The other type of occupational asthma is without a latent period and the worker develops symptoms immediately upon working with the same substance. History of atopy and smoking are important determinants to induce occupational asthma that occurs through an IgE-dependent mechanism.94 Bronchial Asthma may. not to stimuli outside the workplace.10 In a recent population based study. who develop adult onset asthma more often than men. or chemicals on one or several occasions-reactive airway dysfunction syndrome.12 About 15% of bronchial asthma are due to occupational exposure as reported from USA.13 About 250 agents have been identified that can cause occupational asthma and some of them are indicated in earlier in the section under aetiology.9.11 The age-and sex-adjusted incidence was 95/100. therefore. Isocyanates that are widely used in many industries are responsible for the most common form of the disease and the prevalence of isocyanate-induced asthma in exposed workers is close to 10%. and Canada.000 at or after the age of 65 years. or both. Late onset asthma has sometimes been equated with intrinsic asthma. although the immunologic mechanism has not been identified for all agents. but not during working hours at the onset of the illness. often give a history of asthma beginning at the menopause. bronchial hyperresponsiveness.17 HLA class II alleles are involved in some cases of isocyanate-induced asthma.16 Exposure is the most important determinant whether occupational asthma develops. This period may vary from a few weeks to over 20 years. and occupational asthma may belong to this category. due to conditions in particular work environment. be under diagnosed and under treated. few have described patients with onset of asthma after the age of 65 years.14 There can be two categories of asthma related to the workplace. Asthma induced by drugs. in the evenings and at nights. Occupational asthma with latency includes all instances of immunologic asthma. but in some patients there will be other important causes that must be recognised. higher is the prevalence of occupational asthma. Higher the degree of exposure to an agent. About 40% of patients with occupational asthma have symptoms within 2 years of exposure and in 20%. fumes. symptoms develop after 10 years of exposure. Many patients report that their symptoms started after a respiratory tract infection. workaggravated asthma is preexisting or concurrent asthma that is aggravated by irritants or physical stimuli in the workplace.15 On the other hand.8 Although several studies report the characteristics of older patients with asthma. This is usually due to exposure to high concentrations of irritant gases. They are: occupational asthma and work-aggravated asthma. Available studies are limited by small number of patients. Occupational asthma is characterised by variable airflow limitation. the incidence of asthma was found to be more common in the elderly. The duration of exposure is not important. Asthma of adult onset may be the first sign of the development of polyarteritis nodosa. Improvement in symptoms occurs at weekends or during longer periods away from work and worsening on return to work suggests but does not . peak expiratory flow monitoring. But for screening examinations in the workplace or for field epidemiological surveys. most of the allergens are not available commercially. late-phase allergic reactions. airway cooling. and 94% have nocturnal awakenings at least once a month. This is exaggerated in asthmatics. Peak flow monitoring is important to recognize this problem. The diagnosis should always be confirmed by objective measurements. Runny and itchy eyes and nose and sneezing often accompany respiratory symptoms. There are many advantages and disadvantages of all these tests. circadian rhythms may be particularly relevant. the inability to identify an agent should not rule out the diagnosis of occupational asthma. Such list of agents is available. While no single mechanism can explain these changes. and serial FEV1 measurements at work under supervision. The test only identifies sensitisation. impaired mucociliary clearance.Clinical Presentation of Bronchial Asthma 95 confirm occupational asthma. it has a low specificity. Bronchial responsiveness to histamine and allergen challenge increases during sleep and mast cell mediator release . in the absence of airflow limitation. they can only be used for high-molecular weight and some low-molecular weight agents. Establishment of a relation between asthma and work. The history should include specific job duties and work processes for both the patient and the coworkers. bronchial responsiveness to methacholin or histamine. immunological testing. but not disease. The number of criteria required to establish the relation to work depends on the purpose for which the diagnosis is made. Although immunological tests are simple and sensitive. The disease should be suspected in a person exposed at work to agents known to cause occupational asthma. Detailed assessment of workplace exposure may help determine the specific type of occupational asthma. and the relation to work should be objectively demonstrated. An occupational cause should be sought for all new onset asthma in adults. less stringent diagnostic requirements can increase the sensitivity of case detection. A number of mechanisms have been hypothesised to explain the phenomenon of nocturnal asthma including exposure to dust mite allergen. specific inhalation challenges in a hospital laboratory. Various methods used to diagnose occupational asthma include questionnaire. While questionnaire is simple and sensitive. A visit of the site by the physician may help to understand the work situation better. They are more stringent if the diagnosis is required for medical purposes. the presence of pharmacologically induced bronchial hyperresponsiveness. Normal airway tone increases during sleep and is magnified in asthmatics.18 However. Diagnosis of occupational asthma includes: a. measurement of FEV1 before and after work. Nocturnal Asthma Nocturnal asthma symptoms are frequent and about 39% of asthmatics awaken nightly. Further. Diagnosis of asthma and b. gastro-oesophageal reflux. History of both past and current exposures is required to be obtained since previous exposure to such agents may have induced permanent asthma. The diagnosis of asthma is based on compatible history and the presence of variable airflow obstruction or. and changes in circadian rhythms of circulating hormones (adrenaline and steroids). effects of posture and sleep stages on airway tone. Normally there is a rhythm city in the lung function parameters with maximum readings between 3-4 PM and the lowest being at 3-4 AM. inflammation.18 1. “The morning dipper” 3. which may allow their ingress into pulmonary tissue. .91:671-74. Brittle Asthma This is a form of intractable and persistent asthma resistant to all conventional therapy. They occur randomly throughout 24 hours. The patient may be atopic or non-atopic. The “drifter”. The rhythm city is maintained during the day and reduction occurs early in the morning. Morning Dippers These are the patients who have worsening of their symptoms during early hours of the night and is discussed above. A subgroup having a reversible FVC.96 Bronchial Asthma is enhanced. Chest 1987. 2. It is observed in sleep workers that the attack is worse towards the end of sleeping hours.89:461-62. During day times. deCotiis BA et al. quoted in Haahtela T. These patients usually need frequent bronchodilators. but stabilisation is difficult. Ministry of Health and Social Welfare. The importance of inflammation in early asthma. Serial measurements of PEFR show a chaotic pattern. The irreversible asthma” a. In children. Circulating eosinophils increase. so that no abnormality may be detected during the visit to the doctor. not all patients are resistant to conventional therapy. Braman SS. A group never achieving a normal peak flow. the patient may be completely normal and stable. 1994. and responsiveness during sleep and produce the observed clinical picture. The salient feature of this asthma is their response to sympathomimetic drugs but without stabilisation. National Asthma Programme in Finland 1994-2004. b. “Brittle” asthma 2. Waking does not change the attack. the attack is usually worse around 2 AM and in adults it is variable increasing slowly and rapidly from midnight. REFERENCES 1. PATTERNS OF AIRFLOW OBSTRUCTION IN CHRONIC ASTHMA Chronic asthma may be classified according to patterns of variations in their airflow obstruction. Helsinki. c. Most often they are misunderstood to have deliberate or emotional asthma. Respiratory Med 1995. with normal to grossly abnormal patterns of airflow obstruction. either spontaneously or after specific drug therapy. The characteristic symptomatology is described above. Low readings may reverse to normal with small doses of bronchodilators. but showing a reversible component. Cromoglycate and steroid therapy will not be able to stabilize. having irreversible airflow obstruction gradually improving over weeks of intensive therapy. but irreversible FEV1 and PEFR. but gross wheezing may be present over a short period of time. There will be no wheeze at one moment. Barrows AA. Airway hyperresponsiveness in allergic rhinitis: A risk factor for asthma. Together with a decreased plasma catecholamine and cortisol levels all these factors may influence airway tone. However. Burr ML. Chest 1997. New Engl J Med 1995. Weiss MA. 4.300:1602. Natural history of occupational asthma.91:157S.44-57. Diurnal rhythm of asthma. 12. 16. Asthma and rhinitis. 9.90:937-44. Malik SK. Am Rev Respir Dis 1991. Clark TJV. 6. In: Bernstein IL. Br Med J 1972.92:613-17. Rachelefsky GS. L’Archeveque J. A population based study in Rochester.1-4. 8. Late onset asthma. . 5. The role of infection in asthma. Bauer BA. Lee GS. Bernstein DI (Eds). 10. Roy K et al. 7. Occupational asthma.73:526. Malo JL. 17. J Allergy Clin Immunol 1992. Katz RM. Asthma in the elderly: an epidemiological survey. Incidence and outcomes of asthma in the elderly. Lee HY.88:376-84. relevance of type of agent and other factors in the rate of development of symptoms in affected subjects. In: Busse WW. Chest 1987. Malo JL. Bernstein DI. New York: Marcel Dekker. Chan-Yeung M. Malo JL. Occupational asthma in national disability survey.Clinical Presentation of Bronchial Asthma 97 3. Br Med J 1990. Davis SM. Br J Dis Chest 1987. Bernstein IL. et al. Epidemiology of occupational asthma. Wollan PC. Definition and classification of asthma. Reed CE. Br J Dis Chest 1977. Braman SS.1:1041-44.4:93-95.333:107-12. Stretton TB. Asthma in the elderly: a comparison between patients with recently acquired and long-standing disease.91:137S. Chest 1987. Chan-Yeung M. Boston. On observing patterns of airflow obstruction in chronic asthma. Yunginger JW.71:73-86. Chan-Yeung M. Banerjee DK. Silverstein MD. Holgate ST (Eds). Blane P. 1993. D’Aquino C. Charles TJ. Ghezzo H.143:336-40. Turner Warwick M. Brooks SM. Paediatrics 1984.111: 303-10. Under diagnosis of asthma in the elderly. Chest 1987. Steinium-Aarniale B. 1995. 14. 13. Malo JL. Asthma in the workplace. Malo JL. Blackwell Scientific Publications. Ayres JG. Kaemmerlen JT. Chronic sinus disease with associated reactive airway disease in children. 18. Chan-Yeung M. Cartier A. Siegel SC. Minnesota. 11. Chan-Yeung M. BMJ 1979.81:23-29. Chest 1985. Bernstein IL. 15. Reactive airway dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Asthma in the elderly. Obstruction is often reversible. Features of an airway disorder such as cough. foreign body. tumour. Symptoms of Asthma To avoid misdiagnosis it is essential to remember that people with asthma may suffer from a variety of symptoms. cystic fibrosis or obliterative bronchiolitis). there are numerous relatively common lung diseases and differentiation of an airway disorder needs to be made from both infections. Even when the symptom of breathlessness is thought to be due to lung disease. and pulmonary thromboembolic disease and restrictive lung disorders. with many descriptions existing. inflammatory symptoms are usually associated with widespread but variable airflow obstruction and an increase in airway response to a variety of stimuli.in susceptible individuals.98 Bronchial Asthma 6 Diagnosis of Bronchial Asthma The diagnosis of asthma is a clinical one.g. In some people. radiographic or histopathological investigation. either spontaneously or with treatment”.. or to a generalised problem (such as asthma. The clinical diagnosis of asthma is not always simple and the absence of an agreed definition of the disease is a problem. there is no confirmatory diagnostic blood test. chronic obstructive pulmonary disease (COPD). Some of the symptoms of asthma are shared with diseases of other systems. wheeze and breathlessness should be corroborated where possible by measurement of airflow limitation. none of which is specific for asthma: • Wheeze • Shortness of breath • Chest tightness • Cough The hallmark of asthma is that these symptoms tend to be: • Variable • Intermittent • Worse at night • Provoked by triggers including exercise . However. They may be due either to a localised airway obstruction (e. bronchiectasis. vocal cord dysfunction or post-tracheostomy stenosis). the diagnosis can be corroborated by suggestive changes in lung function tests. while making a diagnosis of bronchial asthma The International Consensus Report definition of asthma should be kept in mind which states that it is “a chronic inflammatory disorder of the airways…. Similarly. A good medical history is enough in most of the time to diagnose bronchial asthma. behaviour. episodic. oil.1 exposure to environmental allergens. air pollutants like ozone. duration. if present. or perennial with seasonal exacerbations. and spouse knowledge of asthma and belief in the chronicity of asthma and in the efficacy of treatment. allergic rhinitis). exposure to irritants like tobacco smoke. this is often refered to as cough variant asthma. and frequency of symptoms like number of days per week or month are also important to note. strong odour. should be documented in clinical notes. effect on spouse and children. gases and aerosols. oxides of sulphur. chemicals. and dust collectors. vapors. beta blockers. nocturnal awakening and the effect on growth. crying. Outside acute episodes. polyphonic. work process. Patients who present with chronic asthma may have signs of hyperinflation with or without wheeze. exercise. occupational chemicals. The presence of wheeze (usually diffuse. progress of the disease. hospitalisation. Day-night (circadian) variation with special reference to nocturnal symptoms should be asked for in each case. Special attention should be paid in enquiring about the patient’s living room with particular reference to pillow. the patient will often have wheeze and reduced lung function. type of domestic cooking fuel used. and economic impact needs assessment. Information regarding animals in home and exposure to cigarette smoke. drugs like aspirin. and humidifier. frustrations. Particular attention should be paid to the precipitating and/or aggravating factors. ventilatory support. exposure to occupational chemicals or allergens. parental. bed. fear. limitation of activity especially sports. seasonal. Additional information which may contribute towards a clinical suspicion of asthma includes: personal or family history of asthma or other atopic condition (eczema. and/or alterations in workplace. requirement of oral steroid therapy. This should also include the age of onset and age of diagnosis. Any precipitating and/or aggravating factors like viral respiratory tract infections.Diagnosis of Bronchial Asthma 99 When cough is the predominant symptom without wheeze. feathered or furry animals. Signs of Asthma During exacerbations. Pattern of symptoms may be perennial. cooling. electric. laughter. or material used. previous and present evaluation of the disease. history of life-threatening acute exacerbations. development. there may be no objective signs of asthma. The impact of disease on the patient including number of emergency department visits. dust. and worsening of symptoms after taking aspirin/non-steroidal antiinflammatory medication or use of β blockers. floor covering. or kerosene). living situation with home age. wood burning fire place. either reduced peak flow or an obstructive pattern on spirometry. the impact on family including disruption of family life. ability of the patient and the family to cope with disease. level of family support and economic resources are helpful in planning out a management programme for the patient which is to be evaluated at the time of diagnosis. or continuous with acute exacerbations. and environmental tobacco smoke. location. number of school or work days missed. treatment. direct or side stream. Patient. The symptoms may also be continuous. impact of environmental changes like moving into a new home. worsening of symptoms after exposure to recognised triggers such as pollens. The onset. is important. going on a vacation. carpeting. nonsteroidal . viral infections. and response to such therapy. and heating (central with gas. school or work achievements and lifestyles need to be assessed. emotional expressions like anger. bilateral and particularly expiratory) is a cardinal sign of asthma and. recently it is reported that measurement . typically one gets an obstructive pattern.2 In bronchial asthma. If symptoms are more where a carpet is being vacuumed and bed making makes asthma worse. pregnancy. particularly exposure to cold air. If symptoms are related to certain job activities. and history of smoking or passive smoking are important points to note. thyroid disease. if the asthma worsens in certain months and other symptoms of allergy like allergic rhinitis. All patients suspected to have bronchial Asthma should have spirometry done at least for initial assessment. Diagnosis of allergy in an asthma patient requires a thorough history taking. Bronchial asthma has a significant impact on lung function decline. sneezing. change in weather. However. pollens and outdoor moulds are the responsible allergens.100 Bronchial Asthma anti-inflammatory drugs. asthma in close relatives is important pointers. repeated throat infections. The mid-expiratory flow rate is useful as a screening test but it is too sensitive to assess the severity of obstruction. history of pulmonary infiltrates. However. If symptoms appear when visiting a house where there are indoor pets or if the symptoms improve when the patient is away from home for a week or longer. a red.4 The low FEV1 in bronchial asthma is due to increased resistance because of bronchoconstriction and remodelled airway walls. Physical findings of bronchial asthma are already discussed above. are very important to evaluate since they will be very helpful in identifying the possible agent/factor(s) that care responsible in causing the disease. Laboratory Studies Spirometry should be undertaken to document severity of airflow obstruction and to establish acute bronchodilator responsiveness for all patients in whom the diagnosis of asthma is being considered. The FEV1 is the single best measure of pulmonary function for assessing severity. Family history of allergic diseases. there are other causes of airways obstruction leading to wheezing. sneezing. and FEV1 variability. itchy welt develops. endocrinal factors like menstruation. gastrointestinal disturbances. food additives like sulphites. running nose and nasal obstruction occur at the same time. most likely mites are the responsible antigens.3 When the FEV1 is severely reduced with clear evidence of obstruction (FEV1/FVC ratio less than 75% predicted). either at work and they improve when away from work for a few days will indicate occupational asthma. although PEFR when measured accurately correlated well with FEV1. the rate of FEV1 decline seems to increase in younger subjects only when the baseline function is poorer. Decline in FEV1 in patients with bronchial asthma is significantly influenced by baseline FEV1. itching. The diagnosis may be little more difficult in children and infants rather in adults. etc. it is important to use an accurate spirometer and the procedure being done correctly. In the personal and past history. the vital capacity can also be reduced due to severe obstruction alone which prevents all the air to be emptied out during forced expiration. If the pet licks the patient. adverse reaction to foods. exercise. although not as great as COPD. animal dander is the offending agent. any previous allergic disease like chronic rhinitis. dermatitis. For example. Further evidence of animal dander comes from the fact that eyes may itch and become red after handling the pet. disease duration. Although recurrent episodes of cough and wheezing with breathlessness are almost always due to bronchial asthma in both children and adults. Moreover. Mould allergy is usual if symptoms develop around hay and on being exposed into a damp environment. Usually there will be a normal vital capacity with either impaired FEV1 or impaired MMEF. on waking and in the evening. unstable asthma. portable peak flow meters. quantitative. three readings should be taken and the best recorded graphically for easy inspection. On each occasion. Spontaneous variable airflow obstruction can be assessed by using peak expiratory flow monitoring at home9 or treatment induced variable airflow obstruction can be assessed in the laboratory by measuring the bronchodilator response to β2-agonists or the bronchoconstrictor response to short-acting airway smooth muscle spasmogens like methacholine. reproducible measure of airway obstruction that can be obtained using inexpensive. • Monitor response to therapy during an acute exacerbation. the patient can measure the peak expiratory flow rate (PEFR) himself.5 Loss of this elastic recoil accounted for more than half of the reduction in total maximum airflow in these patients. Further accumulation of inflammatory cells has been reported in the alveolar tissue of these patients.6 While complete spirometry can be done in a laboratory only. or other symptoms of increasing airway obstruction. • Diagnose exercise-induced asthma. thus reducing morbidity and cost of treatment. This is almost analogous to measuring blood pressure with a sphygmomanometer.7. before using a bronchodilator. They should normally measure their PEFR twice daily. smoking. brittle asthmatics. Patients at increased risk. PEFR has a very good correlation with FEV1. and altered surfactant levels. This low elastic recoil in patients of asthma is due to long-term corticosteroid therapy. who are those recently admitted to hospitals with acute asthma. Patients with stable asthma should be encouraged to measure their peak expiratory flow rates at least one or two days a week to detect any slow deterioration and to start recording it regularly if they develop a respiratory tract infection. such as admission to or release from the hospital or initiation of oral steroids.8 The most common strategy employed to support a clinical diagnosis of asthma is to demonstrate the presence of an abnormal.Diagnosis of Bronchial Asthma 101 of maximum static pleural pressure at different lung volumes showed marked loss of lung recoil in patients with moderate and severe asthma. and those using home nebulizers should record their PEFR more often. measurement of PEFR is valuable in medical care settings to: • Assess the severity of asthma as a basis for making treatment decisions. High dose corticosteroids required initially may not be necessary subsequently. mechanical fatigue due to the persistent stretch in over inflation. Patients thought to overuse their β2-agonist inhalers may show previously unrecognised nocturnal asthma or pronounced morning dipping. Home recordings of PEFR should improve the detection of under treated asthma. short-term variable airflow obstruction. Thus in summary. Recordings may also allow unnecessary drugs to be withdrawn. • Detect asymptomatic deterioration in lung function in the office and intervene before it becomes more serious. increase in wheeze. • Monitor degree of airflow obstruction during a series of office visits to assess the overall success of therapy. This simple objective measurement of lung function helps detecting early deterioration of lung function. Such measurement has many benefits. . which has known detrimental effect on connective tissue. It provides a simple. • Monitor response to chronic therapy and provide objective justification for therapy to patients. those requiring varying doses of systemic steroids to control their symptoms. and perhaps four times a day during exacerbations. • Other laboratory investigations for bronchial asthma include: • Complete and differential blood counts. Variability of PEF and FEV1. Although the normal level of diurnal variability is open to question. which measures flow rates at low lung volumes (i. chest X-ray (to rule out other causes of airway obstruction. One or both of these should be measured. is highly suggestive of asthma. either spontaneously over time or in response to therapy is a characteristic feature of asthma. In addition. is not performed. ideally for three days in a week for two weeks seen over a period of time. Incorporating a skin prick test using commonly inhaled allergens is a simple. nasal secretions and stain for eosinophils (neutrophilic nasal discharge indicates sinusitis). A 20% or greater variability in amplitude % best with a minimum change of at least 60L/min. Adequate training and periodic checkups are necessary to verify the accuracy. rapid. FEF50. therefore. at least to one aeroallergen in asthmatic adults residing in the UK. age range 18-50 years. then a diagnosis of asthma must be in doubt. but may be normal if the measurement is made between episodes of bronchospasm. • Sputum examination and stain for eosinophils (sputum eosinophils are highly characteristic of asthma and neutrophils predominate in bronchitic sputum). safe. and most common way of assessing the contribution of atopy. inexpensive. Calculating variability may be done in one of several ways.17-23 Many patients with asthma will demonstrate variability below 20%. making this a reasonably specific but insensitive diagnostic test. FEF25-75). Determination of specific IgE antibodies to common inhalant allergens with skin tests or with in vitro test is useful to find out the role of allergy in the patient’s asthma.16 OBJECTIVE TESTS Obstructive airways disease produces a decrease in peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1).12 whereas a positive result has been found in 15-40% of normal individuals. and to detect associated complications). That is. sputum differential eosinophil count is one of the most useful objective tests in patients with bronchial asthma10 and • Complete pulmonary function studies including flow-volume loops which may reveal the presence of upper airway obstruction. was 90%.. patients with mild asthma whose pathophysiologic abnormalities are linked to the small airways may be under diagnosed if spirometry. and the test can be used as a reliable method to predict the absence of asthma in young adults.e. marked variability of peak flow and easily demonstrated reversibility confirms a diagnosis of asthma. PEFR measures only large airway function.102 Bronchial Asthma The primary limitation of PEFR measurement is that it is effort dependent and valid measurements depend upon the patient’s willingness and ability to exhale as hard as possible. sequential measurement of PEF may be useful in the diagnosis of asthma. If they are repeatedly normal in the presence of symptoms.13-15 Inclusion of this test in suspected asthma cases can reduce the cost of this process significantly. . but smaller changes do not necessarily exclude the diagnosis.11 The incidence of positive skin prick test result. 5 mg by nebuliser) • An increase after a trial of steroid tablets (prednisolone 30 mg/day for 14 days) • A decrease after six minutes of exercise.g.5 mg by nebuliser) • or FEV1 > 15% (and 200 ml) increase after trial of steroid tablets (prednisolone 30 mg/ day for 14 days) • or FEV1 > 15% decrease after six minutes of exercise (running) • Histamine or methacholine challenge in difficult cases Methods for Measuring Reversibility • An increase after inhalation of a short acting β2-agonist (e.24 Bronchodilators reduce hyperinflation.27 provocative challenge with occupational allergens and evaluation of pH for gastro-oesophageal reflux.31 The results are then expressed either as the cumulative dose or the concentration of agonist that produces a 20% fall in FEV1 (PD20). or pharmacological stimuli. Methacholine bronchoprovocation testing is frequently used to diagnose airway . As this procedure may rarely induce significant asthma. The most commonly employed methods used to evaluate airway hyperresponsiveness include inhalation provocation with methacholine or histamine and exercise challenge. Each of the above methods can be used. running. measuring either PEF (a 20% change from baseline and at least 60 l/min) or FEV1 (15% change and at least 200 ml).28-30 This can better be assessed in a specialised pulmonary testing facility using bronchial challenge or provocation techniques. A resting measurement is to be taken first and then the patient is to be asked to exercise for six minutes.Diagnosis of Bronchial Asthma 103 Diagnosis of Asthma Using PEF Amplitude % best Highest PEF Lowest PEF Amplitude Percentage PEF variability = = = = = (highest–lowest)/highest × 100 400 1/min 300 l/min 400 l/min – 300 l/min = 100 l/min (400-300)/400 × 100 = 25% The objective measurements helpful in the diagnosis of asthma include: • > 20% diurnal variation on > 3 days in a week for two weeks (to be maintained in a diary) • or FEV1 > 15% (and 200 ml) increase after short acting β2-agonist (salbutamol 400 μg by metered dose inhaler (pMDI) +spacer or 2. Objective tests should be used to try to confirm a diagnosis of asthma before long-term therapy is started.g. e. salbutamol 400 mg by metered dose inhaler (pMDI) +spacer or 2.25 Other investigations that may be helpful include rhinoscopy. a further reading is to be taken and then every 10 minutes for 30 minutes. facilities for immediate treatment should be available. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness. sinus X-ray and bronchoprovocation tests. During such a test changes in pulmonary function are measured with serial spirometry after inhaling incremental doses of an agonist such as methacholine or histamine or after exercise. Bronchoprovocation Test Bronchoprovocation test is indicated to assess the airway hyperresponsiveness in the form of increased bronchoconstrictor response to a variety of physical. chemical.26. Methacholine responsiveness is often used to confirm asthma status in patients.37 Various such predictors are the FEV1 and symptom status. A > 20% reduction in FEV1 following methacholine administration is a common parameter used to determine airway hyperresponsiveness.43 There is no one test or set of tests that should be ordered for every patient. normal persons after a viral upper respiratory tract infection or oxidant exposure. with careful attention to the history.28.32.34 Large. and as a predictor of later development of respiratory disease. and geographical regions are associated with increased responsiveness. and this response is seen in patients with a higher FEF25-75 / FVC ratio. central airway obstruction is best detected by SGaw measurements. positive results may not reflect underlying reactive airways disease. female sex. These situations include cough variant asthma and exercise-induced dyspnoea. Some observed that the slope of the decline of FEV1 with increasing dose of methacholine is a better way of measuring responsiveness because a value can be assigned to all subjects. smoking.40.104 Bronchial Asthma hyperresponsiveness and asthma. a flattening or truncation of the inspiratory flow-volume loop after the patient undergoes methacholine testing is not diagnostic for the presence of inspiratory vocal cord adduction. Asthmatics respond to bronchoprovocation with greater degree of airflow obstruction than normal subjects. physical findings. a > 40% reduction in specific airway conductance (sGaw) can be used to determine airway hyperresponsiveness. where a standardised tool for measurements of bronchial responsiveness to methacholine has been developed to estimate variation in prevalence of increased bronchial responsiveness and predictors of asthma in different groups. COPD. However. a substantial number of patients have a reduction in SGaw alone in response to methacholine.38 Methacholine challenge testing may cause an acute episode of vocal cord adduction and thus. occupational exposure. bronchitis.39 Results of exercise provocation are expressed as the peak fall in FEV1 after exercise.33 Regardless of which test is selected. However. and PEFR variations are not adequate to confirm the clinical diagnosis. physical examination. Smaller airways are more responsive than larger ones. and smokers.36 It is widely used in epidemiological studies.41 Diurnal variation in the measurement of PEFR is an indirect but clinically useful way of the degree of bronchial hyperreactivity even if there may be some variation. and the reduction in responsiveness diminishes with each increase of lung size. the changes in the test parameter following methacholine challenge must exceed 2 SDs or coefficients of variation for repeated measures in the same individual before a statistically significant change can be established.42 Bronchial provocation test is helpful in the differential diagnosis of asthma when the respiratory history. Alternatively. atopy. Although recurrent episodes of cough and wheezing are almost always due to asthma in both children and adults.33 Although either of the two measurements is good enough.35. asthmatic bronchitis. according to the American Thoracic Society guidelines. and laboratory results. a correct diagnosis of asthma will be made in virtually all instances. while both large and small airway narrowing will affect measurements of FEV1. or pneumonia. there are other . if they only wheeze when they have respiratory infections which may be dismissed as wheezy bronchitis. Selection of tests should be individualised.40 Other conditions that are associated with an increased bronchial hyperreactivity include allergic rhinitis. Asthma may be under diagnosed particularly in young children. cystic fibrosis. tracheal tumours. ACE inhibitors) and hyperventilation. lack of good reversibility after bronchodilators. However. etc. congestive cardiac failure. Other Tests Lung function tests may show changes suggestive of an alternative lung disease. cardiac murmur. cardiac diseases. peak expiratory flow variability over a 2-week period. which may anyway coexist with other conditions. and the differential count of eosinophils in blood and sputum). the reversibility testing. it is not possible to differentiate the two conditions. laryngeal tumours. Chest X-rays in all patients with atypical symptoms should be done. laryngeal dysfunction. aspirations. In adults. but these changes are not diagnostic and do not exclude asthma. cough due to drugs (beta blockers. The differential diagnosis of bronchial asthma includes: COPD. COPD may be suspected in the presence of obstructive spirometry. For example. pulmonary embolism. pulmonary emphysema. pulmonary infiltration with eosinophilia. bronchogenic carcinoma. A detailed clinical history as well as investigations as outlined will be helpful in differentiating these conditions. effusion. and cough secondary to drugs.Diagnosis of Bronchial Asthma 105 causes of airway obstruction which produce similar symptoms that need to be excluded. such conditions include mechanical obstruction of the airways. Of all the battery of tests utilised to diagnose asthma (methacholine challenge testing. These situations include: • Diagnosis unclear or in doubt • Unexpected clinical findings (like crepitations. and blood eosinophilia. diagnosis. cyanosis. reduced diffusing capacity (CO uptake) and pressure dependent airway collapse on flow volume curves. or without wheeze) • Unilateral or fixed wheeze • Stridor • Persistent chest pain or atypical features . clubbing. methacholine airway responsiveness and the sputum differential eosinophil count seems to be the most useful objective tests in patients with mild asthma. pulmonary infiltrations with eosinophilia. failure to demonstrate hyperresponsiveness in an untreated person with suspected asthma should prompt reconsideration of the diagnosis. In spite of a cautious and careful approach. chronic bronchitis. The sensitivity of these two tests are 91 and 72% respectively. but is also common in the general population and in patients with COPD. collapse. Occasionally.) • Spirometry or PEFR does not fit the diagnosis (like restrictive defect) • Suspected occupational asthma • Persistent shortness of breath (non-episodic. foreign body. and the specificity is 90 and 80% respectively. Of particular interest is the confusion with chronic bronchitis more so in elderly smokers. Presence of crepitations. interstitial lung disease. and an abnormal diffusion capacity favours chronic bronchitis with emphysema. heart failure. Failure to respond to asthma treatment should prompt a search for an alternative. pulmonary embolism. there may be situations when one has to refer the case to a specialist for opinion and further investigations. bronchiectasis. or additional.44 Increase bronchial responsiveness demonstrated by methacholine or histamine challenge is associated with symptomatic asthma. the FEV1/FVC ratio. sputum. vocal cord dysfunction. absence of eosinophils in the nasal secretion. however. cytokines. It must.45 Diagnosis of Occupational Asthma Careful history and temporal relationship of symptoms with work place will clinch the diagnosis.1: Diagnostic work-up for bronchial asthma COPD and Bronchial Asthma Most often there is a confusion whether the patient is having bronchial asthma or COPD as both the conditions has similar symptoms like cough. sputum eosinophilia. can be similar in COPD.106 Bronchial Asthma • Weight loss • Persistent cough or sputum production • Non-resolving pneumonia A suggested algorithm for the diagnostic work up in younger subjects with suspected asthma is shown in Figure 6. etc. increased bronchial hyperreactivity. inflammatory cells. Because the overall prognosis and course of the disease are entirely different in both the conditions. it is important to establish objectively a relationship between work and asthma symptoms. Wheezing. 6. Dyspnoea Spirometry with bronchodilators (Reversibility testing) Positive Negative Skin testing Positive Exercise/Methacholine Positive Negative Consider other diagnosis Negative Bronchial asthma Fig. but the types of cells and degree of involvement differ. However. the differentiation should always be made. Specific challenge tests of occupational exposure tests are often considered a reference standard for the diagnosis of occupational asthma. be possible that both conditions may coexist.1. Hence. The various tests used are: . There are some similarities also between the two conditions. Cough.1. Tissue eosinophilia. The important differentiating points between the two are shown in Table 6. wheezing and breathlessness. low. • Mast cells increase in smokers • IL-4 and IL-5 gene expression RANTES only in exacerbations . Emphysema No or little emphysema Eosinophilia. eczema etc) • Episodic wheezing • Signs of hyperinflation unusual • Crepitations—unusual findings • Evidence of cor pulmonale—absent • Cyanosis—unusual except in acute severe asthma • Signs of hypercarbia unusual • Chest skiagram—frequently normal Airflow obstruction • Postmortem • Sputum • • Surface epithelium Bronchiolar mucus cells Reticular basement membrane Congestion/oedema Bronchial smooth muscle Bronchial glands Cellular infiltrates Cytokines • • • • COPD • More older people • History of smoking. frequent • Chest skiagram will show changes of COPD like increased lung volumes. and RANTES gene expression • Enlarged mass. IL-5. • Marked eosinophilia (activation) • Mast cells increase (Decrease in severe/fatal cases) • IL-4.Diagnosis of Bronchial Asthma 107 Table 6:1: Important differentiating points between bronchial asthma and COPD Parameter Bronchial asthma Clinical • Young age of onset • Associated history of allergy (rhinitis. Variable (irreversible component • Progressive deterioration of may be there in late stages) lung function Hyperinflation. obliteration of cardiac dullness. exposure to pollution • No history of allergy • Signs of hyperinflation (hyperresonant notes on percussion. metachromatic • Neutrophils (infective exacerbations) cells. flat diaphragms. mucus plugs • Excessive mucus (mucoid/ purulent) (exudates + mucus). but no change in mucin histochemistry • Predominantly CD3. • Mild eosinophilia except during exacerbations. tubular heart. diaphragm) • Air entry diminished • Rhonchi and crepitation present • Cor pulmonale is a frequent complication • Cyanosis may be a finding • Signs of hypercarbia. creola bodies Fragility undetermined • Fragility loss Mucus metaplasia debated • Metaplasia/hyperplasia definite Homogenously thickened and • Variable or normal hyaline present Present • Variable/fibrotic Enlarged mass (large airways) • Enlarged (Small airways) • Enlarged mass. CD25. CD25 (IL-2R)+. attenuation of peripheral vessels. HLA-1 and HLA-DR+. eotaxin. CD4. urticaria. CD8. emphysematous bullae etc. CD68. increased acidic glycoprotein • Predominantly CD3. • Small airway disease. low. Lung. ii. USA. Specific challenge tests are required to identify the substances in the work place causing the symptoms. The clinical investigation of occupational asthma is shown in Figure 6. this is time consuming and not devoid of danger.2 and are recommended by the Expert Panel of the National Asthma Education Program by the National Heart. Animal products. .108 Bronchial Asthma i. An improvement in symptoms and lung functions away from work and recurrence of symptoms and deterioration in lung function after returning to work. The patient is asked to measure and record the PEFR every 2 hours from waking to sleep for at least 2 to 3 weeks at work. an individual may switch into different categories over time. Measurements of lung function (FVC and FEV1) when the patient has been away from the work environment for a period of time and again when he returns to work. followed by at least 10 days off work. as defined by the National Asthma Education Programme (NAEP) Expert Panel of 1991. The FEV1 or PEFR is expected to be greater than 80% when asymptomatic and to vary 20% with symptoms. can be summarised as: Mild: It is characterised by intermittent daytime symptoms up to two times in a week. severity of bronchial asthma. Different patterns of PEFR are described. moderate. iii. Significant increases in airway responsiveness when away from work. They should be performed by experienced personnel in hospital settings where resuscitation facilities are available and frequent observations can be made. and severe on severity of disease. Furthermore. Serial measurements of nonspecific airway responsiveness in conjunction with prolonged recording of PEFR has been proposed as an additional test to provide objective evidence of sensitisation. Allergy skin tests with high molecular weight compounds may be useful in identifying the responsible agent.47 This enables the clinician to categorize the overall assessment of a patient’s asthma and select appropriate therapy. and Blood Institute. and infrequent nocturnal cough or wheezing less than two times in a month. suggest an occupational relationship. Specific IgE antibodies to various occupational allergens may be demonstrated by RAST or by ELISA. associated with appropriate changes in PEFR. However. and because asthma is highly variable. positive skin tests and the presence of IgE antibodies indicate sensitisation and may occur in exposed workers without asthma. Thus. brief wheezing. The characteristics are shown in Table 6. iv. This is not very helpful in establishing a causal relationship between symptoms and work exposure. coffee.2. cough.46 Classification of Asthma Bronchial asthma can be defined as mild. However. Prolonged recording of PEFR by the patient at work and at home is a good method of establishing the causal relationship. Measurement of lung function before and after a work shift. or breathlessness with activity. Such specific antibodies against low molecular weight compounds conjugated to a protein like trimellite anhydride and isocyanate have been demonstrated in some exposed subjects. confirms that the symptoms are related to the work environment. flour. these characteristics may overlap. The method has the disadvantage of falsification of data and inaccurate readings. and castor bean produce immediate positive reactions on skin testing in sensitised subjects.47 The characteristics are general. 2: Diagnostic work-up of occupational asthma .Diagnosis of Bronchial Asthma 109 Fig. 6. Lung volumes often Spirometry may not be Usually a > 15% increased. Pulmonary function PEFR Normal or minimal Airway obstruction Substantial degree of Spirometry airway obstruction. without the use of systemic steroids Regular therapy not required except for exacerbations Exacerbations of cough and wheezing more frequent. Urgent care treatment < 3/year Periodic use of bronchodilators required during exacerbations for a week or more Steroids needed for short periods Requires continuous multiple round-theclock drug therapy including daily steroids either aerosol or systemic in high doses . not increased. Incomplete reversibility to acute aerosol bronchodilator Methacholine > 20 mg/ml Between 2-20 mg/ml < 2 mg/ml sensitivity (PC20) After optimal treatment is established Response to Exacerbations respond and duration of to bronchodilators therapy. Flow airway obstruction. Marked exercise vigorous exercise activity limitation tolerance like prolonged running Frequency of Not more than 1-2 2-3 times/week Considerable. 60-80% predicted. Almost nocturnal times per month nightly sleep interrupasthma tion. Often severe. May not tolerate Diminished Very poor. Tends to have sudden severe urgent visits to emergency department or doctor’s office > 3/year Hospitalization > 2/yr Frequency of Few clinical Cough and low grade wheezing Continuous symptoms symptoms signs/symptoms between acute exacerbations of cough and wheezing between exacerbations almost often present always present Degree of Good. Severe exacerbations infrequent. reduced expiratory flow curve shows Lung volumes at low lung volumes. May have aerosol bronchoaerosol bronchosubstantial increase in dilator even with near dilator lung volumes and normal baseline marked unevenness values.2: Classification of bronchial asthma Characteristics Pretreatment Frequency of exacerbations Mild Exacerbation of cough and wheezing no more often than 1-2 times/week Moderate Severe Virtually daily. Exacerbations frequent. Normal expiratory volume curve shows Flow volume flow volume curve. Usually a normalised even with response to acute > 15% response to steroids.110 Bronchial Asthma Table 6. of ventilation. evident. < 60% predicted. Early morning chest tightness School or work Good May be affected Poor attendance Attendance > 80% predicted. marked concavity. Chest 2002. Gold WM. and occasional hospitalisation. 18. Woltmann G. Macaubas C. PS Shankar. Diurnal variation of asthma. Lung. A comparison of the validity of different diagnostic tests in adults with asthma.141:584. Nature 1999. frequent exacerbations. Kramer MR. REFERENCES 1. Clark TJH. Laitinen LA. Cuttitta G.140:1368-72. 1997. Br J Dis Chest 1977. Lung function decline in bronchial asthma.344:344-45. 15. Shinar CM. Permutt S. Co-relative study with methacholine challenge testing. 16. Stumbles PA et al. Lancet 1994. Wagner EM. The FEV1 or PEFR is expected to be 60-80% at baseline and vary between 20-30% with symptoms. De Bock GH. 17. 14. Rebuck AS. Wassermann K. Schreiber J et al. The epidemic of allergy and asthma.402:B2-B4. 10. Bleecker ER. Chest 2002. Chest 2002. 7.122:821-25. 13. Behera D. Holt PG. Hunter CJ. exacerbations lasting several days. Holgate ST. Dekker FW et al. Severe: This is characterised by continuous symptoms including nocturnal symptoms.121:1051-57. J Ass Phy India.122: 1944-48. Wardlaw AJ. Clin Sci 1993. Chinn S et al. and emergency treatment.105:1042-1045. 12. The British Guidelines are parallel to the NAEP guidelines. 5. Validity of peak expiratory flow rate variability for the diagnosis of asthma. 2. Indian College of Physicians. Higgins BG. Pavord ID. Value of measuring diurnal peak flow variability in the recognition of asthma: a study in general practice. Hest 2002. Jamison JP. Normal values of Pulmonary Function Tests. Prevalence of atopy in asthma.121:673-74. Peripheral lung resistance in normal and asthmatic subjects. Gupta ML. Tov N. Licuanan J. Empey DW. The distribution of peak flow variability in a population sample. Gelb AF. 9.402:B12-B17. Weinnman GG. Is the short-term response to inhaled beta-adrenergic agonist sensitive or specific for distinguishing between asthma and COPD! Chest 1994. Zamel N. Am Rev Respir Dis 1990. Jacobs L. .92:636-37. 1995 (NIH Publication No.. Behera D: Pattern of airflow obstruction in Bronchial Asthma—An observation on Home-Monitoring of Peak Expiratory Flow Rate.344:350-62. Kesten S. Nadel A. Am Rev Respir Dis 1976. 3. Thiadens HA. limited activity levels. Cibella F.45:94-96.121:715-21. In: Pulmonary functions tests in Health and Disease (Ed). Hetzel MR. Value of a negative aeroallergen skin-prick test result in the diagnosis of asthma in young adults. a joint effort of the National Heart. 150-59. 1998. Brightling CE. 4. Bella V et al. Britton JR.85:367-71. N Engl J Med 2001. Busse WW. Allergy skin testing. American Academy of Allergy and Immunology J Allergy Clin Immunol 1993. Liu MC. Eur Respir J 1998. Nature 1999. and occasional emergency care.Diagnosis of Bronchial Asthma 111 Moderate: Moderate asthma is characterised by symptoms more than 1-2 times weekly affecting sleep and activity levels.71:87-92. Corne J. However. 6. The FEV1 or PEFR is less than 60% at baseline and highly variable. the Global Strategy for Asthma Management and Prevention Workshop. The role of allergy in the development of asthma. 113:131. Graif Y. Unsuspected loss of lung elastic recoil in chronic persistent asthma. McKinley RK. Am Rev Respir Dis 1989. 11. Board of Directors. Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Smith S. Is asthma another interstitial lung disease? Chest 2002. 8. Advances in immunology: Asthma. Yigla M. 19. 96-3659A) classifies severity of asthma into different (discussed subsequently). Lemanske RF.12:842-47. and Blood Institute and the WHO. Allergy Proc 1991. Bronchial responsiveness to histamine or methacholine in asthma: Measurement and clinical significance. 34.122:812-20. Reddel HK. Jones A. Biven RE.68:347-55. Thibault L. Chest 2002. Kunzli N. Perkins PJ. Norman P.51:503-09. 35. 25. Turcotte H.Alexander F.143:323-30. ATS News 1980 (Spring).121:1042-50. Thorax 1996. Anderson SD. and asthma symptoms. Bronchial hyper-reactivity. Krzyzanoski M. The presence of airway reactivity before the development of asthma. Nadel JA. Am Rev Respir Dis 1980.121:1818-23. Laprise C. Peak flow variability in the SAPALDIA study and its validity in screening for asthma-related conditions. 32. Morris MJ. Ryan G. Vocal cord dysfunction induced by methacholine challenge testing. Chinn S et al. American Thoracic Society Guidelines for bronchial inhalation challenges with pharmacologic and antigenic agents.757-61.12:143. Am J Respir Crit Care Med 2000. Bewtra AK. asthma like symptoms. Pattemore PK. Boushey HA.126:235-40. methacholine. Schindler C. Nair NM. Am Rev Respir Dis 1991. Thorax 1987. Burney PGJ. Schwartz J. Mason P. Am Rev Respir Dis 1990. 23. Eur Respir J 1994. Mostgaard G.160:427-34. 29. 37. Tweeddale PM. Chest 2002. Interrelationships between diagnosed asthma. Hopp RJ. A Screening test for airways reactivity. Legris C. 24. 39. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation.151:1320-25. The Odense Schoolchild Study. . Am Rev Respir Dis 1982. J Allergy Clin Immunol 1981. Siersted HC. Stutz EZ. Chatham M. Comparative bronchial response to hyperosmolar saline and methacholine in asthma. and respiratory disease. 26. Rosenthal RR. American Thoracic Society Guidelines for methacholine and exercise challenge testing. Sheller JR. 33. Perruchaoud AP et al. The SAPALDIA Team. 38. Forkert L.42:953-58. Predictors of methacholine responsiveness in a general population. 36. Boulet LP. Chest 1982.161:309-329. and abnormal airway behaviour in adolescence. 22. McCool FD. Chatham M.122:1988-93. Chest 2002. Salome CM. Holtzman MJ. The interrelationship among bronchial hyperresponsiveness. Luczynska G.141. 21. Am Rev Respir Dis 1990. Thorax 1994.42:487-90. the diagnosis of asthma. Am J Respir Crit Care Med 1999. The European Community Respiratory Health Survey. Hargreave FE.121:389-414. 1999. 41.142: 549-554. 40. Asher MH. Libowitz MD. Smith PL.156:403-409. A comparison of histamine. Townley RG. Chest 2002. 28. Hyldebrandt N et al. Quackenboss JL. Parker AL. Asymptomatic airway hyper-responsiveness: A three year follow-up.2-8.82:15-18. O’Donnell E. Peat JK et al. Bleecker ER. Norman PS. Bleecker ER.49. 31. Relationship to symptoms. Thomson NC et al. Nonisotonic aerosol challenge in the evaluation of bronchial hyper-responsiveness. Pulmonary function characteristics in patients with different patterns of methacholine airway hyper-responsiveness.7:954-60. Asymptomatic bronchial hyper-reactivity and the development of asthma and other respiratory tract illnesses. Smith PL. 30. McHardy GJ. Zemp E et al. Mason P. and exercise airway reactivity in normal and asthmatic subjects. Newton MF. 27. thorax 1987.112 Bronchial Asthma 20. Boulet LP. Am J Respir Crit Care Med 1997. Which index of peak expiratory flow is most useful in the management of stable asthma? Am J Respir Crit Care Med 1995. Short-term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. The normal range of diurnal changes in peak expiratory flow rates. Harrison AC et al. McLaughlin FJ. A comparison of the validity of different diagnostic tests in adults with asthma. Galvez RA. Guidelines for the diagnosis and management of asthma. National Heart. Latimer KM. 44. Maryland. Brightling CE. 46. Chan-Yeung M. USA. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate. 31:24-29. Malo JL. and Blood Institute. Hunter CJ.Diagnosis of Bronchial Asthma 113 42. Hargreave FE. Chest 2002. Thorax 1982. Immunopathology: Comparison of COPD and asthma. Voltman G et al. June 1991. Ryan G. In: Hansel TT. improvement after bronchodilator. 43. Basel. Karger.79:331-35. Lung. 45. Barnes PJ (Eds): New Drugs for Asthma. 91-3042A. Jeffery P. Dolovich J. and COPD. Publication No. The role of the methacholine challenge in children with chronic cough. Allergy. airway caliber. National Institute of Health.122:1051-57.37:423-29. . New Engl J Med 1995. Occupational asthma. J Allergy Clin Immunol 1987. Levison H. Expert Panel Report. National Asthma Education Programme. Prog Respir Res. 2001. 47. Bethesda.333:107-12. Age and Ethnicity Asthma-related death rates are higher among older patients than in any other age group.114 Bronchial Asthma 7 Prognosis of Bronchial Asthma FACTORS FOR ASTHMA MORTALITY Although the possibility of asthma-related death exists for all patients with asthma. resulting in more serious and long-lasting bronchial inflammation and reactivity. several studies have revealed factors associated with an increased risk of such deaths. but little emphasis has been placed on the possibility that confidence in better drug treatment may modify patient’s behaviour so as to place him at greater risk of illness. There are many hypotheses to explain this. and the mortality rate in this group has increased significantly during the past decade. Previous Life-threatening Acute Asthma Exacerbations Individuals who have had acute exacerbations of asthma that resulted in respiratory failure and required intubation are at increased risk for subsequent fatal exacerbations. and Canada have shown increases over the last two decades in the incidence of deaths from asthma. It is also very likely that prevention of symptoms by use of antiasthma drugs could allow patients to spend more time in environments containing antigens or other agents that provoke asthma. African-Americans of both sexes were about twice as likely to die of asthma as Caucasians.1-6 Several studies from many countries of the world including Britain. AfricanAmericans have asthma related mortality rates that are higher than those of Caucasians. Those who have experienced respiratory acidosis without requiring intubation are also high-risk patients. especially in relatively young age groups. Some of these recognised factors that increases the susceptibility to death from asthma are as follows. Germany. In 1979. particularly members of minority groups. New Zealand. United States. Although the death rate is relatively low in younger patients. an increased trend in asthma deaths among these individuals between the age group of 5 to 34 years have been noted during the last 10 years. The cause of such increase in deaths remains a puzzle. . Excessive confidence in bronchodilator inhalers and nebulisers can make patients stay away from hospitals too long during acute attacks. People in their late teens and early twenties. are over represented in asthma mortality statistics groups. France. and asthma fatality. As a result. these patients seek help only when their asthma symptoms are severe and report to the emergency room for initial care. Some tend to minimise their symptoms and avoid access to health care. Regardless of the possible physiologic and psychological interactions that link anxiety. Patients of lower socioeconomic class are unable to obtain routine preventive asthma care. they tend to either develop decompensating psychiatric disease and symptoms of extreme anxiety or develop even higher levels of denial. lack of access to adequate emergency care can result in life-threatening delay in medical treatment during exacerbations. it is evident that patients who have these psychological disruptions are at increased risk for death. documented depression. Medication Use Medications. adequate facilities like ventilatory support are not available. risk of death is increased. Following a near fatal exacerbation. and schizophrenia. family conflict. Underestimation of the severity of such exacerbations may lead to a life-threatening delay in starting medical treatment or seeking medical care. Patients who have experienced a life-threatening asthma exacerbation have been reported. Other psychological problems that have been documented as associated with those at increased risk include alcohol abuse. depression. and social isolation. are underused at the time of death.7-15 Lack of Access to Medical Care Lack of access to medical care is another risk factor associated with asthma-related death.16 In rural areas. Without the documented objective measures of pulmonary function or realisation by the patient and/or the physician of the severity of the disease. Those with more than two hospitalisations for status asthmaticus in spite of long-term oral steroid therapy are at the highest risk of dying from asthma. recent family loss and disruption. Even in some urban centers. which may in turn. This treatment may temporarily blunt symptoms but mask increasing inflammation and airway hyperresponsiveness.17-19 . particularly steroids. Other associations include life crises. recent unemployment. Some patients may fail to appreciate a poor response to treatment during an acute exacerbation and may rely on frequent repetitive use of inhaled β2-agonist far in excess of recommended doses for therapy at home. lead to abrupt and severe deterioration of lung function. to deny that they are at risk of death. In some patients. on the whole. Psychological and Psychosocial Problems Depression leads to increased death particularly in children. The controversy of the asthma mortality because of β-agonist use is still on.Prognosis of Bronchial Asthma 115 Hospital Admission for Asthma within the Last Year Those patients hospitalised for asthma within the last year have a greatly increased risk of dying from asthma when compared to severity-matched asthma patients in the community that have not been hospitalised. deterioration during an acute exacerbation occurs very rapidly. Prevention of fatal asthma. Barriot P. Can they be predicted? JAMA 1985.899-904. Jackson R et al. A district confidential enquiry into death due to asthma. Thorax 1995. Boseley CM.254-59. Jackson R et al. Wissow LS. Gibson GJ. Vollmer WM. Perception.261-69. Strunk RC.80:481. Campbell DA. Psychological factors and deaths from asthma.116 Bronchial Asthma REFERENCES 1.1117-20. J Allergy Clin Immunol 1989. Crane J. The psychological factors associated with poor compliance with treatment in asthma. 14. Eur Respir J 1994. Rea HH. Felt RW. Burgess C. 3. Depression and asthma: A potentially lethal mixture. and hospitalisation for childhood asthma. Thorax 1986. Starfield B. 11. Prescribed fenoterol and death from asthma in New Zealand. Creer TL. Mrazek DA. A comparison of asthma deaths and near fatal asthma attacks in South Australia. LeBreque JF. Buist AS. 18. Beasley R. 8. Wagener DK. Ann Allergy 1988. Crane J. 4. Fosbury JA. Yellowlees PM. Strunk RC. Lancet 1989. Ernst P.50. a review of 41 asthma deaths in Oregon in 1982. Eur Respir J 1995.60:31-39. Am J Respir Crit Care Med 1994. Pearce N. Further investigations into the recent increase in asthma death rates.330:1329-34. Gittelsohn AM. Harrison BDW. 13. Asthma and the beta agonist debate. McLennan G. . personality. Scragg R.92:460. N Engl J Med 1994. race.132:s107. 9. Jenkins PF. Weiss KB.41:833.1069(Suppl4):2S-3S. Flatt A.48. 12. Am J Public Health 1988. 6. Am J Epidemiol 1990. Wareham NJ. Chest 1987. Suissa S. 19.149:604-10.83:477. Fuhrmann GSW. McLennan G. Campbell DA. J Asthma 1986. Barger LW. 1981-85. Identification of the fatally-prone subject with asthma. 7. Thorax 1995.314:423. 2. Death from asthma in childhood. Benatar SR.7:490-97. Stableforth DE. Mussman M.1:917-27. A cohort analysis of excess mortality in asthma and the use of inhaled beta agonists. Fatal asthma. Cochrane GM. Psychiatric and medical features of near fatal asthma. Geographical variations in US asthma mortality: Small area analysis of exercise mortality. A case-controlled study of deaths from asthma. 1981-83: Case control study. N Engl J Med 1986. Nicholls J. et al.78:777. Poverty.50(Suppl 1):S5-S10. Riou B. Boivin JF et al.254:1193-98. 15. Chest 1994. Psychological barriers to asthma education.8. 10. Thorax 1993. and respiratory control in life-threatening asthma. 17.23. Szklo M. 5. 16. Coates JR et al. Fitzgerald JM. J Allergy Clin Immunol 1987. Creation and critique of a myth. Miller BD. 14 North America15 and parts of Asia.Complications of Bronchial Asthma 117 8 Complications of Bronchial Asthma Infections. Torulopsis glabrata. Rhizopus.1 The most common fungus involved is Aspergillus fumigatus. Bipolaris.18-27 The disease is typically seen in patients with long-standing asthma or cystic fibrosis. and atelectasis due to mucus plugging are the complications of acute bronchial asthma. although higher figures have been reported. Helminthosporium sp.13 Subsequently the entity has been reported more frequently from that country as well as from other regions of the world like Australia. Aspergillus fumigatus is the one responsible for the condition although other species may also be responsible.12 Cor pulmonale secondary to bronchial asthma is extremely uncommon and in fact.29 Pathophysiology Patients with ABPA are usually atopic and have a history of bronchial asthma. eosinophilia. The basic underlying pathophysiologic process in ABPA is a hypersensitivity reaction to the presence . Candida albicans. pneumomediastinum. The prevalence of such sensitisation reportedly occurs in 20-50% of cases of bronchial asthma and the incidence of full-blown pictures of ABPA occurs in about 65 of cases. and Fusarium vasinifectum. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA) Allergic bronchopulmonary aspergillosis is a complex hypersensitivity reaction to Aspergillus antigens because of the presence of the fungus in the bronchial tree and the disorder characterised by bronchospasm. Stemphylium sp. The first three cases were diagnosed in 1952 in England by Hinson et al. Curvularia lunata.2-11 Other organisms that can cause such bronchopulmonary reactions include other species of Aspergillus.16 It was first reported from India in 197117 and a few case series have subsequently been documented. Penicillium. and immunologic evidence of allergy to the antigens of Aspergillus species. Sensitisation to aspergillus antigens may occur in asthmatics without full-blown picture of ABPA. Allergic broncho-pulmonary mycosis (ABPM) is an important complication of asthma. Drechslera hawaiiensis. pulmonary infiltrates. Pseudoallescheria boydii. The incidence of the condition in asthmatics is reported to vary from 3 to 20% of corticosteroid dependent asthma patients28 and 6% of patients with cystic fibrosis meet the diagnostic criteria of ABPA. pneumothorax. Respiratory failure is common during acute severe asthma. the presence of this complication should be an indication that the underlying problem is not asthma. Pseudomonas aeruginosa. Other host factors. Tissue invasion by the fungus usually does not occur. The factors favouring the initial colonisation of the bronchial tree are unclear.33 Recently a possible role of type IV hypersensitivity reaction has been inferred from the demonstration of in vitro lymphocyte transformation in response to Aspergillus antigens in patients with ABPA and the presence of parenchymal granuloma and mononuclear cell infiltration seen on histopathology. Antigenic material from the fungus stimulates production of IgE. may contribute to the pathologic changes seen in ABPA. IgG. immune complex) hypersensitivity reactions occur in this condition. Alternate pathway complement . The type I immediate hypersensitivity reaction is IgE mediated and account for the bronchospastic symptoms of the condition.118 Bronchial Asthma Flow Chart: Clinical spectrum of inhalation of Aspergillus spores Inhalation of Aspergillus Colonisation Normal host No sequel Cavitary lung disease Aspergilloma Chronic lung disease or mild immunocompromised Chronic Nercotising Aspergillosis Immunocompromised host Invasive Pulmonary Aspergillosis Asthma ABPA Colonisation Tracheobronchitis Ulcerative Tracheobronchitis Pseudomembranous tracheobronchitis of fungus in the bronchial tree. inflammation of bronchial and peribronchial tissue and is responsible for the radiological features of ABPA. and IgA antibodies.30. A number of immunologic reactions.31 The changes brought about by the ensuing local immunologic reactions and the tenacious sputum of bronchial asthma favour the trapping of fungal spores and further colonisation.32. including cellular immunity. Both these reactions play a central role in the pathogenesis of ABPA. notably type I (immediate) and type III (antigenantibody. Type III reactions mediated by IgG result in polymorph aggregation. Five stages have been identified in patients with ABPA. Patients may exhibit minimal symptoms.fumigatus characterize this stage. patients are rarely identified at this stage. symptoms. headache.35 These plugs consist of fungal hyphae with eosinophils and mucus. lung contraction.36. and loss of weight. Stage I The classic signs. Other findings include granulomatous inflammation. • Stage II (Remission stage). yet demonstrate extensive pulmonary consolidation on chest radiography. Bronchi contain tenacious mucus. The onset is insidious with nonspecific complaints like anorexia. fibrin. Cough is universal and dyspnoea may be present in a substantial number of cases. monocytes. Bronchial asthma. Presence of immune complexes has been demonstrated in some cases with immunofluorescent studies. The bronchi are dilated and are filled with tenacious exudates containing eosinophilic material and mycelia. There is no tissue invasion by the fungus and granulomas may be seen. Expectoration of such plugs is associated with a dramatic improvement in symptoms particularly wheezing. and mononuclear cells. In practice. Curschmann’s spirals. pulmonary infiltrates. a markedly elevated IgE levels. and the presence of IgE and IgG antibodies to A. fibrosis. Pleuritic chest pain may be present in about half of the patients and is usually localised to the side involved on chest X-ray. eosinophils. The increased frequency of wheezing is associated with intermittent or continuous sputum production. generalised aches and pains. • Stage IV (Corticosteroid-dependent asthma stage). Charcot-Leyden crystals. and lobar shrinkage. • Stage III (Exacerbation stage). Haemoptysis has been reported in 34 to 85% of cases. progressive fatigue. The most significant findings involve bronchi and bronchioles34 with bronchocentric granulomas and mucoid impaction.34 Clinical Features of ABPA The patient is usually an atopic individual with established bronchial asthma of many years. The cellular infiltration consists of eosinophils. Lung biopsy in ABPA (done rarely as diagnosis is mainly clinical and laboratory findings) demonstrates different stages of chronic inflammatory process involving bronchial walls and peribronchial tissues. Rubbery golden-brown plugs of sputum production are characteristic of this condition and have been reported in 5 to 54% of cases. Vasculitis is very rare. Long-standing involvement of the bronchial tree leads on to bronchiectasis. low grade fever. peripheral eosinophilia. In long-standing cases variable degrees of interstitial and alveolar fibrosis are seen. Wheezing and diffuse crepitations are the common findings on chest examination. The underlying asthma usually increases in frequency and severity with less degree of control with the usual anti-asthmatic medications.37 which help to guide the management of the disease.Complications of Bronchial Asthma 119 activation may also take part in the inflammatory response of ABPA. plasma cells and multinucleated giant cells. and laboratory findings present at diagnosis characterize the acute stage. Chronic cases may present with symptoms compatible with bronchiectasis. There is no clear relationship between exposure to antigens and the onset of symptoms. and • Stage V (Fibrotic stage). . The stages are: • Stage I (Acute stage). It is not necessary for a patient to progress through all these stages. Fungal hyphae may be seen in the bronchial lumen without tissue invasion. cyanosis. clubbing. respiratory failure and death may occur in some patients. Radiographic infiltrates. v. iv.38 (Figs 8. Attempt to taper steroid therapy will result in worsening of symptoms and the development of pulmonary infiltrates. Remission after an exacerbation is induced in these patients with corticosteroids and prolonged therapy is not necessary. and who show additional features of allergic disease such as eczema and allergic rhinitis. ii. and maintenance therapy is not required in these patients. In the other subset of patients who have the onset of their asthma after the age of 30. and a discontinuation of corticosteroid therapy over a six month period without recurrence of ABPA. “Tooth-paste shadows” due to impaction of mucus in the damaged bronchi. and. asthma may become refractory to aminophylline. The dose of steroids needed to control asthma usually is not sufficient for preventing the exacerbations of ABPA or the occurrence of both. generally have less cutaneous skin reactivity to common allergens and no other clinical symptom suggests allergic disease. control of respiratory symptoms. Transient changes. the typical changes are fleeting pulmonary infiltrates that tend to be in the upper lobe and central in location. β-agonists and Cromolyn and inhaled steroids may be necessary.5 plate 1 and 2) During acute exacerbations. crepitations. Air-fluid levels from dilated central bronchi filled with fluid and debris. cor pulmonale. Stage V The fibrotic lung disease stage is present when there are extensive fibrotic changes on chest X-ray (end-stage lung disease) with irreversible obstructive lung disease on pulmonary testing. but not to the normal levels. “Gloved-finger” shadows due to distally occluded bronchi filled with secretions. Massive homogenous consolidation which may be unilateral or bilateral. Serum IgG antibodies to Aspergillus may be slightly elevated. In some. Radiology The roentgenography changes in ABPA may be normal in early stages of the disease or they may be transient or permanent. . eosinophilia is absent. mucoid impactions or secretions in damaged bronchi. which may clear with or without steroid therapy is due to parenchymal infiltrates. a decline in total serum IgE levels.1 to 8. Dyspnoea. iii. ABPA may precede the clinical recognition of the disease for many years. Stage III The exacerbation stage is the one when the patent is a known case of ABPA and demonstrates all characteristics of the acute stage or when there is a two-fold rise in the total serum IgE levels in association with radiological finding in the absence of other causes of infiltrates like bacterial or viral pneumonias. Stage IV The corticosteroid-asthma stage is present when patients require oral steroid therapy to control asthma (steroid-dependent asthma) or to prevent recurrent exacerbations. A minority of patients progress to this stage. Usually there are two sets of ABPA patients based on the onset of asthma before the age of 30 who have greater skin reactivity to other common allergens. Steroid therapy is not able to reverse these changes completely. The serum IgE level and eosinophil count may be low or high.120 Bronchial Asthma Stage II The remission stage is characterised by radiological clearing. These transient findings include: i. Perihilar infiltrates simulating adenopathy. Prolonged and permanent remissions may occur after treatment of the acute stage with steroids. vi. Leucocytosis and raised ESR are found during acute episodes. β-2 agonists can prevent the immediate reaction and the late reaction may be prevented by corticosteroids. Bronchial challenges with A. local emphysema. The degree of reversibility is much less compared to that in classic extrinsic-asthma. Cromolyn sodium may prevent both types of reactions. Serial determination of total serum IgE may thus be helpful in detecting patients with ABPA or following the course of ABPA and determining the onset of an acute exacerbation. Abnormalities of pulmonary function tests in ABPA depend upon the stage at which they are performed. However. Other rare findings may be cavitation. . During the earlier stages of pure bronchospasm there will be an obstructive physiologic profile.fumigatus extracts demonstrates an immediate wheal and flare reaction in most cases. the levels decline after remission. and sputum contains eosinophils in most of the patients. neither of these parameters is specific for ABPA. Serologic tests using double gel diffusion method reveal precipitating antibodies in most patients of ABPA.fumigatus. total lung collapse due to mucus impaction.fumigatus characteristically show a dual response in patients with ABPA. Normal chest X-ray does not exclude the diagnosis of ABPA.fumigatus and 10% demonstrate positive precipitating antibodies against this. Repeated cultures are necessary to demonstrate the fungi. IgA. and complement components. Ring shadows which are dilated bronchi. It has been demonstrated that up to 25% of patients of asthma have immediate skin reactivity to A. and iii. Radio immunoassay or ELISA techniques detects antibodies specific for Aspergillus belonging to several immunoglobulin classes. This reaction is frequently followed by a late onset of erythema and edema occurring at the injection site over the next 4 to 6 hours. Proximal bronchiectasis. and spontaneous pneumothorax. Laboratory Findings Peripheral eosinophilia is common. These late reactions are due to deposits of IgG. ii. Parallel line shadows which are tram-line shadows resulting from bronchiectasis. Skin testing with potent A. which are two parallel hairline shadows extending out from the hilum. Tram-line shadows. contracted upper lobes. the tests will reflect a restrictive physiologic profile. The reaction reaches its peak by 8 hours and subsides by 24 hours. The chest CT may be more sensitive in demonstrating the above changes and has replaced the necessity of bronchography.39 Occasionally. The diffusion capacity is reduced in most patients with a good correlation with the duration of the disease. the serum IgE may be low. The serological abnormalities include a marked increase in total serum IgE and specific IgE and IgG antibodies against A. Aspergillus can be cultured from sputum of nearly two-thirds of patients during acute episodes of ABPA.Complications of Bronchial Asthma 121 vii. Thus. honeycomb fibrosis. whereas during the irreversible stages of the disease with bronchiectasis and fibrosis. bronchial challenge test is not required to confirm ABPA and may be risky. IgM. Permanent changes include: i. The levels of both total and specific serum IgE levels are high during the development of pulmonary infiltrations. 3. 3. Withholding therapy until the development of all clinical symptoms and evidence of bronchiectasis may lead to a missed diagnosis in a significant number of patients and to delayed treatment resulting in irreversible pulmonary damage.1: Rosenberg criteria for diagnosis of ABPA Primary 1. Minimal criteria for the diagnosis of ABPA without central bronchiectasis: (labelled ABPA-seropositive) Asthma. 6. 6. 8. certain if all seven are present. Bronchial asthma Immediate skin reactivity to Aspergillus Serum precipitin to A.2: Modified diagnostic criteria of ABPA 1.2. Episodic bronchial obstruction Peripheral blood eosinophilia Immediate skin reactivity to Aspergillus antigens Precipitating antibodies against Aspergillus antigens Elevated serum IgE History of infiltrates in the chest X-ray Central bronchiectasis Aspergillus in sputum History of mucus plug expectoration Late skin (Arthus) reactivity to Aspergillus antigen The diagnosis of ABPA is considered likely if the first six primary criteria are present.fumigatus Total serum IgE > 1000 ng/ml Current or previous pulmonary infiltrates Central bronchiectasis Peripheral eosinophilia (1. Essential criteria for the diagnosis of ABPA with central bronchiectasis : Asthma. 4. Table 8. Rosenberg et al35 have suggested the following which is accepted by most investigators. 2. 2.40 A. 7.000 cells/μL) Not all of these criteria need to be present to diagnose ABPA. Immediate skin reactivity to Aspergillus antigen Serum IgE > 1000 ng/ml Central bronchiectasis B. 5. 7.122 Bronchial Asthma Diagnosis There are no universally accepted criteria for the definite diagnosis of ABPA. 2. Table 8. Secondary 1. 5. 4. Immediate skin reactivity to Aspergillus antigen Serum IgE > 1000 ng/ml History of pulmonary infiltrates Elevated levels of serum IgE and IgG antibodies to A.1 and 8.fumigatus . ABPA may be subdivided into the following groups of patients with or without central bronchiectasis.39 They are listed in Tables 8. Greenberger and Patterson recently modified the diagnostic criteria for ABPA.fumigatus Increased serum IgE and IgG to A. 3. Therefore. and cotrimazole.Complications of Bronchial Asthma 123 From a North Indian hospital (PGIMER. Tuberculosis. may be the initial diagnosis. In that situation a diagnostic work-up for ABPA is warranted. some cases can also be due to other species of Aspergillus. The other etiologies of eosinophilic pneumonias can usually be differentiated on clinical and immunological grounds. sweat chloride test. because of its similar upper lobe involvement on chest X-ray. particularly. skin test reactivity and elevated serum IgE levels. in 89 patients. Carcinoma of the lung. The first one was thought to be achieved by employing inhalation of anti-fungal agents such as amphotericin B. However this approach has now largely been abandoned because of frequent recurrences and because of the need for repetitive treatments more often. and Torulopsis globata are examples which have been shown to cause such reactions similar to ABPA in the lungs. Curvularia lunata. In recent years. or by precipitating antibodies (122 of 338 cases) against Aspergillus species. Chandigarh) a total of 651 patients with clinical suspicion of ABPA27 were reported during a period of 8 years (January 1991 to December 1998). allergic bronchopulmonary reactions have also been observed due to moulds or bacteria. Repeated sputum examination will be negative for acid-fast bacilli. Differential Diagnosis A number of disorders may be confused with ABPA. constitutional symptoms. diagnosis was confirmed on the basis of Rosenberg’s criteria. Cystic fibrosis patients also may be confused with ABPA. 338 cases (52%) were positive either by sputum microscopy/culture (66 of 203 patients). increased dyspnoea or wheezing and rhonchi were the main presenting symptoms. Treatment Therapeutic approach to treat ABPA may be directed to achieve two goals: (i) to remove the source of antigenic stimulation by eliminating the fungus from the bronchial tree. these patients have a number of features in common with ABPA including isolation of the fungus from the sputum. Overall. Pseudomonas aeruginosa. nystatin. and (ii) suppressing the bronchial hypersensitivity reactions and their associated local parenchymal changes. precipitating antibodies against aspergillus species were positive in 64 (72%) and sputum microscopy/ culture was positive in 56 (63%) of these 89 patients. Clinical profile and laboratory findings showed that the disease was more common among males. A high degree of suspicion is necessary to avoid this confusion. Candida albicans. Poor control of asthma. bronchospasm. In fact. Because of the later effect the bronchus becomes . Skin reactivity against aspergillin was seen in 73 (82%). It is not uncommon to find patients receiving antitubercular therapy. Stemphylum species. and other associated nonpulmonary features will help to distinguish the two conditions. bronchoalveolar cell carcinoma. by skin reactivity (150 of 309 cases). Oral corticosteroid therapy is the treatment of choice in ABPA. Although classically ABPA is caused by Aspergillus fumigatus. the age of onset of cystic fibrosis. Helminthosporium species.19 History of asthma with such chest X-ray should arouse the suspicion. However. mucopurulent expectoration. They act by suppressing the allergic inflammatory reaction by suppressing the immunologic response to aspergillus antigen and decrease sputum production. Central bronchiectasis and fleeting shadows were the most common radiological findings. However. may some times be confused with ABPA particularly in elderly individuals. Dreschslera hawaiiensis. natamycin. The study concluded that patients with ABPA generally benefit from concurrent itraconazole therapy without much side effect and suggested that a lower dose of 200 mg daily is equally beneficial and may be used as a maintenance therapy to sustain remission.36:173-79. or the resolution or absence of pulmonary infiltrates). Period prevalence of allergic bronchopulmonary mycosis in an outpatient population is over 1 percent. Malik SK. Serum IgE levels should also be monitored regularly.43 This dose is usually sufficient to improve pulmonary lesions in two weeks. Usually there is an exacerbation of symptoms during particularly seasons due to an increase in the fungal spores in the atmosphere. frequency of exacerbations. 46% of the patients showed a significant response (a 50% reduction in corticosteroid dose. but its use is limited by the degree of obstruction and mucus plugging.42 The current treatment of exacerbation of ABPA consists of daily administration of prednisone in a dose of 0. 2.7:67-69. The disease has been seen throughout the world and has been a subject of extensive review from across the globe. Most patients. require more prolonged therapy to control their symptoms and minimize relapse. Allergy Bronchopulmonary Aspergillosis: A Retrospective study of 35 cases.43. 4. and decreasing serum IgE level and peripheral eosinophilia. Indian J Chest Dis All Sci 1994. Aggarwal AK. Guleria R. and a 25% improvement in exercise tolerance or pulmonary function test results. clearing of pulmonary infiltrates. and severity of asthma.fumigatus in bronchial asthma. Jindal SK. at which time the same dosage is changed to a single alternate-day regimen. Resolution of radiographic infiltrates and improvements in symptoms have been observed in most patients. Pulmonary function tests should be obtained yearly. 3. Prednisone therapy maintains clinical improvement in over 80% of patients by relief of bronchospasm.47 attempts were made to use alternative drugs. The role of itraconazole. Talwar P.14:95-98.48 When the drug is used in a dose of 200 mg twice daily for 4 months. It is perhaps best to obtain the X-ray every three to six months during the first year of follow-up and on a yearly basis thereafter to avoid missing intercurrent pulmonary damage. at a rate of 5 mg/day may be attempted. Kumar L.46 Since there are side effects associated with long-term use of corticosteroid therapy.49-53 REFERENCES 1.45. . Eur Respir J 1991. slow reduction of prednisone. Allergic bronchopulmonary aspergillosis. The frequency of chest X-ray to be taken in following a patient of ABPA is not known. a chest X-ray should be obtained to rule out exacerbation. an anti-fungal agent has been evaluated. and when a twofold increase is present. Inhaled therapy may be beneficial. however. given as a single morning dose for a period of two weeks and then gradually decreasing the dose. Talwar P. This varies with geographic locations and accordingly the steroid therapy should be reduced with caution during these months.124 Bronchial Asthma less favourable for further fungal colonisation. Behera D. Bredin CP. Monthly serum IgE levels are to be obtained. Skin hypersensitivity and precipitating antibodies against A. Bull PGI 1980.44 If the chest X-ray shows improvement and there is a substantial reduction in total serum IgE levels. Panigrahi D. Treatment must be individualised depending upon the stage of ABPA.5 mg/kg. including an increased risk of invasive aspergillosis. Donnely S.4(Suppl 14):1715.41. This dosage is maintained for a minimum of three months. Inhaled steroids are not helpful in preventing the progression of lung damage associated with ABPA. Lung India 1989. Behera D. Malik SK. Chakrabarti A. a decrease of at least 25% in the serum IgE level. 57:73-87.113:428-35. Randhawa HS. J Ass Phys India 1971. Thorax 1952. 23. 7.34:8-11.64:507-12. 14. Mycoses 2002. Chetty A. Panigrahi D. Chakrabarti A. Allergic bronchopulmonary aspergillosis: a retrospective study of 35 cases. Ind J Chest Dis All Sci 1994. 16. Lung India 1989. 13. Ind J Chest Dis 1972. Ind J Chest Dis 1972.84:249-51. Hypersensitivity disease of the Lung.19: 835-841. 30. Menon MPS. Behera D. Backman KS. Shivpuri DN. Allergic aspergillosis. Epidemiology and pathogenesis of Para nasal sinus mycoses. Sandhu RS. Khan ZU.19:61-67. 8. Bedi RS. 18. Concomittant allergic Aspergillus sinusitis and allergic bronchopulmonary aspergillosis with familial occurrence of allergic bronchopulmonary aspergillosis. 11. Bazaz Malik G. Sandhu RS. Chetty A.45:295-99. an Indian report. J Allergy Clin Immunol 1981.503:289-301. Kumar L. Plummer NS. Aggarwal MK. Knutsen AP. Shah JR. 12. Sircar M. Subramanium S. 26. India. Chakrabarti A. Allergic bronchopulmonary aspergillosis: Review of 20 cases.14:72-77. Talwar P. Scand J Respir Dis 1976. J Ass Phys Ind 1971. Raman DSV. Behera D.1:231-33.152:1379-81. Allergic bronchopulmonary aspergillosis: A study of 46 cases with special reference to laboratory aspects. Allergic bronchopulmonary aspergillosis in Indian children with bronchial asthma. Randhwa HS et al. Allergic bronchopulmonary mycosis caused by Fusarium vasinfectum. Invitro T-cell response in patients with cystic fibrosis and allergic bronchopulmonary aspergillosis. Allergic bronchopulmonary aspergillosis. Sharma SC.7:67-69. J Lab Clin Med 1989. Viswanathan R. Randhawa HS.36:181-86. metropolitan area. Viswanathan R. 17. Ilyas M. Otolaryngol Head Neck Surg 1992. Khan ZU. Allergic bronchopulmonary aspergillosis. Scand J Respir Dis 1976. Allergic bronchopulmonary aspergillosis. Prakash D. Bronchopulmonary aspergillosis. Khan ZU. 9. Behera D. 27. Khan ZU. Jindal SK. Allergic aspergillus sinusitis. Chaturvedi S.Complications of Bronchial Asthma 125 5.44:204-13. A review and a report of eight cases. Bhargava S. Graves TS. Allergic bronchopulmonary aspergillosis. Sandhu RS.54:46-49. Dusaj IS. Sandhu RS. Allergic bronchopulmonary aspergillosis. Patterson R. Hinson KFW. J allergy 1969. University Michigan Med Centre J 1968. Med J Australia 1967.53:289-301. Prakash D.54:46-49. Jain RK. A study of 46 cases with special reference to laboratory aspects. Randhawa HS. Allergic bronchopulmonary aspergillosis in India.36:173-79. Scand J Respir Dis 1972. . Sandhu RS. Chest 1994. Chander J. Ann Allergy 1985. Ind J Chest Dis All Sci 1994. Bazaz Malik G.57:73-87. Subramianiam S.14:72-77.7:317-33. Smith JT. 6.. Shah A. Am J Respir Crit Care Med 1995. Spok A. Mrouch S. Respir Med 1990. Basich JE. Shah JR. Jain RK. Chaturvedi S.19:835-41. Randhawa HS. Baz MN et al. Golbert F. Mishra SK. Aggarwal AK. Ind J Tubercl 1972. Slavin RG.68:98-102. 10.107:745-50. Ann Allergy 1985. Roberts M. 24.105:32-36. Studies on the allergic fungal spores of Delhi. Chakrabarti A. 29. 25. Pamra SP. Guleria R. Scand J Respir Dis 1972. Allergic bronchopulmonary aspergillosis in Indian children with bronchial asthma. 19. 20. Patterson R. Ann allergy 1990. 28. Shah A. Khan ZU. Skin hypersensitivity and precipitating antibodies against A. 15. Moon AJ. Sethi S. Allergic bronchopulmonary aspergillosis in corticosteroid dependent asthmatics. Allergic bronchopulmonary aspergillosis. Bhargava S. Malik SK. Elder JL. Randhawa HS.Fumigatus in bronchial asthma. 21. Eight-year study of allergic bronchopulmonary aspergillosis in an Indian teaching hospital. Allergic bronchopulmonary aspergillosis. Mishra SK. in India. Allergic bronchopulmonary aspergillosis in patients with cystic fibrosis. 22. 126 Bronchial Asthma 31. Chauhan B, Santiago I, Kirschmann DA et al. The association of HLA-DR alleles and T-cell activation with allergic bronchopulmonary aspergillosis. J Immunol 1997;159:4072-76. 32. Wang JL, Patterson R, Rosenberg M et al. Serum IgE and IgG antibody activity against Aspergillus fumigatus as a diagnostic aid in allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1978;117:917-27. 33. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Ann Rev Med 1999;50:303-16. 34. Bosken CH, Myers JL, Greenberger PA et al. Pathologic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol 1988;12:216-22. 35. Rosenberg M, Patterson R, Mintzer R et al. Clinical and immunological criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 1977;86:405-14. 36. Patterson R, Greenberger PA, Radin RC et al. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med 1982;96:286-91. 37. Patterson R, Greenberger PA, Hawig JM et al. Allergic bronchopulmonary aspergillosis; natural history and classification of early disease by serologic and roentgenographic studies. Arch Intern Med 1986;146:916-18. 38. Mintzer RA, Rogers LF, Kruglik GD et al. The spectrum of radiologic findings in allergic bronchopulmonary aspergillosis. Radiology 1978;127:301-07. 39. Greenberger PA, Patterson R. Diagnosis and management of allergic bronchopulmonary aspergillosis. Ann allergy 1986;56:444-48. 40. Greenberger PA. Immunologic aspects of lung diseases and cystic fibrosis. JAMA 1997;278: 1924-30. 41. Rosenberg M, Patterson R, Robert M et al. The assessment of immunologic and clinical changes occurring during corticosteroid therapy for allergic bronchopulmonary aspergillosis. Am J Med 1978;64:599-606. 42. Wang JL, Patterson R, Roberts M et al. The management of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1979;120:87-92. 43. Capewell S, Chapman BJ, Alexander F et al. Corticosteroid treatment and prognosis in pulmonary eosinophilia. Thorax 1989;44:925-29. 44. Safirstein BH, D’Souza MF, Simon g et al. Five-year follow-up of allergic bronchopulmonary aspergillosis. Am Rev Respir Dis 1973;108:450-59. 45. British Thoracic Association. Inhaled beclamethasone dipropionate in allergic bronchopulmonary aspergillosis: Report to the Research Committee of the British thoracic Association. Br J Dis Chest 1979;79:349-56. 46. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest 2002;121:1988-99. 47. Ganassinni A, Cazzadori A. Invasive pulmonary aspergillosis complicating allergic bronchopulmonary aspergillosis. Respir Med 1995;89:143-45. 48. Stevens DA, Schwartz HJ, Lee JY et al. A randomised trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000;342:756-62. 49. Davis SF, Sarosi GA. Role of serodiagnostic tests and skin tests in the diagnosis of fungal disease. Clin Chest Med 1987;8:135. 50. Pennington JE. Aspergillus lung disease. Med Clin North Am 1980;64:475. 51. Glimp RA, Bayer AS. Fungal pneumonias. Part 3. Allergic bronchopulmonary aspergillosis. Chest 1981;80:85 52. Ricketti AJ, Greenberger PA, Mintzer RA, Patterson R. Allergic bronchopulmonary aspergillosis. Chest 1984;86:773. 53. Fink JN. Allergic bronchopulmonary aspergillosis. Chest 1987;87(Suppl):81S. Management of Bronchial Asthma 127 9 Management of Bronchial Asthma A number of guidelines on the management of bronchial asthma, both in children and adults are developed in recent years.1-11 They include those of the British Thoracic Society, NHLB, USA, and the Global Initiative for Asthma, etc. The recommendations are based on the same principle and basically the same. The goals of management of bronchial asthma as recommended by these agencies are as follows: i. To recognise asthma ii. To maintain a normal activity level including exercise. iii. To maintain a normal or near normal (best) pulmonary function rates. iv. To prevent chronic and troublesome symptoms like coughing or breathlessness in the night, early in the morning, or after exertion. v. To prevent recurrent exacerbations. vi. To minimise absence from work or school vii. To enable normal growth to occur in children, and viii. To use the least minimum drugs to avoid adverse reactions from medications used for asthma. Since bronchial asthma is a chronic condition with acute exacerbations, treatment requires a continuous care approach to control symptoms, to prevent exacerbations, to treat adequately such exacerbations, and to reduce chronic airway inflammation. Prevention of exacerbation is an important principle of therapy. This includes avoidance of triggers and allergens. Round-the-clock medication may be beneficial to many patients. Children and adults, who have poor exercise tolerance, recurrent symptoms, and frequent nocturnal attacks and patients with moderate asthma will often benefit from the regular administration and more aggressive use of antiasthma medication, particularly anti-inflammatory drugs. In contrast, patients with mild intermittent asthma with uninterrupted sleep at night, and good exercise tolerance may need only occasional treatment for the relief of symptoms. Periodic assessment of these patients is essential to assure that their therapy is appropriate. The treatment of asthma should also be based on the understanding of the underlying pathophysiologic mechanisms and the objective assessment of severity of the disease. It is now appreciated that asthma is an inflammatory disease and therapy should include antiinflammatory agents to reduce inflammation and to relieve or prevent symptomatic airway narrowing. Anticipatory or early interventions in treating acute exacerbations of asthma reduce the likelihood of developing severe airway narrowing. 128 Bronchial Asthma Thus, the integral components of asthma therapy include patient education, environmental control, and medication with the use of objective measures to monitor the severity of disease and the efficacy of therapy. The interrelationship of all these approaches is shown in Figure 9.1. Basically the treatment of asthma consists of both; i. Nonpharmacologic therapy and ii. Pharmacologic therapy. The optimal nonpharmacological treatment consists of i. Patient and family education; ii. Avoidance of agents that induce or trigger asthma like allergens, irritants like smoke, and reasonable attempts at reducing exposure to respiratory viruses; and iii. Immunotherapy. The pharmacologic therapy is used to treat reversible airflow obstruction and airway hyper-responsiveness. Medications include bronchodilators and antiinflammatory agents with some acting as both. NONPHARMACOLOGIC MANAGEMENT Patient and Family Education Patient education by the treating physician is a powerful tool for helping patients to gain self-confidence to control their asthma.12,13 Since much of the day-to-day responsibility for Fig. 9.1: General principles of management of asthma Management of Bronchial Asthma 129 managing asthma falls on the patient and the patient’s family, encouraging active participation in a partnership with the clinician can improve patient adherence to the treatment plan and stimulate family effort to improve control of asthma.14,15 In fact a patient is his best physician since he alone can recognise well about his illness, its progression, regression, response to treatment, and imminent acute attack. It should start at the time of diagnosis and should be continued throughout as an integral component during continued care. Family participation is an essential component of this programme. Establishment of a partnership with the patient, encouraging adherence to the treatment plan, teaching about the triggers (exercise, viral respiratory tract infections, allergens and irritants) and how to avoid, eliminate, or control them, explaining the patient regarding medications both preventive and rescue therapy, their adverse effects and educating about the adverse drug reactions are important components of this plan. Moreover teaching the patient how to recognise the severity of asthma and the appropriate time to seek medical advice during acute exacerbations are important. Giving information alone does not alter behaviour. Written and audiovisual reinforcement of spoken language further helps patient confidence. Giving these informations along with written self management plans will help the patient who may adjust treatment to keep themselves symptom free that reduces morbidity and health costs.16,17 Although now there is definite evidence of benefit from patient education and issuing of self management plans, certain areas like who need them, and what form they should take (number of action levels, thresholds for intervention) are poorly defined. Proper use of inhalers is very essential.18,19 Patient should demonstrate use of the metereddose inhaler to the physician, and the technique should be reviewed at every visit. Since home-monitoring of PEFR is an essential component of asthma management, the patient needs to be taught how to use a peak flow meter correctly and how to interpret it.20,21 Psychosocial issues as outlined above which increases asthma morbidity and mortality need to be taken care of. Management of Allergy Since allergy has a very significant role in the pathophysiology of asthma, interventions to control this are important. There can be two ways to approach this problem: (i) environmental controls; and (ii) immunotherapy. Environmental Control Outdoor allergens like pollens and mould are best avoided by staying indoors particularly during the midday and afternoons. An air conditioned environment is the best way. Various nasal filters are available, which may be helpful to prevent penetration of allergens. However, this has not been proved to be very effective. Indoor allergen elimination is possible by paying special attention to the following. To avoid exposure to animal danders, the animal should be removed from the house. Removal of pets may not afford immediate relief even when followed by vigorous cleaning, since allergens continue to stay in the home for many months. Application of 3% tannic acid will denature and render such substances nonallergic. If the pet cannot be kept out of the house, there should be least contact with the patient and the animal should not be allowed at all to the bed room. Washing and bathing the pet frequently may reduce the amount of dander and dried saliva to be deposited on carpets and furnitures.22 130 Bronchial Asthma Reducing exposure to dust mites can be achieved by the following four plans of attack:23-25 a. By placing barriers between the patient and reservoirs of dust mite Elimination of mite exposure is possible by encasing the mattress in an airtight cover and encasing the pillow, particularly plastic mattress covers. These are not only inexpensive, but they effectively reduce dust mite exposure and clinical symptoms of asthma. Microporous covers are also available which allow passage of water vapour for patient comfort while excluding mites and their allergens. b. To kill and remove mites Regular washing of bedding and pillows by washing it at least once weekly. The bedding should be washed in hot water (>58°C) frequently. This kills mites and removes mites from an important exposure source. Ascaricides, tannic acid, dry heating, and liquid nitrogen have been used to kill mites, but they need further study particularly in terms of side effects to the patient and they need professional application.26 It is also important to remove the dead mites once they are killed, by vacuuming otherwise they continue to be the source antigen. HEPA filtration removes air-borne mites but leaves undisturbed the major reservoir antigen in carpets, beddings, and upholstery. c. Making the environment less hospitable for mites The patient should avoid sleeping or lying on upholstered furnitures. The carpets and other dust collectors that are laid on concrete are to be removed. Reduction of indoor humidity to less than 50% by air conditioning or mechanical ventilation are less favourable to the growth of mites. Although not so effective in removing live mites, regular vacuuming removes their food and shelter. d. To remove the patient to dust-free environment Although practically inconvenient and expensive, this is a very effective measure, and can be adopted whenever feasible while dust busting is completed at home. To prevent growth of moulds, special attention should be paid to areas with increased humidity. Such areas like bathrooms, kitchens, and basements require adequate ventilation and frequent cleaning using chlorine bleach. Sweat on foam pillows encourage mould growth. They should be encased or changed frequently. While cleaning, the patient should wear a dust mask. Climate control by air conditioning is beneficial, because it allows windows and doors to be closed and by reducing indoor humidity, discourages mould and mite growth. Humidifiers are potentially hazardous. If not cleaned regularly and properly, they facilitate the growth and aerosolise mould spores. A number of other devices are available for cleaning allergens from the indoor air. Two such major devices are mechanical filters and electrical filters. Other indoor irritants like tobacco smoke,27 wood smoke, strong odours or sprays (perfumes, talcum powders), household cleaning substances, and fresh paints irritate the airway and trigger asthma symptoms. Therefore, these should be avoided. Exposure to ozone and sulphur dioxide worsen asthma by interacting with allergens or other triggers and should be avoided as far as possible. Since occupational exposure is an important cause of bronchial asthma in adults, avoidance to such exposure is important. However, patients with suspected occupational asthma should not be advised to cease work until the diagnosis is proven and until all methods for reducing exposure at the work place have been explored. Specialist respiratory physician, occupational physicians, and employers will all need to be involved in this process. Management of Bronchial Asthma 131 Immunotherapy Allergenic extract immunotherapy is in use since the early 1900’s in an attempt to protect against grass pollen. Allergy immunotherapy has been shown to reduce the symptoms of asthma in a number of double-blind studies with a wide variety of allergens, including house-dust , grass pollen , cat dander and cladosporium and alternaria.28-31 Such therapy reduces the late reaction to allergens in the lung, reduces asthma symptoms following injections. Long-term use also reduces bronchial hyperresponsiveness. These suggest that allergen immunotherapy can be employed to prevent the development of allergic inflammation and perhaps the resulting bronchial hyperresponsiveness.32-37 However, the British Thoracic Society guidelines recommends that hyposensitisation (immunotherapy) is not indicated in the management of bronchial asthma.9 This therapy is employed only after performing a careful diagnostic study of history and skin tests to identify possible offending inhalant allergens. The history of symptoms must correlate accurately with allergen exposure with confirmed IgE-mediated reactivity to one or more suspected allergens, usually by wheal and flare skin reactivity or by serology such as RAST. The decision regarding immunotherapy depends upon three important considerations. (i) It must be established that there is a clinically important allergic component to asthma. (ii) In patients with a significant allergic components who are not obtaining full clinical improvement with standard environmental control and medication, and (iii) Failure of maximal environmental control measures. Currently the methods and frequency of administration of allergenic extract immunotherapy vary considerably. The dosage and frequency vary considerably. The allergens used are often poorly standardised and characterised, and the methodology is illdefined. With most forms of allergenic extracts, the initial frequency of injections is usually once weekly, with doubling of the dosage at regular intervals and progression to a series of monthly maintenance injections, depending upon the antigen preparation employed and the individual patient requirements. The therapy is dose-dependent and specific for the allergen employed, the higher the dose, the greater the clinical improvement. Allergic signs and symptoms may develop subsequent to injections, manifested either as local or systemic anaphylactic reactions (rare). There are no well-defined guidelines regarding the duration of therapy. Most physicians attempt to discontinue therapy after three or four years of a successful regimen, The National Blood, Heart, and Lung Institute, USA1 recommends that once patient achieves maintenance levels of immunotherapy, the interval between injections should be extended, with a goal of monthly injections. If the patient’s symptoms improve, treatment is usually continued for 3-5 years, although under some circumstances more prolonged therapy at monthly intervals may be warranted. If there is no evidence of response following two allergy seasons after reaching the maintenance or highest level tolerated by the patient, immunotherapy should be discontinued. Allergy immunotherapy should be administered only under the direct supervision of a physician who is adequately trained. The mechanisms for clinical improvement are unknown, but one or more immunological changes may be responsible for such improvement. Among these changes are: a. A rise in serum IgG blocking antibodies; b. Suppression of the usual seasonal rise in IgE antibodies, which follows environmental exposure, Management of asthma: A consensus statement. National Heart. An increase in specific T-suppressor cell generation. Statement by the British Thoracic Society. USA.306:77682. Asthma. National Asthma Campaign. Crane J.301:797-800. national asthma Campaign et al. et al. Evans D. 7. A reduced basophil reactivity to allergens. Guidelines on the management of asthma. King’s Fund Center. Clin Exp Allergy 1992. King’s Fund Center.5:195-205.301:651-53. Therefore. Clark NM. e. Maryland. 1-Chronic persistent asthma. Arch Dis Child 1989. Royal College of Physicians of London. Thorax 1997. Arch Dis Child 1992. Community-based asthma care. Guidelines for the diagnosis and management of asthma. 3. December 1995. National Asthma Campaign. BMJ1993. An increase in blocking IgG and IgA antibodies in respiratory secretions. The King’s Fund Center. Patient education is key to successful management of asthma. British thoracic Society. Feldman CH. The duration of treatment is often prolonged and costly. NIH Publication No. Research Unit of the Royal College of Physicians of London. Expert Panel Report. 15. British thoracic Society and others. 96-3659A. Summary charts. immunotherapy is only allergenspecific.1065-79. 1995 Review and Position Statement. Bethesda.64.132 Bronchial Asthma c. immunotherapy is not widely used as an important component in the management of bronchial asthma. Gotz M. Lung. Guidelines for the management of asthma in adults.85:457. Patient education. Thorax 1993. the problem of immunotherapy is the recognisation of the allergen. REFERENCES 1. 4. Most of the times. and f. 11. Guidelines for the management of asthma: A summary. 12. Burgess C.48:S1-S24. Chest 1989. 5. Moreover relapse occurs in most patients after discontinuation of therapy. Clin Rev Allergy 1987. The role of health education in medical management in asthma. 6. The British Guidelines on Asthma Management. trial of a “credit card” asthma self-management plan.7:1260-65. BMJ 1993. 91-3042A. 13.52(Suppl 1): S2-S8. Global Initiative for Asthma. Respir Med 1991. Clark NC. a follow-up statement. International Paediatric asthma Consensus Group. 9. Warner JO. British Paediatric Association. 16. Guidelines for the management of asthma in adults. Landau LI et al. Asthma self-management education: Research and implications for clinical practice. BMJ 1990. Royal College of Physicians of London. 2. Eur Respir J 1994. Mellians RB. Brewis RAL. self-management plans and peak flow measurements. International Consensus report on the diagnosis and management of asthma. Publication No. Research Unit of the Royal College of Physicians of London. d. National Asthma Education Programme. national asthma Campaign et al.Suppl:S47-S52. British Paediatric Association. J Rev Respir Dis 1989. Statement by the British Thoracic Society. identification is not feasible and as mentioned. 14.9:287-92. 2-Acute severe asthma. The King’s Fund Center. British thoracic Society. D’Souza W. National Institute of Health. . Reduced lymphocyte responsiveness to allergen. US Department of Health and human services. 10. June 1991.67:240-48. 8.95:1110-13.22(Suppl):1-72. A practical guide for public health officials and health care professionals. BMJ 1990. However. and Blood Institute. J Allergy Clin Immunol 1989. Colloft MJ. 31. Williams MH. Clarke SW. Effect of antiallergic agents and bronchial hypersensitivity in short-term bronchial asthma. Fergusson AC.60:264-68. Yano S. 28.88:300. Peak flow monitoring.151:353-59. 27. J Allergy Clin Immunol 1990. Gonzalez-Santos P. Michel FB. Carswell F. Boulet LP.85:225. Wilson P.22(Suppl 2):1-28. Hejjaoui A et al. Paediatrics 1983. 19. Bjorksten B. Seasonal asthma in Northern California. Sehou C. Controlled trial of hyposensitisation to house dust. Aas K. Double-blind. 21. Wahn U. Murray AB. et al. 33. Bousquet J. 22. Van Bever HP. III. 24. 29. Fel.74:230-39. Stevens WJ. Double-blind.91:418-22. Am J Med 1980.84:546-56. Kiellman NM. Vathenen AS. Clin Expt Allergy 1989. Lau-Schadendorf S. Findlay SR. 20. Cooke NJ. Wallshaw MJ. Efficacy and safety of unfractionated and high-molecularweight preparations in rhinoconjunctivitis and asthma. 32. Moss RB. et al. 37. Dust free bedroom in the treatment of asthmatic children with house dust mite allergy: A controlled trial.90:135-38. Weber A. Horst V. Home peak flow meters. 23. Ehnert B.Management of Bronchial Asthma 133 17. Reducing domestic exposure to dust mite allergen reduces bronchial hyper-reactivity in sensitive children with asthma. Chest 1991. Lilja G. Asthma self management education programme by home monitoring of peak expiratory flow. Hsu YP. Mizushima Y. J Allergy Clin Immunol 1984.302:738. allergy causes and efficacy of immunotherapy. Hoshino K. J Allergy Clin Immunol 1983. Clin Exp Allergy 1992. Sundin B.58:199-215. Graff-Lonnevig v. Evans CC. Horst M.85:460-72. J Allergy Clin Immunol 1989. Mendoza GR. 35. Buettner P. Wedner HJ. Hejjaoui A. placebo-controlled rush immunotherapy with a standardised alternaria extract. Leiterman KM. Suppression of late asthmatic reaction by hyposensitisation in asthmatic children allergic to house dust mites (Dermatophagoides pteronyssiunus). D1 is markedly reduced following sequential washing of cats. J Allergy Clin Immunol 1993.69:891-94.19:399. Axelson O. Q J Med 1986. Shim C. Am J Respir Crit Care Med 1995. Immunotherapy in cat-induced asthma: Double-blind trial with evaluation of in vivo and invitro responses. 36. . Asthma and increases in nonallergic bronchial responsiveness from seasonal exposure. Maasch HJ. 26.63:474-78. Placebo-controlled immunotherapy with mixed grass-pollen allergoids. Symptoms of bronchial hyper reactivity and asthma in relation to environmental factors. Pavia D. Thomson NC et al. 25. Iganacio-Gracia JM. Cartier A.28:161. Fredriksson M. 34. Simple instructions for using pressurised aerosol bronchodilators.71:399-406. Arch Dis Child 1988. The control of dust mites and domestic pets: A position paper.78:590-600. 18. Effect of 2 years treatment. J R Soc Med 1980. J Asthma 1991. allergen avoidance in house dust mite sensitive adult asthma. The adequacy of inhalation of aerosol from canister nebullisers. Use of nonstimulatory peptides: A new strategy for immunotherapy? J Allergy Clin Immunol 1991. Acta Paediatrc Scand 1971. Andrae S. Newman SP. Bousquet J. 30. J Allergy Clin Immunol 1986. Immunotherapy wit cat and dog dander extracts IV. Reid MJ.100:57.83:37-44. Ayres J. Glinert R. Br Med J 1991. Hawasaki A. J Allergy Clin Immunol 1990.73:776-79. Chapman MD. Ohman JL Jr. Proxyphylline (β-hydroxypropyl theophylline). METHYLXANTHINES Theophylline. Other commonly salts include formulations with calcium salicylate. Bronchodilators • β-adrenergic agonists • Anticholinergics • Methylxanthines (now can be classified as anti-inflammatory) 2. sodium glycinate. that results in delayed degradation of cAMP and cGMP. Phosphodiesterase Inhibition Earlier it was believed that theophylline acts as an anti-asthma drug as it relaxes bronchial smooth muscle. Anti-inflammatory agents • Corticosteroids • Cromolyn sodium or cromolyn-like compounds • Methylxanthines • Leukotriene antagonists • Miscellaneous compounds including antihistamines. caffeine and theobromine. Mechanism of action of theophylline remains unclear despite the long history and widespread use of the drug. Etophylline (β-hydroxyethyl theophylline). and choline (oxtryphylline).4 Various mechanisms proposed for the molecular mechanism of action has been proposed and are shown in Table 10. theophylline inhibits phosphodiesterase (PDE) which breaks down cyclic nucleotides in the cell. and Enprophylline (3-propylxanthine). the ethylenediamine salt is perhaps the commonest compound used in many countries. in vitro.134 Bronchial Asthma 10 Pharmacologic Management of Asthma The drugs used for the treatment of bronchial asthma are classified as: 1.1. Aminophylline. Many “salts” of theophylline preparations are commonly marketed and have been in use over many years. Several families of PDE .1-3 Other substituted xanthines have also bronchodilator property and include: Dyphylline (dihydroxypropyl theophylline). the principal methylxanthine used in asthma therapy over the past six decades and the most widely prescribed anti-asthma treatment worldwide. is a dimethylxanthine similar in structure to the common dietary xanthines. Although the exact mechanism of such relaxation was not known. adenosine antagonism may not be the exact cause of bronchodilatation.5 of which PDE III is predominant in airway smooth muscle relaxation and PDE IV is important in inflammatory cells. Anti-inflammatory Effect Recent evidence shows that theophylline may also possess some anti-inflammatory activity. inhibition of different adenosine receptor types and subtypes may be important for this differential action. Adenosine Receptor Antagonism Adenosine causes bronchoconstriction in bronchial asthma both in vitro and clinically when given by inhalation. 12 Bronchodilating effects of theophylline appear to closely parallel the serum concentrations.5-8 Theophylline is a nonselective PDE inhibitor. Since there is a linear relationship between log serum concentration and bronchodilator effect within this range. This bronchoconstricting effect of adenosine is prevented by theophylline.Pharmacologic Management of Asthma 135 Table 10. Such inhibition occurs at concentrations ten-fold higher than those usually attained clinically. However.14 This involves the release of histamine and leukotrienes from airway mast cells. the dose should be increased if symptoms persist and the patient is at the lower end of the serum concentration range.18 Although the increase is small. Increased Catecholamine Release Intravenous theophylline increases the secretion of adrenaline from the adrenal medulla. Since there is some evidence that PDE levels may be higher in asthmatics than normal individuals. a more conservative approach would be to aim for levels between 5-15 mg/ml.13.16 Since the potent bronchodilators enprophylline doxofylline.9. The anti-inflammatory effect has been shown both in vitro and in vivo studies. Although a steady-state serum concentration between 10-20 μg/ml gives optimal effect. it may be important. Theophylline is a potent inhibitor of adenosine receptors (both A1 and A2 receptors) at therapeutic concentrations and this may be the basis of its bronchodilator effect.1: Mechanism of action of theophylline Phosphodiesterase inhibition Adenosine receptor antagonist Increase in circulating adrenaline Mediator antagonism (anti-inflammatory effect) Inhibition of calcium ion flux Effect on respiratory muscles are now recognised. Total PDE activity in human lung extracts is inhibited by only 5-20% at therapeutic concentrations of theophylline. do not have action against adenosine receptors.21 and the inflammatory response.17. theophylline may have a greater than expected inhibitory effects on PDE in asthmatic airways than in normal airways.19 Theophylline reduces both bronchial hyper-reactivity20. this modest inhibition may be sufficient to cause a substantial increase in intracellular cyclic nucleotide levels in the presence of endogenous activators of adenylyl cyclase.11 Inhibition of PDE could also lead to synergistic interaction with β-agonists. The effects .10 However.15 This shows that theophylline is capable of antagonising the effects of adenosine at therapeutic concentrations. sustained high fever.21. and intravenous isoproterenol increases the elimination of the drug. The drug is also eliminated rapidly from the body by some individuals. Therefore. Other possible effects may be release of calcium from intracellular stores or may have some effect ion phosphatidylinositol turnover which is linked to release of calcium ion from intracellular stores. Theophylline is then eliminated through multiple parallel pathways that include demethylation and oxidation. troleandomycin.22 A number of studies suggest that during various contractile maneuvers theophylline increases Pdi/Edi. and to some extent into intracellular space. especially children. stimulation of the central nervous system. and with drugs like cimetidine. it is distributed rapidly through extracellular body fluid. Theophylline may increase calcium uptake into the intracellular stores also. decreased basic protein release by eosinophils. it may influence calcium entry via receptor-operated channels. high protein diet and about a 25% mean decrease in clearance associated with a high carbohydrate low protein diet. cerebral vascular constriction. and erythromycin.20 It also demonstrates immunomodulatory effects in vivo because of the inhibitory effects on T-lymphocytes. Theophylline inhibits plasma exudation in guinea pigs. phenobarbital. The ratio represents force/ unit of input. Other pharmacological effects of theophylline include a transient diuretic effect. decreased proliferation of T-lymphocytes. In obese individuals. and inhibition of late response to allergens. Approximately 90% of orally administered theophylline is metabolised in liver. increased + CD8 cells in peripheral blood and decreased T-lymphocytes in airways in asthmatic patients. Although it has no effect on entry of calcium ions through voltage-dependent channels. Effect on Respiratory Muscles In addition to bronchodilatation. Cigarette and marijuana smoking. Once absorbed. gastric acid secretion. The antiinflammatory effect is seen in much lower concentrations than its bronchodilatory concentrations. The drug’s elimination is reduced by such factors as liver disease. Major changes in diet also have a potential effect with 25% increases in clearance associated with a low carbohydrate. decreased release of ROS (reactive oxygen species). it improves respiratory function by increasing the strength and reducing the fatigue of respiratory muscles particularly diaphragm. decreased cytokine release from monocytes. decreased release of reactive oxygen species from macrophages.23.24 The drugs also increase mucociliary clearance. congestive heart failure. . the dose of the drug should be reduced in these circumstances. where Pdi denotes intrathoracic pressure swings across the diaphragm which reflects muscle force and Edi is the electromyographic recordings taken at the skin surface opposite the diaphragm insertion to measure the nervous input to the muscle. Theophylline is rapidly and completely absorbed from the gastrointestinal tract when it is administered in the form of solutions and tablets. and inhibition of uterine contractions. Theophylline also exert activity on cardiac ventricular contractility. phenytoin. These effects are of little clinical importance when appropriate doses are used for the treatment of asthma (or apnea of prematurity).136 Bronchial Asthma include decreased mediator release from mast cells. Inhibition of Calcium Ion Flux and Other Extrapulmonary Effects Some evidence suggest that theophylline may interfere with calcium mobilisation in airway smooth muscle. it should be given as a slow intravenous infusion with careful monitoring and a plasma theophylline concentration should be monitored. newer formulations have been developed with slower controlled release preparations because of unacceptable fluctuations during the use of plain tablets.27 However. Intravenous aminophylline has been used in the management of acute severe asthma for over 50 years. the drug may have an additive effect on other medications. A repeat serum concentration 30 minutes after the loading infusion determines the need for an additional loading dose and provides a baseline for monitoring change during a subsequent maintenance infusion. Theophylline is used for the treatment of both acute and chronic asthma. In chronic asthma. Use of intravenous aminophylline may increase the death rates. A conservative maintenance infusion based on mean clearance and targeting a steady state serum concentration of 10 μg/ml is maintained with as follows: . intestinal transit time in some patients may be so rapid that sustained-release preparations designed to release drugs especially slowly with long absorption half-lives. They are now not been used. with usual maximum is as. Suppository and rectal solutions are also available. will pass out of the gut before absorption is complete. Fixed dose combinations of theophylline with ephedrine that were the most frequently used formulations previously were associated with synergistic toxicity while providing a small additive effect. substantial peak-to-trough differences in serum concentrations are found in individuals who eliminate the drug rapidly. However. One should be familiar with these properties of the product selected. there are evidences to suggest that use of aminophylline in the emergency room reduces subsequent admissions to hospitals. In children the starting dose is 10 mg/kg/day. this is a drug which is cheap and still used as an important drug in many hospitals in the management of acute severe asthma. On the other hand. In some cases. if possible. and in other cases drug absorption is impaired. Intravenous aminophylline is less effective than nebulised β-agonists.25 Thus some authors recommend that the drug should be reserved for those patients who fail to respond to β-agonists. each μg/ml increase in serum concentration requires 0. Theophylline has long been marketed in a wide variety of formulations. During the past decade. prior to infusion. initial theophylline should be calculated on the basis of ideal rather than actual body weight to avoid overdosing. These longer acting preparations may also be affected by the presence of food in the gut or by the fat content. its has been questioned recently in view of the risk of adverse effects compared with nebulised β-agonists.5 mg/kg of a loading dose. Other products are relatively unaffected by food administration. The traditional preparation for oral and parenteral use has been theophylline with ethylenediamine known as aminophylline. Whenever a decision is taken to use aminophylline intravenously.5 L/kg. In other words. 1 year or more < 1 year 16 mg/kg/day 0.26 There is no added advantage if aminophylline is used in addition to β-agonists. the usual starting dose is 10 mg/kg/day up to 800 mg maximum dose. the rate of drug release is greatly accelerated.Pharmacologic Management of Asthma 137 with greater than 120% ideal body weight. Although once-a-day dosing may be satisfactory in adults who eliminate the drug slowly. Both twice-dosing and once-a day dosing are now available. Furthermore.2(age in weeks) + 5 = mg/kg/day For the management of acute asthma. The loading dose is aimed for a target serum concentration no higher than the mid point of the 10 to 20 μg/ml that is determined by multiplying the desired change in serum concentration by an average volume distribution of about 0. The therapeutic range of theophylline was based on measurements of acute bronchodilatation in response to the acute administration of theophylline. Subsequent infusion is adjusted according to the serum concentration. According to these principles the initiation of therapy should be at doses of 400 mg/day or 16 mg/kg/day.008 × age in weeks + 0.6 mg/kg/hr Adults 0. Since this dosage is low. Since side effects are also related to plasma concentration. whichever is less. the aim should be to attend such optimum concentration over a period of 1-2 weeks. adequate control of symptoms is not expected and for that period. these may be markedly reduced by aiming for plasma concentrations of 5-15 mg/l (28-55μM). either 600 mg/kg or 16-20 mg/kg. whichever is less. Theophylline has little or no effect on bronchomotor tone in normal airways.22 mg/kg/hr Children (1-9 years) 0. theophylline is used as an additional bronchodilator if asthma remains difficult to control after moderate to high dose inhaled steroids. the final doses requirements are highly variable. This level should be in the steady state (at least 48 hours in the same dose). the drug is cheap and is in use for several decades in many developing countries as a main stay of treatment. as long as no adverse effects are observed.31 However. but it reverses bronchoconstriction in asthmatics. While average doses are higher on a weight-adjusted basis for children than adults. Improvements in slow-release preparations. Because of the variability in the rates of elimination. To attend an optimal dosage one should proceed with patience. whichever is less. Nonetheless. It is useful to monitor serum theophylline concentrations when a patient begins his therapy and then at 6-12 months. . Monitoring serum concentrations is an important part of acute or chronic care of asthma. considerable variability is observed at all ages. The dose is then adjusted according to the serum concentration which should be measured about 4 hours after a dose when none have been missed or added for three days. have further improved the problem of fluctuations in plasma concentrations. including that of once-a-day products. The routine of theophylline in chronic stable asthma has recently been questioned. Therefore. The recent use of salmeterol and formoterol may still threaten the position of theophylline. rather than the previously recommended doses of 10-20 mg/l (55-110μM). After the next three days. it is possible that the nonbronchodilator effects of theophylline may be exerted at lower plasma concentrations.8 mg/kg/hr Children (9-16 years) 0. the dose should be 800 mg/day or 18-24 mg/kg/day. another drug should be used for control of symptoms. Monitoring is required in those who fail to exhibit the expected clinical effect while receiving an appropriate therapeutic regimen and in patients who develop an adverse effect to an usual dose. the dose is to be increased to 800 mg/kg for those more than 45 kg in weight and if less than 45 kg in weight.138 Bronchial Asthma Infants under age 1 0. The other important use of theophylline is its use as maintenance therapy for chronic asthma. Rapid attainment of therapeutic concentrations is associated with a high degree of minor complaints which may discourage the patient from continuing therapy. The frequency of measurements depend upon the specific clinical situation.28-30 In various guidelines of management of bronchial asthma (discussed subsequently).4 mg/kg/hr The adult dose should be decreased by one half for those with heart failure or liver disease. The dose is then to be increased every three days to 600 mg/day for those more than 45 mg/kg or if the patient weighs less than 45 mg/kg. Cardiopulmonary effects include tachycardia. side effects may be reduced by gradually increasing the dose until therapeutic concentrations are achieved . there is an associated progressively increasing risk of more serious side effects including seizures and death. The commonest toxicity are caffeine-like side effects including minor degrees of central nervous stimulation. Repeated doses of activated charcoal increases the rate of elimination of theophylline already absorbed by two folds. restlessness and nausea and vomiting or a queasiness of the stomach occur frequently after a loading dose and have no direct relationship to the serum concentration. it may produce behaviour disturbances in children. As serum concentrations exceed 20 μg/ml.37 However. relaxation of the detrusor muscle causing difficulty in urination in older men with prostatism. diuresis. The autonomic .39-41 Acute accidental or suicidal overdoses of theophylline are better tolerated than sustained high levels encountered due to uncontrolled therapy. which has no significant adenosine antagonism at bronchodilator doses. headache.36 Some of the side effects of theophylline like central stimulation. Because the drug stimulates the central nervous system. Since theophylline-induced seizures are more dangerous including brain damage and death. most commonly when the level exceeds 40 μg/ml. gastric secretion. The seizures may not be preceded by other central nervous system symptoms. There are many factors which affect serum theophylline concentrations. The effect of theophylline on behaviour and learning of children have received attention recently.Pharmacologic Management of Asthma 139 Side Effects The signs and symptoms of theophylline intoxication involve many organ systems.33-35 although a carefully designed study could not confirm this. possibly due to the result of a gastrointestinal dialysis.32 Other adverse effects include stimulation of respiratory center causing tachypnoea. Most patients rapidly acquire tolerance of these side effects when therapy is maintained and avoid them when the dose is gradually built up. the commonest side effects of theophylline like nausea. vomiting and headache are also seen with enprofylline. be avoided by drugs such as enprofylline. These factors and actions to be taken are shown in Table 10. diuresis. therefore. and arrhythmias even at serum concentrations considered to be therapeutic. and simultaneous administration of a cathartic such as sodium sulphate increases the transit time of charcoal and any remaining undisclosed drug. an aggressive approach to the treatment of an overdose is necessary. β-ADRENERGIC AGONISTS Normal β-adrenergic Receptor Physiology The autonomic nervous system is responsible for regulating the airway tone through the release of neurotransmitters that activate specific autonomic receptors. and arrhythmias may be due to adenosin receptor antagonism and may. Initial therapy with ipecac or other measures to induce vomiting removes remaining aminophylline in the stomach.2. Of more serious consequence are the reports that its use is associated with impairment of learning. Multifocal atrial tachycardia may herald sudden cardiac death. and important metabolic effects such as hyperglycaemia and hypokalaemia.38 Prevention of toxicity is important by monitoring the serum concentrations and by aiming for lower plasma concentrations as indicated earlier to some extent. Activated charcoal stops further absorption. Extracorporeal charcoal haemoperfusion allows more rapid clearance. The density of these cells in a particular site is important for physiologic responsiveness. stereospecificity. In humans. guanosine monophosphate (GMP). The sympathetic system is further subdivided into alpha and beta components. the sympathetic system causes bronchodilatation via cyclic adenosine monophosphate (cAMP). The effect in other tissues can stimulate various secretions like insulin. and β 2-adrenoreceptors mediate bronchodilatation. Rifampicin ↑metabolism Ticlopidine Smoking ↑metabolism ↓metabolism ↓metabolism ↓dose of theophylline ↑dose of theophylline advise to quit smoking system is divided into the parasympathetic or cholinergic system. and the non-adrenergic non-cholinergic inhibitory system. Broadly speaking. strict specificity. while the parasympathetic system is responsible for bronchoconstriction mediated by cyclic 3'-5'.44 The general effect of activation of β2-receptors at smooth muscle sites is inhibitory. cirrhosis Age ↓metabolism Decrease dose ↓metabolism (<6m. and saturability. Alpha receptor stimulation is associated with vasoconstriction and the inhibition of nonepinephrine release. bronchial. and affinity appropriate to the adenylate cyclase-coupled β-adrenergic receptors. Carbamazepine ↑metabolism (1-9 y) ↑metabolism Cimetidine Macrolides: Erythromycin TAO. cor pulmonale CCF. febrile viral illness ↓metabolism ↓dose by 50%. although this may not be an absolute rule. β-receptors have both chronotropic and ionotropic effects on the heart.140 Bronchial Asthma Table 10. Essential characteristics of β receptors are rapid and reversible kinetics of binding. Further. They are oriented in the membrane in such a way that the adrenergic ligand binding sites expose directly to the extracellular space.2: Factors affecting serum theophylline levels Factor Decreases Increases Action to be taken Food ↓ or delays absorption ↑absorption (fatty foods) Select appropriate preparation Diet ↑metabolism (high protein) ↓metabolism (high carbohydrate) Major changes in diet not advised Systemic. the β-adrenoreceptors are subdivided into β1. and on smooth muscle cells like vascular. etc. the sympathetic or adrenergic system.and β2-subgroups. Clarithromycin Quinolones Ciprofloxacin. and uterine smooth muscle cells. elderly) Adjust dose as per serum levels increase dose ↓metabolism Alternative H blockers (ranitidine/famotidine) ↓metabolism Alternative antibiotic or adjust theophylline Alternative antibiotic or adjust theophylline ↑dose of theophylline Phenobarbitone Phenytoin.42 β-adrenergic receptors are integral membrane glycoproteins.43 Majority of the β2-receptors are located in glial cells. if serum level not available Hypoxia. relaxation of central and peripheral . 47 Further. The interaction of the hormone. There is now evidence that β receptors may be coupled directly to maxi-K channels via the alpha-subunit of Gs.45 β-receptors mainly work through the enzyme adenylate cyclase activation and cyclic AMP formation. at least in part. are the preferred and most effective bronchodilators available for the treatment of bronchial asthma and are often the first and most important drug to be used worldover. Recognition of the pharmacologic differences between β1. This coupling protein contains a guanine nucleotide binding site. Mammalian cells controlled by β-adrenergic hormones contain plasma membrane-bound adenylate cyclase and specific hormone receptors. Thus. was known to the Chinese for more than 5000 years. it has been become clear that β2 agonists may cause bronchodilatation. The enzyme adenylate cyclase is stimulated by catecholamines in virtually all tissues in which β-receptors can be found. β2 agonists increase intracellular cAMP concentrations which are essential in the relaxation response. the kinases cause a reduction of calcium dependent coupling of actin and myosine and this results in smooth muscle relaxation.48 and may therefore. in which the biological response elicited is directly proportional to the percentage of receptor occupied (occupancy theory). Increased bronchial reactivity could result from a decreased β-adrenergic or nonadrenergic inhibitory activity.42 The older sympathomimetic agents ephedrine. ma huang. These systems have a protein(s) which couples their receptors to the adenylate cyclase catalytic protein. cAMP functions as a second messenger of catecholamine or hormonal action by modifying enzyme activities and permeability barriers. ephedrine was introduced into western medicine. β2 agonists or sympathomimetics. Modern bronchodilator therapy started in 1900 when the use of adrenal extract to treat asthma was described. At present. more β-2 specific bronchodilators.42 In 1924. A reduction in receptor number will alter the sensitivity of the tissue to catecholamines. and is labelled as Ns.46. receptor.Pharmacologic Management of Asthma 141 airways is mediated entirely by β2 receptors. There is a general mechanism of hormone to receptor to adenylate cyclase interaction. The sympathomimetic bronchodilators are the keystone of therapy of bronchial asthma. The principal type of receptor coupling to adenylate cyclase by β2-adrenergic receptors is referred to as a “stoichiometric coupling”. epinephrine. although its parent plant.52-62 Β-2 agonists are often the first and most commonly used drugs for the treatment of bronchial asthma. and guanine nucleotide binding protein with the adenylate cyclase catalytic unit and in the presence of magnesium ions. Nonetheless. induce relaxation without any increase in cAMP.44 In bronchial smooth muscle. These drugs had both alpha and beta-adrenoceptor activity which were described by Ahlquist in 1948. These enzymes transfer terminal phosphate groups from ATP to amino acid residues of certain proteins.48-51 Maxi-K channels are opened by low concentrations of β2 agonists which are likely to be therapeutically relevant. This is possible by the activation of protein kinases. results in the formation of cAMP from adenosine triphosphate (ATP). Most probably it is caused by decreased responsiveness of β-adrenergic receptors. longer acting. The tissue will require more drug to provide the same degree of receptor occupation as the receptor concentration is lowered. Recently. via maxi-K channels in airway smooth muscle cells which are directly linked to relaxation. they are still important antiasthma medications. and isoproterenol have been generally replaced by the newer. . and α receptors has led to the development of adrenergic agonists that can preferably act on β2 receptors of bronchial smooth muscle with little direct stimulation of the β1 receptors of the myocardium. β2. because they are subject to removal by active uptake mechanisms and to rapid metabolism by catechol-o-methyltransferase (COMT) and monoamine oxidase (MAO).142 Bronchial Asthma Biochemistry The β-adrenoceptor agonists are sympathomimetic amines whose parent compound is β-phenylethylamine. β2 β1. Injection Inhaler 3-5 4-6 4-6 β2 Oral. Mechanisms of Action Sympathomimetic amines have six general types of action: peripheral excitatory. prolonged bronchodilating action and oral administration is possible. They consist of a benzene ring attached to an amine group by two carbon atoms. β2. β1. By modification of the 3. β1. β2 Injection.3. methacholine. The distinctive features of different β-agonists depend on the basic structure. metabolic. or exercise. Injection 4-6 β2 β2 β2 Inhaler Inhaler Oral. Increasing the size of the terminal amino group substituent protects the drug against degradation by monoamine oxidase. β2-agonists cause a direct relaxation of the pre-constricted or spontaneously contracting human bronchial smooth muscle. inhaler. and central nervous system actions. and asthma. peripheral inhibitory. They have a relatively short halflife. which are the sites of action of COMT. inhaler. They are orally inactive because of their inactivation by gastrointestinal sulphatases. inhaler 6-8 4-6 6-8 β2 β2 Inhaler Inhaler > 12 > 12 . inhaler Oral. cardiac excitatory. Their bronchodilator action is evident in normal persons. and on the substitution on the amine group in particular. in patients with chronic obstructive pulmonary disease. 43 Modification of the phenylethylamine nucleus has helped to increase β2-specificity and duration of action. The various β2-agonists are shown in Table 10. Catecholamines refer generically to all compounds containing a catechol nucleus (benzene with two adjacent hydroxyl groups) and an amine group. They cause a marked reduction in nonspecific bronchial reactivity to stimuli such as histamine. inhaler. Oral 2-3 α.3: Adrenergic bronchodilators Receptor activity Availability Duration of action(hours) α. and further increases the duration of bronchodilatation.4-hydroxyl groups on the benzene ring. β2 (β1). Injection Inhaler 1-2 1-2 3 β2 β2 β2 Oral. inhaler Oral. The mode of bronchodilatation seems to be due to a decrease in catecholamine-stimulated adenylate Classification Ephedrine Catecholamines Epinephrine Isoproterenol Isoetharine Resorcinols Metaproterenol Terbutaline Fenoterol Saligenin Salbutamol Miscellaneous Bitolterol Pirbuterol Procaterol Long acting drugs Formoterol Salmeterol Table 10. endocrine. salmeterol. there being two isomers. Salbutamol. are currently available in many countries.72. modulation of neural pathways. prostaglandins.receptors to a lesser but dosedependent extent. bradykinin. full agonists. which in turn activates adenylate cyclase and leads to generation of cAMP. β2-agonists inhibit cholinergic neurotransmission in the human airway. which arise from differences in molecular structure.82 Optimal Pharmacological Profile of β-adrenoceptor Agonists They exhibit a range of physico-chemical properties. they should always be used with an inhaled glucocorticoid. and particularly salmeterol are weak and have low efficacy at β1 and β2-adrenoceptors.68-70 They are available in inhaled forms.81 but with similar bronchodilator action at 12h.Pharmacologic Management of Asthma 143 cyclase activity. β-agonist activity resides predominantly in the R-form. which can result in reduced cholinergic-reflex bronchoconstriction.71 Both provide effective bronchodilatation over a 12-hours period and thus. and SS) in fenoterol and formoterol. Several studies have demonstrated the superiority of salmeterol and formoterol to regular treatment with either salbutamol or placebo. and fenoterol have a higher affinity than isoprenaline and salbutamol. acetylcholine. Because of the widespread presence of β-receptors. inhibition of mediator release. β2-adrenoceptor agonists vary in their selectivity for β2adrenoreceptors. the associated rank order of potency being: formoterol > salmeterol > fenoterol = isoprenaline > salbutamol. Both drugs also protect against airways challenge with methacholine for a period of 12 hours. At β2-adrenoceptors. While salmeterol acts longer but is a partial agonist. Fenoterol and formoterol are full agonists. but to a limited extent.65 including leukotrienes. histamine and endothelins.67 Long acting β2-agonists.63.74 International guidelines have recommended both drugs to be added in the treatment of bronchial asthma.72. and fog. but there is no difference in the efficacy between the two drugs in any severity of bronchial asthma. but none is β2-specific. All β-agonists are racemic mixtures of optical isomers.75-77 Both these drugs differ pharmacologically.78-80 although formoterol is more potent than salmeterol in vitro. The other mechanisms of action of β-agonists. salmeterol xinafoate and formoterol fumarate. and salmeterol and salbutamol are partial agonists.agonists may affect many cells like stabilisation of mast cells. The final effect is an increase in cellular cyclic adenosine monophosphate. include. and duration of action at subtypes of β-adrenoceptors in a number of target cells. Since the human airway smooth muscle cells express β2-receptors from the trachea to the terminal bronchioles. SR.66 which may be the cause of effectiveness of these agents in blocking the bronchoconstricting effects of allergens. compared with isoprenaline. and increased mucociliary clearance. reduction of microvascular leak. RS.73 Because these drugs have no anti-inflammatory effect. although not proved conclusively.64 these drugs as functional antagonists can prevent and reverse the effects of all substances. They all stimulate β. exercise. they are more useful for patients who have nocturnal asthma. R and S in salmeterol and four isomers (RR. with a faster onset but a shorter duration of action. efficacy. which ranges from 40-fold to 1000-fold more potent than the S-isomer. formoterol. Further. whereas formoterol and fenoterol are potent. This effect derives from and is mediated through a plasma membrane-associated β-adrenergic receptor: the guanine nucleotide regulatory protein. the β2. Relative potency estimates show that 50 mg salmeterol corresponds to 9 mg formoterol. and determine their pharmacological profiles with respect to affinity. The functional β2-adrenoceptor . formoterol is a nearly full agonist. The duration of action is dose dependent. dysrhythmia. administration via inhalation results in less drug absorption and therefore fewer adverse effects than either oral or inject able routes. anxiety.4. restlessness and rarely hypoxemia.42 Another advantage of giving bronchodilators by inhalation is that they are not distributed to the rest of the body in large concentrations and therefore may be given in much smaller doses.agonists. fenoterol. Side Effects The predictable side effects of β-agonists include tachycardia. such as mast cells and epithelial cells. The doses of some of these drugs are given in Table 10. Inhaled therapy has a more rapid onset of action when compared with oral formulations and a similar duration of action. Measurements of lung volumes before and after bronchodilators add sensitivity when examining for bronchodilator responsiveness. and tremor. Although. Thus. all currently available β-agonists achieve a measurable effect within 5 minutes and by 10 minutes. Aerosol or oral inhaled therapy is comparable or better than oral therapy in producing bronchodilatation and cause fewer systemic side effects such as cardiovascular stimulation. β2agonists are the medications of first choice for treatment of acute exacerbations and for the prevention of exercise-induced asthma. inhaled therapy appears superior to oral therapy because the latter causes more adverse effects and require higher doses to achieve similar effects. inhaled administration is preferred. Since there is a rapid action. with the exception of salmeterol. due to stimulation of β2adrenoceptors in skeletal muscles is a common side effect of these class of drugs. and the therapeutic ratio of bronchodilatation to side effects is greatly improved.85 Since the onset of action is rapid.86 Since the frequency of adverse effects are directly proportional to the plasma concentration. and salmeterol is highly lipophilic. this can be attributable to the direct effect of the drug on the smooth muscle β-adrenoceptor. the adrenergic aerosols are currently among the safest drugs available for asthma therapy.84 Further. The duration of action is concentration-dependent for all β-agonists. incidence usually declines with continued administration. even when administered in substantially lower dosages. whereas formoterol is moderately lipophilic. that are less easily reached by oral drugs. which are more effective in preventing induced bronchoconstriction than equivalent doses of oral β2-agonists. inhaled drugs may reach superficial cells in the airways. When given by inhalation. Furthermore. there are some . Tremor.144 Bronchial Asthma selectivity is lowest for fenoterol and highest for salmeterol. nebulised β2-agonists are the first choice for acute severe asthma and may be life saving. gaining access to the active site of the β2-adrenoceptor through the cell membrane. but. hypokalemia. Salbutamol inhalation reduces hyperinflation of the lungs.83 Recently there is a trend to use more of inhaled form of these drugs rather than oral preparations because of adverse effects and slow onset of action. tremor. The rates of onset of action of salbutamol. 80-90% of the maximal response has actually been achieved. β2-agonists such as salbutamol and fenoterol are hydrophilic and interact with the β-receptor directly. Tremor is inseparable from bronchodilator action. and formoterol are more rapid than those of salmeterol. which appears to be intrinsically long-acting (salmeterol >> formoterol>fenoterol>salbutamol) due to additional exo-site binding in the β2-receptor protein. They can be used either intermittently to control episodic airway narrowing or chronically to aid in the control of persistent airway narrowing. palpitation. The advantage of slowrelease oral agents has been taken over by the introduction of long-acting inhaled β2. possibilities include the development of rebound airway hyperresponsiveness.8 1.63-3. Several recent studies have suggested that regular use of β-agonists increases the responsiveness of airways to challenges with agents such as methacholine and histamine in children and adults. and may develop to the antiasthmatic effects of inhaled β2-agonists.37-1.39 0.5 — — — 0.95 0.16-0.Pharmacologic Management of Asthma 145 Table 10.1-0. There are also some concern regarding damage to the mucosal epithelium due to repeated inhalation. Although the mechanisms of diminished control or increased hyperreactivity are not known.92 Most studies suggest that clinically significant tolerance does not usually develop in patients with asthma. Thus.27 0. cardiac arrhythmias and myocardial ischaemia resulting from β-agonist therapy usually occurs in patients with preexisting cardiovascular disease. increased bronchial secretions.87-91 numerous other studies using a recommended dose of β-agonists by metered dose inhalers have failed to show the development of complete tolerance.68-1. Very rarely.5-22 0. Adverse drug reactions involving the cardiovascular system may also occur.11 6-12 μg 50 μg Nebulizer (mg) Oral (mg) 2.86 Although some evidences suggest that tolerance to the bronchoprotective effects of both short. Cardiovascular complications may result from decreased serum potassium levels or direct stimulation of the myocardium. The paradoxical response is an abrupt worsening of asthma symptoms and/or a decrease in expiratory flow rates shortly after inhaling a therapeutic aerosol.32-0.25-5 10-15 — — — — — — — — 5-20 2-4 2. Very rarely lactic acidosis may occur.4: Dosage of sympathomimetic agents per treatment Drug Adrenaline (1:1000) Isoproterenol Isoetharine Metaproterenol Salbutamol Terbutaline Bitolterol Formoterol Salmeterol Subcutaneous (ml) 0. patients with asthma may experience paradoxical bronchoconstriction as a result of inhaled β-agonists administered by metered-dose inhalers (MDI). Another potential reason for increased asthma symptoms during prolonged therapy with these drugs may be the development of tolerance or subsensitivity resulting from downregulation of β-adrenoreceptors.9 0.25-0. It is not clear whether the reaction is due to the drug itself or due to another component or contaminant of the particular canister or batch of canisters or due to a hypersensitivity reaction to the hydrocarbon propellant.02 1. tolerance is not . However. Adverse reactions of the cardiovascular system may occur with the combination of systemic adrenergic agonists and theophylline. This phenomenon is a tendency of biological responses to wane over time in the presence of a stimulus of constant intensity. There are controversies regarding the link between the use of fenoterol and increased asthma deaths in New Zealand.6 0.5-5 — — — areas of concern.18-0. it is characterised by a small reduction in the bronchodilator response and by a slight shortening in the duration of action after inhaling a β-agonist.65.5 0. especially among the elderly.and long-acting β2-agonists does develop. Similarly some recent reports associate the regular use of a potent inhaled β2-agonist with diminished control of asthma.5 — — — Metered dose inhaler or MDI (mg) 0.4-0.3-1. When tolerance develops. or both. 93 Patients having Arg-16 → Gly form of the receptor. most clinicians believe that the mortality attributable to SABA is most likely based on over dosage and/or abuse by poorly controlled patients.104 . when a sudden increase in asthma mortality was attributed to overuse of a short-acting.96 A subsequent meta-analysis of six similar surveys not only failed to confirm this conclusion but found that mortality was increased to a slight extent only in patients who used SABA on a regular basis. reports are conflicting. and exercise. isoprenaline in the 1960s and fenoterol in the late 1970s. There is no epidemiological evidence to suggest that β-agonists have an appreciable effect on mortality outside these epidemics. These will involve an uncoupling of the hormone-receptor complex from the guanine nucleotide binding protein. Concerns about possible deleterious effects of the first reported from the United Kingdom. It could occur at the level of the receptor. The problem may be avoided by taking long acting β 2-agonists only at night. one in several countries in the 1960’s and the other in New Zealand in the late 1970s. Australia and New Zealand in the mid-1960s. Subsensitisation occurs because of the receptors in the tissue are exposed to persistent stimulation by agonists. stimulatory or inhibitory. a more selective. the risk/benefit ratio of these agents have evoked controversy throughout the last half of the 20th century. the Gln→Glu form.102 A similar phenomenon occurring a decade later in New Zealand appeared to be associated specifically with regular use of inhaled fenoterol.95 There is some concern recently regarding the use of β2-agonists and excess asthma mortality. resist down regulation and is having less airway hyperreactivity. allergens.. relatively short-acting β2-agonist (SABA).43 Thus repeated administration of β-agonists makes the airways even less responsive.96-101 Some Controversial Facts About β2-Agonists Despite the worldwide use and the significant contributions of inhaled synthetic sympathomimetic agents in the therapeutic management of bronchial asthma. which is more likely to be down regulated have more frequent asthma in the night. were associated with a rapid increase in the use of a β-agonist formulation delivering a high dose by metered-dose inhalers. Although. The two epidemics of asthma death recorded in the literature. repeated exposure to catecholamines may reduce the number of β-receptors in the airways that are free to interact with catecholamine bronchodilators. The problem can occur at one or several different points in the formation of cAMP. Whether steroids protect against development tolerance is not known. Further. It is possible. dose-fortified formulation of isoproterenol.97 A Canadian retrospective case-control analysis of pressurised SABA in patients with asthma suggested that increased asthma mortality was not necessarily due to fenoterol alone but also occurred after overuse of any pressurised SABA of the same class. such as adenosine. Recent studies of the polymorphism of human β2-receptors suggest that some forms of the receptors may be more likely to be down regulated. that receptor down-regulation could account for some of the diminished control of asthma and increased airway hyper-reactivity reported during chronic regular use of these drugs.94 In contrast.146 Bronchial Asthma usually of major clinical significance and does not diminish the overall usefulness of inhaled β2-agonists in asthma therapy. however. Tolerance is seen most commonly with triggers that operates through mast cell activation. and/or involve down regulation mechanisms. it seems likely that those epidemics were due to high-dose β2-agonist use.103 Even if this controversy keeps on appearing off and on. where they have better access to receptors and downstream signalling cascades. By contrast. (pollen sensitive asthmatics). As examples of antiinflammatory effects. There was a failure to detect a significant difference in adenosine monophosphate-induced airway responsiveness between salmeterol-treated and placebo-treated patients when they were challenged with the agent during the height of the pollen season. The lipophilic nature of these agents would enable them to partition into the outer phospholipid layer of cell membranes. Airway caliber (FEV1).90. Similar concerns were also expressed when LABAs were available. The increase in airway hyperresponsiveness showed only a small insignificant increase in the treated group compared to the placebo group. airway hyperresponsiveness indices and exhaled NO were measured before the administration of salmeterol or placebo and at mid season. measured both direct and indirect airway hyperresponsiveness using methacholine and adenosine monophosphate and exhaled NO was measured as an index of airway inflammation. A recent controlled study111 performed over a 6-week period using placebo or salmeterol that utilised a well-defined allergic phenotype of mild asthma. and many asthma management guidelines recommended against their regular use over prolonged periods. Similar concerns were expressed about the LABAs. Fortunately.109 These contradictory results have been ascribed to patient-specific differences in sensitivity to the deleterious effects of bronchodilators. and a well-defined exposure period (a grass pollen season). presumably because of their overabundant distribution and relative refractoriness to tachyphylaxis in this tissue site. variability of allergic status among patient groups. continuous use of LABAs without evidence of a rebound effect after cessation of therapy. A number of studies in the mid 1980s and early 1990s demonstrated that regular use of SABAs increased airway hyperresponsiveness and actually worsen asthma control. Patients receiving salmeterol experienced significant protection against a fall in FEV1 during the height of the allergy season. augmentation of eosinophil survival and enhancement of the late allergic response. or a masking activity of β2-agonists . downregulation of β2-agonist receptors on smooth muscle is not clinically relevant. intensification of the T-helper type 2 immune response.110 The later effect might occur because these agents inhibit only the early allergic response and might exacerbate the ongoing inflammation associated with the late allergic response.Pharmacologic Management of Asthma 147 The above controversies led to more intensive exploration of the nonbronchodilator properties of SABAs and also long-acting β2-agonists (LABAs). more recent studies demonstrated that the LABA-induced protective effect against airway hyperresponsiveness was unimpaired after relatively long-term.107 However. suppress airway smooth muscle growth. SABAs may also favor the synthesis of receptors associated with neurogenic inflammation that could play a role in the phenomenon of increased airway hyperresponsiveness that has been noted after long-term use of these agents. 105. and inhibit the function of immunocompetent lymphocytes.108. and in fact early clinical trials reported that both short-term and long-term use of LABAs dampened the β2-agonist protective effect against methacholine-induced bronchospasm without evidence of smooth muscle tachyphylaxis.106 Such investigations have revealed a complex and contradictory array of biological activities that encompass both proinflammatory and anti-inflammatory effects. The interactive effects of these agents as well as individual agents have been studied extensively. The result emphasised the difference between natural exposure and a single experimental allergen challenge studies reported earlier. β2-agonists are known to attenuate release of mediators from mast cells. the proinflammatory effects include suppression of interleukin12 production in antigen-presenting cells. Since the adenosine monophosphate indirect . Atropine. long-term salmeterol did not attenuate the chronic effects of mediators during the season and therefore did not function as an anti-inflammatory agent. who in turn learnt its usefulness from Indians. they cause fewer systemic side effects. urinary retention.113 The newer anticholinergic agents are watersoluble. Atropine was used for many years for the management of bronchial asthma. and constipation. atropine.148 Bronchial Asthma challenge reflects bronchoconstriction caused by mast cell mediators. the later is almost no more used.114-118 A better understanding of the cholinergic mechanisms that control airway caliber in health and disease and the development of newer synthetic analogs of atropine that are poorly absorbed. The drug has a delayed onset of action. Atropine should not be used in patients with narrow angle glaucoma and prostatic hypertrophy.112 The recreational and medicinal properties of atropine have been well-known to many cultures for many centuries. blurred vision. The exhaled NO levels were increased both treatment arms during the height of the pollen season. quaternary ammonium compounds that are poorly absorbed. and their alkaloid extract.112. These results strengthened the safety profile of salmeterol and indicated that long-term use of a LABA alone will not provide a clinically effective anti-inflammatory effect. in the form of the leaves and roots of Datura stramonium. but retain the anticholinergic properties of the atropine. and it was introduced to Western medicine by the British military officers in the early 1800s. but there was neither an augmentative nor inhibitory effect in the salmeterol group. the balance between the salutary and adverse effect of both SABAs and LABAs are tilted towards a more clinical benefit to the patient in the management of bronchial asthma. Anticholinergics Anticholinergics are the oldest forms of bronchodilator therapy for asthma and are recommended as early as the 17th century. At that time. The majority of the autonomic nerves in human airways are . Ultimately perhaps. was very well known to Indians for use in respiratory disorders. its use declined. dryness of the oral mucosa. With the advent of newer more selective drugs without these unpleasant side effects of atropine. stramonium. With the availability of potent β-adrenergic agonists in the 1920s. have revitalised the interest in anticholinergic therapy. Several anticholinergic agents that are in use worldwide include: • Atropine • Ipratropium bromide • Thiazinamum • Oxytropium bromide • Glycopyrrolate • Tiotropium bromide Rationale for the Use of Anticholinergics To understand the rationale of use of these agents it is important to understand the mechanisms of bronchoconstriction and bronchodilatation that are mediated by the autonomic nervous system. Atropine is usually given as a powder nebuliser with a β-adrenergic agent. Its side effects include tachycardia. In recent years there has been an increased interest in inhaled atropine sulphate. belladonna. especially in patients with chronic bronchitis. and when they are given by inhalation. had their place in most pharmacopoeias. 123 Ipratropium bromide is a muscarinic cholinergic antagonist that inhibits smooth muscle contraction by competing with the neurotransmitter acetylcholine at the muscarinic receptor. However by blocking prejunctional M2 receptors. The M1 receptors are present within the parasympathetic ganglion and mediate increased cholinergic transmission. M1 receptors are also found on alveolar walls. thereby limiting the degree of bronchoconstriction produced.120. Inhibition would reduce cholinergic tone and thus would reduce bronchoconstriction. 125 The M3 receptors play the major role in causing bronchoconstriction. In humans. the release of acetylcholine at these sites results in smooth muscle contraction and the release of secretions from submucosal glands stimulated by their muscuranic receptors.126 This may weaken the effect of the postjunctional M3 muscarinic receptor blockade on airway smooth .124 These drugs are thus less effective than inhaled β2-agonists because they counteract only cholinergic neural bronchoconstriction. although their function is unknown. the efferent paraganglionic fibres of which enter the lungs at the hilum and travel along the airways into the lungs. resulting in exaggerated cholinergic reflexes. The loss of M2 receptor function has been demonstrated after viral infections. ipratropium bromide and oxytropium bromide are nonselective antagonists and produce their beneficial effect by blocking M3 receptors. which are known as M1. recently it is recognised that there are at least five subtypes of muscarinic receptors expressed in the airways. M3 receptors are located on the airway smooth muscle. histamine on the airways. for example. Thus.122. M2. The receptor activation leads to a release of calcium ions from intracellular stores and a decrease in intracellular adenosine 3’.Pharmacologic Management of Asthma 149 branches of the vagus nerve. where they are likely to be involved in mucus secretion. Ipratropium bromide and oxytropium bromide are quaternary ammonium derivatives of atropine and are bronchoselective when delivered by inhalation. M1 to M5. They will only block reflex cholinergic bronchoconstriction and will have no effect on bronchoconstriction resulting from the action of.126 Atropine. Finally. These receptors are thought to be dysfunctional in asthma. which may be a relatively minor part of the broncho-constrictor mechanism in asthma. As discussed earlier. They are activated by the release of acetylcholine and promote its reuptake. They may facilitate nicotineic transmission or be responsible for maintaining cholinergic tone. they increase the release of acetylcholine and thus may have relatively deleterious effects. Anticholinergic medications antagonise transmission at the muscarinic receptors. and many stimuli can provoke bronchoconstriction via vagal pathways. the types described are up to 5. the resulting excessive concentrations of acetylcholine at the motor endplate can promote significant bronchoconstriction.121 When the M2 receptors are dysfunctional. there are at least three pharmacologically distinct subtypes of muscarinic receptors within the airways. Cholinergic pathways are important to regulate the acute bronchomotor responses. and M3 receptors. resulting in the contraction of airway smooth muscle. and smooth muscle of the airways as well as in the vascular structures.119 The efferent innervations is derived from the postganglionic fibres that end in the epithelium. whereas the M2receptors mediate the feedback inhibition of acetylcholine release from airway sensory nerves. M3 receptors also are located on submucosal glands.5’-cyclic monophosphate levels.120 Recently. submucosal glands. Prejunctional M2 receptors on the postganglionic nerves act as negative feedback loop in neuronal transmission. Cholinergic-induced bronchoconstriction appears to involve primarily the larger airways. Similar changes can be seen after ozone exposure or antigen challenge. whereas β-agonist medications relax both large and small airway contraction equally. . This suggests that antagonists that bind selectively to M1 and M3 receptors may be more effective in inhibiting cholinergic effects on the airways. The drug is available as a lactose based powder formulation containing 18 mg of active substance and is used once daily. blurred vision. and possible effects on the eye (glaucoma) can be prevented by using a mouth piece during nebulisation.5 to 2 hours and a very prolonged effect compared to ipratropium bromide. urinary retention. the incidence of dry mouth. up to 8 hours than ipratropium bromide. and the duration of action is up to approximately 6 hours.131-133 It does not appear to affect mucus secretion and ciliary movement. In children ipratropium has bronchodilator action in acute exacerbations of asthma. When used via MDI aerosol. the benefits of its use in day-to-day management of asthma in children and adults have not been established. this drug was used extensively as a nebulised solution by intensivists and emergency department specialists for years.136. The onset of action is 3 to 30 minutes with up to 50% of the response occurring in 3 minutes and 80% in 30 minutes.134 The only remarkable side effect is the inhibition of salivary secretions at high doses.134 It has a longer duration of action. The agents also block postganglionic efferent vagal pathways. and the compound is poorly lipophilic and not significantly absorbed from the respiratory or GI tract. Tiotropium bromide is a recently developed.130 The drug is topically active. The natural antichiolinergic.135 The peak onset of action is 1-2 hours. probably via an inhibitory effect on M1 receptors. the recommended dose of ipratropium bromide is 2 puffs (40 μg) 4 times daily. The drug is used in a dose of 200-400 μg per day and is perhaps less effective in chronic asthma. Another significant advantage of ipratropium bromide in the critically ill asthma patients is the lack of tachycardia. nausea and tachycardia may limit the usefulness of atropine. atropine. The drug has been shown to be effective during status asthmaticus when used in nebulised form in combination with β-adrenergics. anti-muscarinic medication.129. The principal anticholinergic agent is ipratropium bromide. In human bronchi. It is also a nonselective muscarinic antagonist. The drug has been found to be an effective bronchodilators in patients with COPD and selective patients with asthma both alone and when used in combination β2-agonists and theophylline. They are relatively free of systemic side effects because they are minimally absorbed into the systemic circulation and do not cross blood-brain barrier. long acting.128 It is readily absorbed across the oral and respiratory mucosa and when higher doses are used to maximize bronchodilator effect.150 Bronchial Asthma muscle and submucosal glands. The effect lasts for 10-15 hours. This agent is selective for both M1 and M3 receptors. It has no or very little systemic effect. selective. is rarely used in patients at the present time. The drugs also inhibit hypersecretion of mucus in the airways. Oxytropium bromide is a quaternary ammonium anticholinergic compound that is based on scopolamine instead of atropine. a nonselective muscarinic antagonist. but has a slower onset of effect. with a peak bronchodilator effect observed within 1 to 2 hours. although its use appears to be most effective in patients with COPD with partially reversible airflow obstruction. It has no effect on urinary flow. However. These properties are ideal for acute asthma treatment. which does occur with β2-agonist use. or intraocular tension. however.137 The drug has a prolonged inhibitory effect acetylcholine released from postganglionic nerve endings in the airways. They also block reflex bronchoconstriction caused by inhaled irritants.127 The anticholinergic drugs act by reducing intrinsic vagal tone to the airways. the drug has a similar inhibitory effect with a slow onset of action with the peak bronchodilator effect observed after 1. 141. an enzyme essential for activation of arachidonic acid metabolism.147 but eosinophils are less responsive. They can be used in combination with β-agonists.140 Glucocorticosteroids are active against bronchial asthma. The hormone penetrates freely into the cell and binds to the receptor forming an inactive complex. The complex may cause reduced transcription with inhibition of protein synthesis like cytokines. Then it is translocated to the nucleus where it binds to specific sequences (glucocorticoid-responsive element) on the upstream regulatory part of steroid-responsive gene. Corticosteroids Glucocorticosteroids are the most potent anti-inflammatory drugs useful in the treatment of bronchial asthma.153 Although the molecular mechanisms of the anti-inflammatory action of steroids are better understood. Inhaled glucocorticosteroids have revolutionised the treatment of asthma and are highly effective in controlling asthma in all patients. which are the primary effectors of hormone actions.142 The anti-inflammatory action of corticosteroids is as follows. Although they do not reduce the release of mediators from mast cells themselves. The particular genes and proteins regulated by corticosteroids depend on the type of cells. eosinophil survival is markedly reduced due to blockage of the effect of cytokines like IL-3.150 The other most important effect of steroids is on T lymphocytes where the synthesis of cytokines is reduced. Il-5. The hormone thereby increases or decreases the levels of mRNA and usually of the proteins that the genes encode. and GM-CSF. their frequent use is justified.144 It is also likely that steroids act on many different cells of the airways. secretory products.149 Inhaled steroids also reduce markedly the proportion of circulating low-density eosinophils in asthmatic patients through inhibition of IL-5 secretion.148 But.Pharmacologic Management of Asthma 151 In certain clinical situations these drugs may be useful bronchodilators for the treatment of bronchial asthma. which is necessary for mast cell survival in the airways. possibly due to inhibition of IL-3. mainly through their antiinflammatory effects.138 They are recommended for patients who cannot tolerate β-adrenergic agonists because of severe tremor or underlying cardiac disease and for patients with bronchospasm precipitated by β-adrenergic antagonists139 or acetylcholinesterase inhibitors. which inhibits the enzyme phospholipase A2. and GM-CSF.145 they lead to a significant reduction in mast cell numbers. These proteins may be enzymes.146 Steroids inhibit release of mediators by macrophages. With the realisation of the role of inflammation as an essential and important component of asthma. Additional effects directly related to antiinflammatory action include reduced plasma exudation from postcapillary venules in the airways. Il-5.154 the key cellular targets in asthma have not yet been conclusively established.152 Further. can activate or inhibit transcription of these genes. which play significant role in perpetuating the inflammatory response.151 and inhibition of mucus glycoprotein secretion. An important effect of steroids in asthma may be the inhibition of synthesis of key cytokines like IL-3. It appears that airway epithelial cells are important target cells and besides the above . inhaled steroid therapy causes a reduction in bronchial hyperresponsiveness to histamine and the underlying T-cell-dominated inflammation in the bronchial wall. This may increases the production of a substance called lipocortin-1. which is further activated or transformed to an active complex having an enhanced affinity for DNA forming the nuclear-bound complex. and regulators of various functions including transcription of other genes.143 This complex then by binding to regulatory elements associated with certain genes. there is complete resolution. such as increased release of mast cell mediators.162 Effects of corticosteroids in asthma patients are considerable.159 Steroids facilitate the action of adrenergic bronchodilators.155 nitric oxide. After regularly inhaling steroids over one to three months. Dampening of the recruitment and activation of eosinophils results from their direct effect on these cells as well as upon T-lymphocytes.160. iv.157 They also may inhibit the expression of inducible genes in airway epithelial cells by blocking key transcription factors such as nuclear factor-kappa B and activator protein-1. mast cells. basophils. Inhibition of cytokine gene transcription and translation leading to inhibition of cytokine secretion and increased intranuclear breakdown of these mediators. expression of adhesion molecules. and macrophages.adrenergic receptors on cell surface.168 Some studies have even indicated that delayed introduction of inhaled corticosteroids results in an impaired response. 153.154 Thus.156 and adhesion molecules. inflammatory cells disappear completely. apparently by altering the ratio of α to β.5. IL-8.164. Prevention of the direct migration and activation of inflammatory cells. or as aerosols.169. collagenase.152 Bronchial Asthma mentioned mechanisms including the inhibition of expression of cytokines like IL-1. and prolonged survival of inflammatory cells. ii. the important mechanisms of anti-inflammatory action of corticosteroids can be summarised as follows: i. In biopsies of patients after ten years of inhaled steroids. Interference with arachidonic acid metabolism through alteration of lipocortin synthesis and that of the synthesis of leukotrienes. Local activation of a variety of cell types including neutrophils. there has been less fear now to treat patients with steroids . bronchial biopsy shows many fewer eosinophils.161 Oral prednisolone therapy prevents the development of down regulation and subsensitivity of lymphocyte β2-adrenoceptors in subjects given long-term treatment with oral β2-agonists.164 Exacerbation rates are markedly reduced by treatment with inhaled corticosteroids in asthma. orally. and lymphocytes. they also inhibit lipid mediators.167.170 Recent studies on the longterm effect in patients who are treated with terebutaline and beclomethasone dipropionate indicate that the initial improvement in lung function are well preserved over 5 years. although basement membrane thickening may persist. v. and symptoms within weeks. They inhibit the production of IL-1. and gradual amelioration usually continues up to at least 1 year. iii. Direct evidence for the anti-inflammatory effect of inhaled steroids is provided by biopsy studies in asthmatic patients. elastase. regulated on activation normal T-expressed and secreted (RANTES) and GM-CSF. Inhibition of cellular response to cytokines. Corticosteroids can be administered parenterally. endothelial cells. Because of the availability of inhaled steroids. macrophages and possibly eosinophils by γ-interferon may be blocked by inhibition of this substance from T-lymphocytes by glucocorticoids. and plasminogen activator. cytokines and prostaglandins. Improvements in airways hyperresponsiveness are slower in onset. 158 and in patients with mild inflammation of the airways.163-168 Treatment with inhaled corticosteroids improves FEV1. peak expiratory flow. An acute anti-inflammatory action mediated via inhibition of microvascular leakage.146.171 Inhaled steroids prevent the accelerated decline of FEV1.172 The wide-ranging clinical benefits associated with corticosteroids are shown in Table 10. which have minimal systemic side effects. Early treatment of severe acute exacerbations of asthma with oral corticosteroids prevents progression of the exacerbation. It is now clear that the duration and severity of an acute asthma attack can be substantially reduced by therapy with corticosteroids. mood alteration. Acute short-term therapy is begun usually with a relatively high dose of 40-80 mg of prednisone daily and can be maintained up to 5-10 days or tapered over the same interval. occurring approximately 3 hours after administration with peak effectiveness occurring about 6-12 hours after administration. should be attempted to see if oral corticosteroids could be reduced or eliminated. the onset of action is gradual. and aseptic necrosis of the femur. weight gain. decreases the need for emergency visits and hospitalisation.1: Anti-inflammatory effects of glucocorticosteroids either with a short course therapy or for longer times. rounding of face. Therapy with oral steroids should be maintained until peak expiratory flow rates are stable near the best predictable value. In all patients requiring chronic maintenance therapy with steroids. . hypertension. peptic ulcer.Pharmacologic Management of Asthma 153 Table 10. increased appetite. Oral therapy can be continued only if that shows to reduce chronic symptoms substantially or reduce the frequency of severe episodes.5: Clinical benefits of glucocorticosteroids * Improved pulmonary function Diurnal variability in pulmonary function Protection against antigen-induced bronchoconstriction Asthma exacerbation rate Hospital admission rate Asthma mortality rate * Prevention of long-term lung damage and therefore irreversible airflow obstruction The anti-inflammatory effects of glucocorticosteroids are shown in Figure 10. fluid retention.10.1: Glucocorticosteroids Eosinophils Mast cells T-Lymphocytes Mucus secretion Plasma exudation Mediator formation CYTOKINES β-Adrenoceptors INFLAMMATION Fig. The major adverse effects associated with high-dose shortterm systemic therapy are: reversible abnormalities in glucose metabolism. When oral steroids are used to treat acute severe asthma. and reduces the morbidity of the illness. a trial of inhaled steroids. • A part of the inhaled drug is absorbed resembling parenteral injection bypassing liver with reduced hepatic degradation of the active compound and able to produce systemic effects.176 In patients with mild asthma treated with inhaled steroids for a long time. although the reduction takes place slowly over two months or more as the chronically inflamed airway heals slowly. Long-term oral steroid therapy is associated with significant side effects such as osteoporosis. As a companion drug to β2-agonists. inhaled steroids reduce symptoms. Since they reduce the number of circulating lowdensity eosinophils.173 Inhaled steroids inhibit the late response reflecting inflammation to allergen and prevent the increase in airway hyperresponsiveness that follows allergen exposure. The drug should be given as a single-morning dose and pulmonary function tests should be used to objectively assess efficacy.174 They also reduce AHR when given regularly. The introduction of beclomethasone dipropionate to asthma therapy in the early 1970’s represented a major advance in asthma management. it is suggested that inhaled steroids have an effect in the circulation or in the bone marrow. this phenomenon can be as a result of local airway effect through inhibition of synthesis of the eosinophil-stimulating cytokine IL-5 and RANTES. Various guidelines described subsequently advocate use of inhaled corticosteroids for longer periods of time than previously recommended in patients with mild asthma and at higher doses than previously considered feasible in patients with severe asthma. The lowest possible drug dose should be employed including attempts of alternate-day therapy.150 However. Inhaled corticosteroids are now gaining widespread acceptance as safe and effective agents for the management of childhood asthma. Studies in dogs have suggested that inhaled steroids affect the production of leucocyte progenitors in the bone marrow. They are very effective in controlling the symptoms of asthma and usually achieve rapid control. but it is not clear whether this results from affecting the synthesis of some stimulatory factor in the airways or from the action of the systemically .154 Bronchial Asthma Oral steroids should not be used alone without maximising other forms of therapy.175 When discontinued. impaired immune mechanisms. hypothalamo-pituitary-adrenal axis suppression. Patients with chronic asthma severe enough to need large oral maintenance doses are unlikely to respond adequately to inhaled treatment alone. • Aerosol treatment is not effective in acute severe asthma.180 • Both efficacy and side effects of aerosol glucocorticoids are dose dependent. They are unique among anti-asthma medicines that no other anti-asthma drug currently available share such a wide ranging profile of clinical benefits. prolonged use of oral steroids should be reserved for patients with severe asthma despite use of high-dose inhaled corticosteroids. reduce the need for rescue bronchodilators. Therefore. myopathy. • Aerosol treatment is more effective if divided into several doses throughout the day. and patients vary in their dose requirement. An important unresolved question is whether inhaled steroids exert a therapeutic effect on the airways through a systemic action. but independently. Cushing’s syndrome. cataracts. hypertension. symptoms and AHR revert to pretreatment levels.177 In patients with atopic asthma. and in rare instances. and improved lung function compared to regular treatment with β2-agonist alone. changes in the bronchial eosinophils and lung function during steroid therapy occur .178 Some basic principles regarding inhaled corticosteroids include:179. Inhaled steroids are safe and effective for the treatment of asthma. there may be long symptom free periods before recurrence. and is developed from the androstane 17 β-carboxylic acid and is a highly potent. Flunisolide.5 5. Mometasone furoate.183 Steroid receptors.1 3.0 3.8 18. The dose varies from < 400 μg per day to as high as 1600 μg depending upon the severity of bronchial asthma.5 9. Fluticasone propionate. and increased uptake and retention in the lungs as a result of its high lipophilicity. implying greater bronchial delivery by the delivery device.193 Estimated clinical comparability of doses for inhaled corticosteroids are shown in Table 10.190.6: Comparison of potency of inhaled corticosteroids Drug Beclomethasone Budesonide Flunisolide Fluticasone Triamcinolone Topical potency (skin blanching) 600 980 330 1. It has greater airway selectivity. the relative receptor affinity can be calculated and compared with other corticosteroids.185-189 Beclomethasone is the first inhaler steroid available nearly for the past 30 years and is used widely. Budesonide is a glucocorticoid aerosol with high ratio between topical and systemic corticosteroid effects.194 Table 10. Fluticasone propionate introduced in the 1990s.d. Budesonide. Triamcinolone acetonide.181 It is also uncertain whether steroids deposited in the proximal airways can be distributed via the airway circulation to the more distal airways.191 The drug is usually administered in a dose of 200-400 μg twice daily.6 . The inflammation of asthma affects the whole of the bronchial tree. selective anti-inflammatory steroid which binds with a high affinity to the glucocorticoid receptor of the human lung (18 times that of dexamethasone and 3 times that of budesonide). These observations are made on the basis of clinical trials comparing effects in reducing symptoms and improving PEFR.182.d. from the large central airways down to the small peripheral airways.5 3. is one of the most potent inhaled steroids currently available. If the receptor activity of a corticosteroid is determined under standardised conditions (usually with dexamethasone as reference). Budesonide given by a Turbuhaler has effects similar to twice the dose delivered by MDI. Fluticasone propionate is at least as effective as beclomethasone dipropionate 1000 μg b. are likewise located through out the bronchial tree. For all therapeutically used corticosteroids in asthma. fluticasone has effects similar to twice the dose of budesonide and beclomethasone when given via MDI in a microgram basis. rapid fast-pass metabolism (so less systemic side effects. It is estimated that beclomethasone and budesonide achieve comparable effects at similar microgram doses by MDI.6. betamethasone valerate.200 330 Corticosteroid receptor binding half-life (hrs) 7.5 10. the site of action of inhaled corticosteroid therapy.9 Receptor binding affinity 13.4 1.192 500 μg b.7. The same is shown in Table 10. However. and Ciclesonide.184 Various inhaled steroids available for clinical use include Beclomethasone dipropionate. The potency of a glucocorticosteroid is described by its receptor affinity and intrinsic activity. which is a compound-specific property. the intrinsic activity directly corresponds to the receptor affinity. Beclomethasone has similar effects to twice the dose of triamcenoline acetonide on a microgram basis. It is approximately 2-fold more potent than beclomethasone dipropionate and 4-fold more potent than budesonide.Pharmacologic Management of Asthma 155 absorbed fraction of the inhaled steroid on the bone marrow. which is highly effective in controlling asthma in all patients. which is based on that for fluticasone dipropionate 813. dysphonia is commonly seen (in more than 50%) if patients are given high-dose therapy. singers.140 concern has been expressed about their local and systemic side effects. and T-lymphocytes at the oral mucosal surface. The primary cause of husky voice is a steroid-induced dyskinesia of the voluntary musculature that control vocal cord tension. whereas laryngeal thrush is extremely rare. oropharyngeal candidiasis and dysphonia (huskiness) and only a minority of patients develop these complications (<5%). Dysphonia is common. All these complications are caused by the active drug and not by the propellant and are clearly related to the daily dose.156 Bronchial Asthma Table 10. severe. Other rare local complications include esophageal candidiasis. painful . Compulsive throat clearing and hypothyroidism aggravates and perpetuates the huskiness. Side Effects Although inhaled glucocorticoids have revolutionised the treatment of asthma being the most commonly and widely used anti-inflammatory drug treatment. switch board operators. and mouth rinsing immediately after inhaling the drug. teachers. Spacers also markedly reduce the incidence of this complication. Voice rest may improve the condition in these patients.195 The important local side effects of inhaled steroids are throat irritation. although other co-determinants are important.197 The problem is more common.196. The two are not causally related. slowing the speed of inhalation and/or by using a spacer. These measures include reduction of the daily dose. A 12-hour interval between doses appears sufficient to allow temporary recovery of these functions and to prevent this complication. sports coaches or employees in a noisy work place.7: Pharmacokinetic basis for evaluation of efficacy and safety of inhaled glucocorticosteroids Glucocorticoid Activation in the lung Beclomethasone dipropionate Flunisolide Triamcinolone acetonide Budesonide Fluticasone propionate Mometasone furoate Ciclesonide Relative receptor activity Lung tissue affinity Oral bioavailability (%) Expected theoretical therapeutic ratio + 1345 High 41 Intermediate – – 180 361 Low Low 20 23 Less favourable Less favourable – – 935 1800 Medium/low High 11 <1 Intermediate Favourable – + 1235* 1200 High High <1 <1 Favourable Favourable Receptor affinity are calculated with respect to dexamethasone as reference compound except * . and persistent in patients who use their voice maximum like preachers. This can be alleviated by any thing that reduces the deposition of the drug around the larynx. a longer post-inspiratory breath hold to reduce drug deposition during exhalation. The Candida overgrowth occurs due to the inhibitory effect of the drug on the normal host defense functions of neutrophils. However. Candidiasis and thrush depend upon the frequency of dosing and the concomitant use of antibiotics and/or oral steroids. macrophages. diarrhoea. Because of the importance of airway inflammation in the pathogenesis of asthma. Side effects can also be reduced by choosing a steroid such as budesonide or fluticasone propionate that undergoes extensive first-pass hepatic metabolism. reflex cough and bronchospasm.140. rash.202. inhaled corticosteroids are being used more frequently as primary therapy for moderate and severe asthma. abdominal pain. easy bruising. There is some fear of systemic effects because of oral. This can be reduced by using a largevolume spacer and mouth rinsing or other steroid sparing agents like cromolyn sodium.and late phase allergen-induced airway narrowing and acute airway narrowing after exercise (less than inhaled adrenergic agents). The systemic activity of any particular dose in different patients and patient groups depends largely on the fraction of the emitted dose that reaches the important absorptive surface in the lung periphery. such as occasional coughing upon inhalation of the powder formulation.205-207 Cromolyn sodium produces only minimal side effects.204 There is no way to predict reliably whether a patient will respond to Cromolyn sodium. Cromolyn sodium inhibits early. This fraction is determined by the interaction of numerous factors. . Systemic bioavailability varies with the preparation selected. This approach not only provides symptomatic benefit but also reduces airway hyperresponsiveness. gastrointestinal. including variations in normal lung anatomy.Pharmacologic Management of Asthma 157 and protracted atrophic glossitis. Approximately 80% of an inhaled corticosteroid dose will be deposited in the mouth and subsequently swallowed. and pulmonary absorption of the drugs. A 4-6 week trial may be required to determine efficacy in individual patients. inhibition of longitudinal bone growth in children and suppression of adrenocortical function. cataract formation. and sulphur dioxide. CROMONES (CROMOLYN SODIUM AND NEDOCROMIL SODIUM) Cromolyn Sodium Cromolyn sodium is the best nonsteroidal anti-inflammatory drug for asthma available currently. exposure to cold dry air. and nonspecific symptoms including nausea. The side effects may include bone and skin thinning.199-201 but a minimum daily dose should be sought once clinical response has been achieved. dry throat.198 However. they are infrequent. each of which reduces peripheral delivery of the inhaled drug. Very large doses of inhaled drugs may cross the placental barrier as shown in experimental animals. Then. Clinically significant adrenal suppression and altered bone metabolism are rare below 800 μg/day. and heartburn. It controls the symptoms of bronchoial asthma and bronchial hyperresponsiveness and reduces the number of acute exacerbations with an acceptable safety profile. The drug is available in a capsule form (5 mg) taken as an inhaler as well as metered dose inhaler and even as a nebuliser solution. pruritus. by the inspiratory techniques used. They are also effective in controlling symptoms in patients with mild asthma. impaired taste or smell. headache. allowing little of the drug to enter the systemic circulation. the degree of pulmonary function impairment and presence or absence of associated chronic bronchitis.203 This drug has been available for 35 years. gas. chronic oesophagitis resulting from combined Candidaherpes simplex infection. the only source of systemic absorption will be from the fraction absorbed from lung deposits. constipation. When administered prophylactically. thus giving the potential for systemic adverse events during long-term therapy. and in particular. Recent studies have shown that cromones may be most beneficial for patients whose predominant symptom is coughing. hyperventilation. They may be considered as the first line therapy in children and as a prophylactic agent against allergen-induced asthma. The drug is most effective in mild asthma and require at least 4-12 weeks to show any clinically significant effect. however. It is difficult to predict which patients will respond. It is given in a dose of 2-4 mg twice daily and this dose is roughly equivalent to 4 puffs of Cromolyn sodium. They appear to work best in patients with mild asthma. Recent data suggests that the ability of the drug to act as a prophylactic agent is not related to its mast cell stabilising effect nor the H1-receptor antagonistic properties. another study has found no evidence of a decrease of inflammatory cells after treatment with cromones. but not always. . Although the exact mechanism of action of cromones as anti-inflammatory drugs is not clear.217.214 Other studies suggest that cromones may block swelling-dependent chloride channels. In clinical trials the drug has been used in a dose of 4 mg four times a day with most beneficial therapeutic effects. and epithelial cells may be important. sensory nerves.204. inhibits PAF-induced eosinophil infiltration and bronchial hyperresponsiveness. and sulphur dioxide. It also reduces the acute airway narrowing response to exercise. mist. placebocontrolled trials have proved the efficacy of the drug in the prophylaxis of asthma particularly in children.208 However. prophylactic drug used in many countries in the management of asthma.218 Originally it was thought that the drug is a mast cell stabiliser that has the additional property of being a potent H1-receptor antagonist.158 Bronchial Asthma Nedocromil Sodium This is a pyranoquinoline derivative and is shown to inhibit mediator release prophylactically in a variety of in vitro systems. Ketotifen Ketotifen is an orally active. and more costly. The major advantage of ketotifen over other prophylactic drugs is that it can be used orally.215 Additional chloride channels in mast cells. Advantages of cromones are that they control symptoms of asthma and effectively block bronchoconstriction induced by a number of agents and factors. Both drugs are safe and have no significant side effects. and therefore they are to be used four times a day which is an inconvenient regimen for long-term prophylaxis. is not yet used extensively in clinical practice. Various clinical trials have proved that longterm therapy reduces nonspecific airway reactivity in atopic and nonatopic asthmatics. The drug. The other disadvantage of these drugs is their short action. Therapy with nedocromil is not associated with any significant adverse effects.209-213 The drugs are also likely to affect several other inflammatory cells including sensory nerves. The drug like many other prophylactic antiasthma drugs. The disadvantage of cromones are that they are weak anti-inflammatory drugs compared to inhaled steroids. Large double-blind. it is believed that the drugs stabilise and prevent mediator release from mast cells. The major side effect of the drug is sedation.216 One study has found that nedocromil has steroid sparing effects but other studies have not confirmed this.208 It also inhibits allergen-induced acute and late-phase asthmatic reactions and modulates allergen-induced increases in bronchial hyperresponsiveness. particularly 5-lipoxyenase. only a few could be used clinically in human beings because of safety factors. another orally active drug is marked in Japan in the mid-1995. The therapeutic strategies were i.Pharmacologic Management of Asthma 159 Antihistamines With the development of new classes of nonsedating antihistamines.2. 246 These drugs are at least 200 times more than the early LT antagonists and they cause a shift up to 100-fold in the bronchoconstrictor dose-response curve.219. Only terfenadine inhibits exercise induced asthma.244 Pranlukast. their role and usefulness in treatment of asthma require additional studies and they are not recommended as anti-asthma drugs. azelastine and cetirizine) moderately inhibit the early asthmatic response. Although some studies with H1 antihistamines in asthma have demonstrated some therapeutic benefits. They also reduce bronchoconstriction induced by several natural triggers of asthma including exercise. The newer antihistamines also inhibit mediator release from in vitro cell systems.238 Generally four classes of drugs are currently under development and some of them are available for clinical use as anti-asthma or anti-inflammatory therapy.239 attempts were made to modulate their pharmacological actions so that they can be of some clinical use by the way of blocking the leukotriene receptors or inhibition of their synthesis.241 ii.240 but the attempt was unsuccessful. Clinical trials have shown their superiority over placebo in grass and pollen induced asthma. A single 20 mg oral dose of zafirlukast produces marked protection against exercise-induced bronchoconstriction with the maximum effect .221. These agents block the acute bronchoconstricting effect produced by inhaled histamine. They are very active in preventing bronchoconstriction induced by agonists both in healthy and asthmatic individuals.8 and Figure 10. including eosinophils and mast cells.220 The rationale for their use was that subjects with asthma demonstrate hyperresponsiveness airways to histamine and require only small quantities of this mediator to demonstrate changes in their pulmonary functions. Leukotriene Antagonists and Synthesis Inhibitors Cysteinyl leukotrienes (LT) play a significant part in the pathogenesis of bronchial asthma as discussed earlier. but not that produced by methacholine. Pharmacological inhibition of specific enzymes. allergen and aspirin. which interferes with LT synthesis or activity. They are depicted in Table 10.221-238 These leukotrienes are produced and released from proinflammatory cells.242 Although a number of the above compounds were tried initially. bronchoconstriction and eosinophil recruitment into the airways. The drug also has some calcium channel blocking properties.245. Dietary provision of alternative fatty acid substrates within membrane phospholipids which will products with less proinflammatory activity. Since the structure of leukotrienes was described in 1979 . and iii. They have also bronchodilating action.243 Zafirlukast is active both orally and when administered by inhalation and is the most potent oral cysteinyl LT antagonist. Most of these drugs (terfenadine. cold air. astemizole. there has been renewed interest in their use. and are at least 1000 times more potent bronchoconstrictors than histamine or methacholine in normal subjects and patients with bronchial asthma. They mediate many of the pathophysiologic processes associated with asthma including microvascular leakage. Modulation of end organ effects with selective cysteinyl leukotriene receptor antagonists. -571 A-64077. a 46% reduction in night waking.248 In aspirin-induced asthma. significant improvement occurs in evening peak flow.250 Zafirlukast and pranlukast are well tolerated in clinical trials. ABT-761.247 400 μg of the drug inhaled also produced a similar degree of protection.10. Efficacy of objective and subjective measures in patients with symptoms are dose related and the greater response are achieved with 40 mg total dose of zafirlukast. Compared with placebo. MK-0591. BAYx1005 Fig.249. Z-D2138 MK-886. Thick arrows shows sites of action that finally prevents the final pathophysiological activity being observed 5-30 minutes after stimulation. where there is an increased production of cysteinyl LTs.8: The anti-leukotriene group of drugs Name Leukotriene D4 antagonists Zafirlukast Probilukast Pranlukast Tomelukast Verlukast 5-Lipoxygenase inhibitors Zileuton FLAP Inhibitors Compound ICI-204.219 SK and F 104353-Q ONO-1078 LY 171883 MK-679. the LT-antagonists improve lung function and inhibit bronchoconstriction induced by aspirin. a 30% reduction in rescue use of inhaled β2-agonists.2: The four groups of drugs directed against leukotriene synthesis and activity. and a 26% improvement in morning asthma and daily symptoms are observed.251 Doses up to 80 mg .-476.160 Bronchial Asthma Table 10. 264 Although this group may constitute a very small proportion of the total cases. mucociliary transport. leukotriene receptor antagonists demonstrate hybrid anti-inflammatory and bronchodilatory properties. Of the above mentioned drugs. microvascular permeability. dry mouth. proliferation of airway smooth muscle cells in chronic severe asthma. and pranleukast. Therefore. The only disadvantage of zileuton is its relatively low potency and short half-life (2. The drug is as effective as theophylline in moderate asthma. dosing is to be made four times a day.85 doubling dose shift. zyluton. and inhaled steroid doses can also be reduced. β-agonist use. It also prevents the response to cold air challenge and to aspirin in aspirin-induced asthma.263 Alternative Treatment for Oral Steroid Dependence Approximately 10% of patients with asthma have severe disease and require high doses of inhaled or oral glucocorticoids. this is an antioxidant and potentially can interfere with redox reactions in other metalloenzymes. It also increases the FEV1.262 Current International Guidelines recommend using an leukotriene receptor antagonist as first-line therapy in patients with mild. and interaction with nerves. and somnolence. leukotriene-receptor antagonists confers significant additive pro-inflammatory effects to therapy with a low-dose inhaled corticosteroid. and the 5-lipoxygenase inhibitor.260 A meta-analysis found that these agents reduced exacerbations by 50% and reduced the requirement of additional asthma therapy. zafirleukast. No factor has been identified to predict such a response except that cysteinyl leukotrienes release from leukocytes is correlated with leukotriene receptor antagonist response. They require more frequent medical attention. more often hospitalised. they consume more than 50% of the resources. improvement in daytime and nocturnal asthma symptom scores. while cysteinyl leukotrienes are important pro-inflammatory and bronchoconstrictor mediators in the pathogenesis of asthma. . Clinical studies have shown improvement in FEV1. The drug also has a steroid-sparing effect in severe asthma. four oral antileukotriene drugs are now available for the treatment of asthma: monteleukast. mucus secretion.257. It helps in reducing the symptoms of asthma.258 For this reason. these drugs also affect eosinophil reflux.252 Besides being effective in preventing bronchoconstriction due to various triggers. However. The reported side effects of these drugs are: headache. and reduction in reliever β2-agonist use in patients with patients treated with leukotriene antagonists. or as second-line therapy in conjunction with inhaled corticosteroids. persistent asthma. need more expensive drugs.253-255 The 5-lipoxygenase inhibitor zileuton is the best studied drug. thus the estimated protection amounted to almost one doubling dose reinforcing the role of these agents as anti-inflammatory therapy in asthma. Some of these patients may have more severe disease because of relative resistance to the effect of glucocorticoids. as an alternative to increasing the dose of inhaled corticosteroid.259 In summary. not all patients will show a significant clinical improvement.256 Oral zyleuton in a dose of 800 mg inhibits the early response to allergen challenge and reduced LT synthesis. recent asthma guidelines have recommended that antileukotrienes have a role in the management of bronchial asthma (see below).261 Another meta-analysis from 13 trials showed weighted estimated protection of leukotriene receptor antagonists amounted to a 0. Even if the drug appears to be safe in clinical trials.251. Further.5 hours).Pharmacologic Management of Asthma 161 twice daily have been given to patients with beneficial effects increasing still further at the higher doses. Doses more than 15 mg/wk may have unacceptable side effects. This interferes with thymidine synthesis and thus blocks DNA synthesis and cell division. vomiting. The mechanism of action as an anti-inflammatory drug include inhibition of histamine release from basophils. This approach is often helpful. Anxiety about asthma deaths might lead to overuse of steroids. iii. Before labelling someone having steroid resistance preventable factors need to be considered. v. specific antigens.280. Steroid-sparing effect disappears on discontinuation of methotrexate. including troleandomycin. Superimposed psychosocial factors and hyperventilation syndrome may cause further problem. These include poor compliance. Treatment of patients with severe.266 These patients should not be prescribed corticosteroids. No consistent effect on airflow or bronchial responsiveness is expected. the following provisional conclusion may be made from available literature: i. it is an antineoplastic agent and in low doses (5-25 mg/ week) it acts as an anti-inflammatory and immuno-suppressive agent. dapsone. act due to their action of inhibition of T-lymphocytes. azathioprine. gastro-oesophageal reflux. In the steroid dependent asthma. but as severe asthma only. when methotrexate is added in addition to subjective improvement. shows response to bronchodilators but none to corticosteroids. treatment with high-dose inhaled corticosteroids should be maintained over a period of several weeks to months.271-273 Although some clinical trials have shown benefit from low dose methotrexate. 267-270 Since asthmatic inflammation may be regulated by Th2 lymphocytes. This approach has the lowest incidence of adverse effects and has a high likelihood of clinical efficacy. a patient. Some of these approaches are still experimental and should be used only in specialised centers. and dietary factors. and the dose of oral steroids should be reduced slowly while monitoring pulmonary function.281 There is significant reduction in steroid doses. intravenous immunoglobulins. inhibition of cytokine release (IL-1) from mononuclear cells. hepatic dysfunction. Several modalities of therapeutic regimens have been advocated/tried to help reduce oral steroid dependence in severe asthma. Some patients are truly corticosteroid resistant. Methotrexate is an antimetabolite which antagonizes folic acid by inhibiting dihydrofolate reductase. and cyclosporine. Various drugs have been proposed as alternatives to systemic steroids. Some patients having severe asthma and who show some response to steroids should not be labelled as steroid resistant cases. . hydroxychloroquine. gold. i. vi. inhaled frusemide. occupational factors.265. and intravenous magnesium sulphate. In spite of the controversy and confusion.162 Bronchial Asthma and miss more time for work or school than patients with milder form of the disease. methotrexate. (15 mg/wk) others do not support this. The common side effects are nausea. No predictive factor could be found about the responders. At higher doses. some of these drugs which are immunosuppressive. a trial of high doses of inhaled corticosteroids (2 to 4 times the usual doses) is essential. ii. Methotrexate may be a steroid agent in some steroid-dependent patients. the treatment may be continued for long periods (> 3 months) and unlikely to occur after 1 year.273-279 The drug is also found useful in children. To have an appreciable effect. Before attempting any of the following experimental drugs. alopecia.e. and neutropenia. and reduction of neutrophil chemotaxis. iv. persistent asthma who require high doses of systemic steroids presents a therapeutic challenge. Such high doses of steroids for longer periods of time have multiple systemic side effects. oral ulcers. Steroid weaning should be done before methotrexate trial. Chest 1982. Shahid M. new opportunities for the treatment of asthma.12:19-27. But the experience in clinical practice is not much. Kazanowski JJ.43:2041-51.46:499-503. The drug should be viewed as a risky preposition in comparison to long-term oral steroid therapy. Primary sequence of cyclic nucleotide phosphodiesterase isoenzymes and the design of selective inhibitors. Reifsynder DH. Other agents like azathioprine. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes.289 Mucocutaneous reactions are the common side effects of gold therapy.290 intravenous immunoglobulin. Could selective cyclic nucleotide phosphodiestrase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol 1992. 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N Engl J Med 1994. van Essen-Zandvliet EEM. in newly detected asthma. Chest 2002. Eur Respir J 1990. et al. N Engl J Med 1991. Is delayed introduction of inhaled corticosteroids harmful in patients with obstructive airways disease (asthma and COPD)? The Dutch chronic non-specific lung disease (CNSLD) study group. N Engl J Med 1991. Kraan J.325:388-92.3:1122-1127. Lundgren R. 170. Brodde OE. Soderberg M. Am Rev Respir Dis 1990. 172. 160.8:340-47. Terbutaline induced desensitisation of human lymphocyte β2-adrenoceptors: accelerated restoration of β-adrenergic responses by prednisolone and ketotifen. Haahtela T. et al. Belvisi MG. 166.331:700-05.110:35-41. 164.121:151-57.76:628-36. Kline PA.76:1096-1101. with an inhaled corticosteroid. A comparison of the bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. Biochem Biophs Res Commun 1994. Van de Stolpe A.327:1413-19. 171. van der Mark THW. Haahtela T.145:669-74.142:832-36. Overbeek SE. Jarvinen M. J Clin Invest 1985. budesonide. Kerstjens HAM. Wilson JW.118:770-78. The effect of hydrocortisone on β-adrenergic receptors in lung tissue. MacDernot J. Effect of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. Comparison of a agonist. Initial improvement in lung function and bronchial hyperresponsiveness are maintained during a 5 years of treatment with inhaled beclomethasione dipropionate and terbutaline. J Allergy Clin Immunol 1985. van Schayck CP. Caldenhoven E. Hughes MD et al. N Engl J Med 1992. 169. 159. 173. in newly detected asthma. Morphological studies of bronchial mucosal biopsies from asthmatics before and after ten years treatment with inhaled steroids. Kava T et al. 162. 168. Akarasereenont P et al. Springall DR et al. Raaijmakers JAM et al. Robbins RA. 157. budesonide. terbutaline. Akharzadeh A. Dolery Ct. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthma drugs in patients with allergic asthma: A comparison between budesonide and terbutaline. Haahtela T. Glucocorticoid-mediated repression of intercellular adhesion molecule-1 expression in human monocytic and bronchial epithelial cell lines. 165. Britten KM. Kosesnadi K et al. Kava T et al. Kerstjens HAM. Jenkinson PMA.11:600-06. budesonide. 181. Murdock KY.154:771-82. Inhaled corticosteroid therapy: A substitute for theophylline as well as prednisolone? J Allergy Clin Immunol 1985. Arch Dis Child 1993. 182. Aerosol steroids as primary treatment of mild asthma. Barnes PJ. Pedersen S. J Allergy Clin Immunol 1987. Vaz de azevedo M. Effects of inhaled fluticasone propionate and oral prednisolone on lymphocyte β2-adrenoceptor function in asthmatic patients.79:734-40. Am J Respir Cell Mol Biol 1994. Weeke B.19:280-88. Asthma treatment with a new corticosteroid inhaler.106:3-10. Chest 1996. Poulter LW.Pharmacologic Management of Asthma 171 174.Reed CE. Reed CE. Eur Respir J 1990.141:S70-S76. late asthmatic response.68:19-28. 184. administered twice daily by spacer inhaler. 180. Bugalho de Almeida A. 190. Hamid Q. Tan KS. Clark TJH. Demers EA. Kline PA. Wooler E.121:1414-20. Aerosol steroids as primary treatment of mild asthma. N Engl J Med 1991.69:351-55. Curr Opin Pulm Med 2003.148. sodium cromoglycate and beclomethasone dipropionate on allergen-induced early asthmatic response. Tatterfield AE. 193. Frame MH. Am J Respir Crit Care Med 1996. Am J Respir Crit Care Med 1996. Koenderman L.325:425. Dose response and therapeutic index of inhaled corticosteroids in asthma.57:864-66. Faul JL. 183. Grove A. Allergy 1998. Marchant JL. J Allergy Clin Immunol 1997. Use of budesonide in severe asthmatics aged 1-3 years. Drugs 1984. Cargill RI. 187. Song Y. 176. Johnson M. Arch Dis Child 1982. Int J Clin Pract Suppl 1999.325:425. Pinto Mendes JA. N Engl J Med 1991. 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Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: Predominant production of leukotriene C4. Paris. 222. Thorax 1995. Kaliner MA. 228. 232. Proc Natl Acad Sci. Black PN. Presented at the European Congress of Allergology and Clinical Immunology. MacGlashan DW.80:481-86. Horton CE. Hansson G. Arendt C.43:84-92. Proc Natl Acad Sci USA 1979. 229. Barnes PJ. Science 1983. Arm JP. Drazen JM. Ann Allergy 1990. J Invest Dermatol 1983. Prostaglandins 1983. Foster DW et al. Pedrali P. Finnerty JP. Barnes NC. 249. Role of leukotriene in exercise-induced asthma: Inhibitory effect of iCI 204219.48:1205-10. Chervinsky P. 258. Bronchoprotective effects of leukotriene-receptor antagonists in asthma: A meta-analysis. double-blind.336:137-40. 219. Cohn J. Pujet JC. placebo-controlled trial of methotrexate in steroid dependent asthma. 261.145:746-49.151:A378. Smith LJ. Lancet 1992. Spector S. Kamis Y. Moss RB. a leukotriene D4 receptor antagonist. Kay AB. 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Barnes NC.282:1419-22. Currie GP. Glass M. 259. Spector SL. 251. in subjects with bronchial asthma. a potent leukotriene D4 receptor antagonist.84:501-10. 263. Binks SM. Barnes NC. Matsuda T. Effects of adding either a leukotriene-receptor antagonist or low-dose theophylline to a low or medium dose of inhaled corticosteroid in patients with persistent asthma. Am Rev Respir Dis 1992. Corticosteroid resistance in chronic asthma. Chest 2002. a novel leukotriene receptor antagonist: Results of the first European. Nonsteroidal anti-inflammatory drugs: Mechanisms and Clinical uses. Corticosteroid sparing agents in asthma. . Trial of cyclosporin in corticosteroid-dependent chronic severe asthma.150:618-23. Steroid resistance in asthma. 262. Paterson IC. Barnes PJ. The effect of six-week therapy with oral doses of ICI 204. Am Rev Respir Dis 1993. Chest 2002. 248. Thorax 2000. Pranlukast. Clin Sci 1993. Adcock IM. Chest 2002.145:A16. Thomson H.151:A379. Chung KF et al. 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Thorax 1993. 247. a once daily leukotriene receptor antagonist. Ann Intern Med 1998. Effects of 6 weeks of therapy with oral doses of iCI 204. 254. Am J Respir Crit Care Med 1995. placebo controlled. Fowler SJ. 253. Melby JC. Leukotriene-receptor antagonists. Ann Intern Med 1968. Glass M. Lau LC.52:523-27.147:1413-18. Lowell FC. Lancet 1999. Sakahato S. Sulphidopeptide leukotrienes in asthma. multicenter clinical study in asthma. Terasima T.174 Bronchial Asthma 246. Q J Med 1995. Am J Respir Crit Care med 1995. Dahlen B. 269. Zetterstrom O. Makkar HK. Respir Med 1993. Lipworth BJ. Nunn AJ. 250. Minkwitz MC. Shiner RJ. Margolskee DJ. Minkwitz MC. Pharmacologic Management of Asthma 175 271. Hu S, Mitcho YL, Oronsky AL, Kerwar SS. Studies on the effect of methotrexate on macrophage function. J Rheumatol 1988;15:206-09. 272. Nolte H, Skov PS. Inhibition of basophil histamine release by methotrexate. Agents Actions 1988;23:173-76. 273. Mullarkey ME, Blumenstein BA, Andrade WP et al. 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Clin Exp Immunol 1985;61: 360-67. 294. Schwartz YA, Kivity S, Ilfield DN, et al. A clinical and immunological study of colchicine in asthma. J Allergy Clin Immunol 1990;85:578-82. 295. Charous BL. Open study of hydroxychloroquine in the treatment of severe symptomatic or corticosteroid-dependent asthma. Ann Allergy 1990;65:53-58. 176 Bronchial Asthma 11 Inhalation Therapy Current therapeutics emphasises the importance of effective delivery of a drug to its site of action—the Targeted Drug Delivery.1-6 The advantage of this approach is avoidance of unnecessary and undesirable exposure of tissues/organs not involved in the disease process to the drug. It is sufficient and advantageous to have the drug delivered only to the site where the drug is needed. Targeted delivery of the drug to the desired site of action means that smaller doses are enough to produce the desired effect and generalised systemic side effects can be eliminated or minimised and a rapid action of the drug can be obtained. The value of inhalation as a route of drug administration has been recognised for thousands of years by the ancient civilisation in India, China, the Middle East and as well as by Hippocrates and Galen. The Ayurvedic system of medicine advocated the use of datura smoked in a pipe for a variety of ailments and atropa belladonna was given by smoking as a standard remedy for asthma. Asthma cigarettes made from Datura leaves are also being used by herbalists. Bronchodilator aerosols have been in use since 1935. In the past adrenergic bronchodilators have been given by hand-held squeeze-bulb nebulisers. This was cumbersome, and modern pressurised aerosols were introduced in 1956 and constituted a breakthrough in inhalation treatment. In recent times, inhalation therapy for asthma has been developed to a high level of sophistication although they are simple to use. The key to inhalation therapy is the aerosol particle. An aerosol is a suspension of fine liquid or solid particles in air. The efficacy of an inhaled drug depends largely on how much of the drug is deposited in the peripheral airways. On the other hand, the deposition of inhaled particles is determined both by the physical characteristics of the air-borne particles and physiological parameters like airflow to the lungs. Particle size is an important determinant of aerosol deposition in the lungs. Most devices (discussed below) generate particles in the size range of 1-10 micron. Only particles in the size range of 2-5 micron can be inspired deep into the lungs; particles 5 micron or more in diameter are impacted in the throat or in larger airways. Particles less than 1 micron behave like a gas and are exhaled in the expired air. Most aerosols contain a wide range of particle sizes and are known as heterodisperse aerosols. The mass median aerodynamic diameter (MMAD) is the median diameter of the aerosol multiplied by the square root of particle density. MMAD is important as regards aerosol deposition rather than the particle sizes. The propellant surrounding the drug particles evaporates on emerging from the canister and the particle steadily decreases as the aerosol moves away from the canister. Other factors that count for aerosol deposition include velocity, inertial impaction, and gravitational sedimentation. However measurements using radioactive teflon particles labelled with technetium-99m with a gamma camera Inhalation Therapy 177 have shown that about 10% of the drug released from an MDI is deposited in the lung. About 80% is deposited in the oropharynx and about 10% is trapped on the walls of the inhaler device. For the purpose of inhalation therapy an aerosol of the drug can be generated in three ways: i. Pressurised aerosol systems; ii. Dry powder system; iii. Nebulisers. Pressurised Aerosol Systems (Metered Dose Inhalers—MDIs) Most medications prescribed for the treatment of bronchial asthma for maintenance or rescue, are administered via a metered dose inhaler (MDI). In Pressurised aerosol systems or metered dose inhalers micronised finely powdered drug is dissolved or suspended in a liquid propellant mixture, and packed in a sealed container (Fig. 11.1). The liquid propellants are highly volatile chlorofluorocarbons, CFC, (Freons) with a high vapor pressure of about 400 kPa. These freons are gases at room temperature, have a low boiling point, are inert, noninflammable, and odourless. Some surfactant is added so that they are not clumped together. On actuation, propellants emerge and break up into aerosol particles each consisting of a drug particle surrounded by the propellant. The valve is metered so that each actuation releases a fixed amount of the drug-propellant mixture. Therefore, it is named as the metered dose inhaler (MDI). During recent years, CFCs have been criticised for their harmful effects on the environment, especially the depletion of the stratospheric ozone layer. The production and use of CFCs were banned by international treaty (the Montreal protocol) in 1987, although their use in medications is not as the amount for this use is very small. Such exemptions to the National and International bans were made for MDIs to allow time for comparative clinical trials of alternative propellants, as required by worldwide regulatory agencies. Although no deadline has been set for the United States, Canada aims to achieve total transition by 2005, and the European Commission predicts that there will be no need for CFC-based MDIs in the European Community by the year 2003. So far, the most promising alternative propellants for MDIs are derivatives of hydrofluoroalkane (HFA). The HFA agents lack chlorine, and thus have zero ozone depletion potential.7-9 Preclinical studies have Fig. 11.1: Components of meter dose inhalers 178 Bronchial Asthma demonstrated the acceptability of these propellants in terms of pharmacology, toxicology, and safety.10 Clinical studies also have shown that these propellant are as equivalent or even better than those use CFCs as propellants.11-18 Clinical trials have demonstrated that the level of asthma control achieved with CFC-beclomethasone dipropionate may be obtained with approximately half the total daily dose of HFA- beclomethasone dipropionate. This is probably due to improved lung deposition with the extra fine aerosol of HFAbeclomethasone dipropionate compared with the suspension of CFC based aerosol lung deposition is also greater with HFA- beclomethasone dipropionate compared with CFCbeclomethasone dipropionate and CFC-fluticasone propionate. Deposition values are related to the particle size distribution of each inhaler, with the smaller particles of HFAbeclomethasone dipropionate providing the greatest lung deposition and least oropharyngeal deposition.19 Evaluation of adherence to treatment is one important step in asthma management. Patients tend to overestimate the usage of MDIs presumably secondary to recall bias or as an effort to avoid criticism Prescription refill histories as from the issuing authorities or verification of the medical bill of the patient and canister weighing are more objective measures, but they do not reflect pattern of usage. Electronic monitors are recently available for accuracy of MDI use.20 Dry Powder Inhalers In an attempt to overcome the coordination problem that is required for the successful use of the pressurised MDIs, a number of dry powder inhalers have been developed. In the dry powder system, micronised drug is mixed with a carrier substance (lactose) and the mixture is filled into a gelatin capsule. The capsule is loaded into the inhaler device and is cut open in the device before inhalation (Fig. 11.2). After piercing or fracturing the gelatin capsule, the patient only needs to do is to inhale through the device to draw the powder out of the capsule. The aerosol is generated by means of the energy contained in the inspired air. The air stream passes the powder in such a way that a turbulent flow is formed which breaks up the particles into a dust or aerosol. The higher the inspiratory flow rate (>60L/min), higher the number of respirable particles. Although it is easier to use than a MDI, it is less convenient because of the need to load the capsule before use. Because of a high flow rate, many patients, particularly children, cannot generate a sufficient inspiratory flow required to break up the aggregates during an acute attack. Thus, too large particles are unable to penetrate into lung periphery. Further, in the panic and distress of an acute situation, the patient may have difficulty in inserting the capsule into the device. Inhalation of the dry Fig. 11.2: Dry powder system Inhalation Therapy 179 powder may cause some irritation and cough in some patients. The gelatin capsules are subject to environmental influences of moisture and temperature during storage. This will make the capsule soggy and could not be broken by the system efficiently. Thus, they may be reserved for those who cannot master the technique of MDI. Recently, a multi-dose, ready to use, additive free dry powder inhaler effective at low inspiratory flow rates are available which can overcome the above difficulties. Different types of DPI such as Turbohalers, Diskhalers, and Accuhalers are available now. These devices have the advantage of being breath activated, and delivery of an accurate dose is less dependent on patient technique. Recently, new generation multi-dose dry powder inhaler (MDPI) is available, which has a triple inhalation control system, so that the patient has acoustic (click), visual (dose counter), and sensory (oropharyngeal sensation confirmation of dosing. Other mandatory features of the DPI are an accurate metering system, a dose counter, and a robust compact design. A unique feature in terms of cost and flexibility is that the inhaler utilises replaceable cartridges that contain up to 200 doses, with the future potential for a wide range of therapies.21 Nebulisers In nebulisation, small droplets are generated suitable for inhalation from a nebulising solution containing the drug. Two types of nebulisers are used for this purpose: a. the Jet nebuliser (Fig. 11.3) which is powered by compressed air or oxygen from a compressor or a cylinder; and b. the ultrasonic nebuliser which derives the energy required to make an aerosol from high frequency sound waves (Fig. 11.4). Nebulisers need a power source and use of nebulisers is time consuming. However, they are useful in very young children or adult patients who cannot manage the use of inhalers and for delivery of large doses of bronchodilators as in acute severe asthma. In addition they are used for delivery of drugs that cannot be formulated in a MDI because of technical reasons since very high doses cannot be packed and for bronchial challenge tests and lung ventilation scanning. The main advantage of nebulisers is the ease of use by patients. It can be inhaled with normal tidal breathing through a mouthpiece or a face mask. Since they can be driven by oxygen, this becomes an extra advantage in acute asthma. Moisture obtained from wet aerosol may be helpful in loosening the mucus. Nebulised bronchodilators can also be administered through pressure-cycled ventilators. Jet nebulisers driven by oxygen/compressed air needs a flow rate of at least 6-8 litres/min generate aerosol particles in the respirable range. The solution used for nebulisation needs to be diluted with isotonic and preservative-free solutions to reduce drug loss due to impacting of aerosols in the dead space of the apparatus. A minimum volume fill of 4 ml (drug + normal saline) with a flow of 6 litres/ min. is recommended to ensure a high aerosol output, small particle size, And short treatment time. In infants, the small minute volume of 3-3.5 litres compared to the nebuliser output of 6 litres/min limits the amount of the drug to be inhaled. Hence, they will need a higher dose. Other precaution to be taken is that the interior of the container be cleaned thoroughly after use to avoid bacterial (Pseudomonas aeruginosa) contamination and the air intake grill and filters to avoid Aspergillus contamination. The choice of the particular nebuliser is important as not all of them produce desired aerosols. As with MDI, only about 10-12% of the drug can reach the lungs, most of it being retained as 180 Bronchial Asthma Fig. 11.3: Jet nebuliser Fig. 11.4: Ultrasonic nebuliser large droplets on the internal walls of the nebuliser itself. Thus, in an acute attack of bronchial asthma, a properly used MDI with a spacer is as effective/useful as a nebuliser. The main advantages of inhalation devices are the greater asthmatic effect (10-20 times of an oral dose is required to produce an equivalent response as by inhalers), rapid onset of action and response, self administration on demand. Short-term prophylaxis and lack of side effects are the other advantages. Various problems of inhaler use include Hand-Lung dyscoordination (failure of timing the inspiration with dose release), cold freon effect, inspiration and breath holding, and cough on inhalation of aerosol. All aerosolised medications that are used for the treatment of asthma are available as metered-dose inhalers (MDI) which are pressurised and propellant-powered; or jet and ultrasonic nebulisers which are electrically powered. The advantage of delivering drugs directly into the airways is that high concentrations of drug can be delivered to the airways, while systemic side effects are usually avoided. The major disadvantage of this mode of drug delivery is that training and skill are required to coordinate activation of the MDI with inhalation of the drug. Therefore, teaching of proper MDI techniques is very essential Inhalation Therapy 181 since only about 10% of the inhaled dose penetrates the lower airways. The most important device is the “spacer” which may be a cone spacer or a tube spacer. The conical shape of the spacer accommodates the enlarging cloud. Spacer Devices Spacer device is an extension chamber interposed between the mouth piece of the MDI and the mouth of the patient (Fig. Autohaler. The mass median diameter of the aerosol from an MDI is reduced from 8.9 microns making possible most of the particles to be in the respirable range. Gentle-Haler. A flow rate of less than 1 L/sec.5: Spacer . This device allows time and distance for the aerosol to travel in space before it is inhaled. In the open mouth technique the inhaler is held approximately 4 cm in front of an open mouth. It is generally agreed that maximum delivery of aerosol into the airways is obtained by inhaling an aerosol bolus from functional residual capacity. and Turbohalers. 11. The slowed down particles held in the chamber can be inhaled few seconds later after the release and there is no need of synchronisation of inspiration and actuation. This helps retaining the modified aerosol in the chamber until it is emptied by inhalation.4 to 4. The spacer is such that impaction loss on the walls is minimal. There are two different general approaches to inhalant techniques with MDI: the open mouth and closed mouth techniques. Fig. Other delivery devices which have been developed in an attempt to overcome the disadvantages of pressurised MDI include the Roto-Haler. even with optimal techniques. It is calculated by laser holography studies that one cubic millimeter of air within a spacer is about 5500 at the end of 5 seconds and is still 3300 after 30 seconds of actuation. with an inhalation time of over 5 second and a breath holding time of 10 seconds is believed to be the optimal technique. 11. The aerosol velocity is also reduced because of resistance offered by air in the space. Smaller particle size helps better deposition in the peripheral airways and reduces deposition in the oropharynx. The particle size is reduced because of evaporation of the liquid propellant. This simplifies inhaler use and quite helpful in those who have coordination problems. Spacer devices are usually of two types: small volume spacers (tube spacers) and large volume spacers or valved spacers of the volume of about 750 ml. The aerosol cloud emerging from the MDI expands into a conical shape as it moves away. The one way valve opens during inspiration and closes during expiration.5). Lung deposition is increased by 133% and reduces throat deposition by 90%. The expired air leaves the mouth piece through a side port. Derham A et al. Price DB. but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extra fine beclomethasone dipropionate. Hales CS. Auxillary MDI delivery systems. A 12-week. Fischer DA. Nature 1990.92(Suppl A):23-31. 400 μg is as effective as chlorofluorocarbon beclomethasone dipropionate 800 μg for treatment of moderate asthma. Thompson PJ. Improved delivery of inhaled steroids to the large and small airways. Atkinson D. CFCs. their replacements and the ozone layer.8(Suppl):S3-S7.182 Bronchial Asthma REFERENCES 1. Nayak A.122:510-16. Jackobson K et al. Hydrofuoroalkane 134a beclomethasone dipropionate.104:1215-22. 11. 7. Chervinsky P et al. 17. Julus S. 3. Chest 2002. Chest 2002. Thorax 1983. Summer W. N Engl J Med 1986. Weinstein S et al. New horizons in asthma therapy: The Novoliser dry powder inhaler. J Aerosol Med 1995. 14. Tharpe L. double-blind. Leach CL. The challenge of reformulation. Aerosol bronchodilator delivery methods. 20. Lung deposition of Hydrofluoroalkane 134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone.92(Suppl A):3-8. Chest 2002. Respir Med 1998. 4. Newhouse MT. Leach CL. Furukawa C. Davidson PJ.8(Suppl):S19-S27. Lanier R.Physical and practical considerations. Chest 1999.344:513-16. . Newman SP. Therapeutic aerosols 1.115:343-51. 15. Dolovich MB.122:1956-65. Boudreau RJ. Davies RJ. J Asthma 1991. Noakes TJ.28:239. 10. Hillman B. Respir Med 1998. Gross G. 8.7(Suppl 1):S1-S2. Aerosol deposition consideration in inhalation therapy.121:871-76. Chest 1985. Hydrofuoroalkane 134a beclomethasone dipropionate extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone dipropionate to approximately half the total daily dose. Chest 1999. 2. Efficacy and safety of beclomethasone dipropionate extra fine aerosol in childhood asthma. Fluticasone propionate via the disk haler or hydrofluoroalkane-134a metered-dose inhaler on methacholine-induced airway hyper-responsiveness. Smith IJ.88(Suppl):S15260S.1943:26. Scrip 1994. Control of asthma by aerosols. Model calculations of the relative effects of CFCs and their replacements on global warming. 5. Hendeles L.38:881-86. Haponik EF.121:1824-32. Chest 2002. Sackner MA. 16. Efficacy response of inhaled beclomethasone dipropionatein asthma is proportional to dose and is improved by formulation with a new propellant.88(Suppl):S161-S69. Clarke SW. Hansel TT. 12.149:618-23. 9. Chest 1985. 6. Elston R. CPMP on possible alternatives to CFCs. O’Conner BJ.122:806-11. Nelson S. Langley SJ. Kunkel G. Stampone PA et al. Juniper EF.116:65-72. Chest 2002. Clinically important improvements in asthma-specific quality of life. Busse WW. Accuracy of three electronic monitors for metered dose inhalers. randomised. 18. Stampone P. Kim CS. 13. J Aerosol Med 1995. Arch Intern Med 1989. Brazinsky S. Sherman JM. Forster TJ et al. 21. 19. Aerosol deposition and delivery of therapeutic aerosols. Holden J. J Allergy Clin Immunol 1999. Curr Opinion Pulm Med 2001.315:870-74. Newman SP. Wang WC et al. Controlled trial of two formulations of cromolyn sodium in the treatment of asthmatic patients > 12 years of age. Hasselquist BE. placebo-controlled study. 1-11 The basic principles are the same in all these guidelines. requires a continuous care approach to control symptoms. The degree of an individual’s asthma severity may change from one season or year to the next. Management of bronchial asthma can be divided into that for chronic asthma and acute severe asthma. To avoid adverse effects from asthma medications x. To recognise asthma and its severity ii. To minimise absence from school or work vii. Management therefore. . specific asthma therapy must be selected to fit the need of individual patients. Global Initiative for Asthma and WHO. The course of asthma varies among patients. To meet patients’ and families’ expectations of and satisfaction with asthma care.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 183 12 Therapeutic Approach in Patients with Asthma I. Notable amongst them are those of the National Heart. British Thoracic Society. To maintain normal activity levels including exercise iv. To minimise the need for as needed (quick-relief) β2-agonist therapy ix. To abolish symptoms particularly those of the chronic troublesome ones like nocturnal cough and dyspnoea. Research Unit of the Royal College of Physicians of London. and reduce chronic airway inflammation. To enable normal growth to occur in children viii. CHRONIC BRONCHIAL ASTHMA—AIMS OF THERAPY The basic goals or aims of management of chronic asthma are: i. Over the years a number of guidelines have been developed. To maintain a normal or near normal or the best possible long-term pulmonary functions v. Lung and Blood Institute of the NIH. the National Asthma Campaign. Chronic Bronchial Asthma Asthma is a chronic condition with acute exacerbations having variable course. The course of disease is not uniform with periods of exacerbations and remissions which varies from days to weeks to months to years. USA. and early morning symptoms iii. prevent exacerbations. the King’s Fund Center. The therapy must be adaptable to change as the disease changes in the individual. Therefore. To prevent recurrent exacerbations of asthma and the risk of severe attacks vi. vi. The therapy is usually dictated by the severity of disease. or other irritants. to prevent exacerbations. f. Therefore antiinflammatory treatment is an essential component of management of bronchial asthma. including exposure to antigens like animal danders. domestic pets. This is particularly true for exerciseinduced asthma. Sometimes aggressive antiasthma therapy fails because an upper respiratory infection has been overlooked. house-dust mite. and pollens. and sensitivity to environmental allergens. cold air. by evaluation of night time symptoms and by assessing pulmonary function. and to reduce airways inflammation. Occupational causes must be considered and appropriate steps be taken. they should be avoided. viii. Allergic and nonallergic rhinitis should be treated with antihistamines. should be avoided where relevant. Since there are many conditions which mimic bronchial asthma. Beta blockers (tablets and eyedrops) are contraindicated.184 Bronchial Asthma PRINCIPLES OF MANAGEMENT Certain basic principles of bronchial asthma needs to be considered before administering any specific therapeutic modalities. There is no cure of bronchial asthma but if the patient follows certain guidelines including medications. If aspirin or NSAIDs are known to induce asthma. Bacterial otitis and sinusitis should be treated with antibiotic therapy. iv. Prophylactic treatment for exercise or before exposure to triggers. medication tolerance. g. the disease can be controlled and the patient can lead life like a normal individual. It should also be realised that asthma is a chronic condition with acute exacerbations with varying periods of remissions. v. Passive smoking should also be avoided. Both adults and children who has upper respiratory tract viral infections.g. Anticipatory or early interventions in treating acute exacerbations of asthma reduce the likelihood of developing severe airway narrowing. The severity of asthma must be evaluated by assessing the activity limitation. vii. Asthma is an inflammatory disease and inflammation may continue even during periods of clinical remission and even in patients with mild asthma. the diagnosis should be established. Inhaled β2−agonist or Cromolyn sodium or both taken prior to an anticipated encounter with a known trigger can prevent or diminish an asthmatic response. Allergens as outlined above (e. i. b. and start to have acute asthma symptoms may need to add or increase anti-inflammatory asthma medications in order to control the asthma symptoms. iii. Active smoking should be avoided. Asthma therapy has the following integral components: . The patient must be taught to avoid: a. ii. or topical nasal steroids. Treatment requires a continuous care approach to control symptoms. The same principle can also be applied to other situations. All these factors need to be incorporated in the formulation of therapy. e. c. Environmental control measures must be under taken to avoid allergens.. Cromolyn sodium nasal spray. All types of smoking should be stopped and exposure to passive smoke should be eliminated. It is essential to deal with common asthma triggers. d. The therapy selected should not have adverse effects that are perceived by the patient to be worse than the underlying disease. 1: Approach to therapy of bronchial asthma depending upon the aetiopathogenesis .17 Fig. Use of the lowest effective dose with a target of controlling asthma but with the minimum of short and long term side effects. and what to do under those circumstances. Patient education and family participation b. Management of asthma requires a partnership between the patient and family and the health care provider. Patients and parents require both verbal and written advice and many will require guided self management plans. Avoidance of identified causes where possible c. Giving those with asthma written self management plans so that they may adjust treatment to keep themselves well reduces morbidity and health costs. Giving information alone does not alter behaviour. but written and audiovisual reinforcement of spoken message aids patient confidence.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 185 a. 12.16.12-15 There is definite evidence of benefit from patient education and the issuing of self management plans. Education should be the basis of sharing of information and the acquisition by the patient and family of understanding and skills. so that the patient can keep well and adjust treatment according to a plan developed with the physician. The above three approaches are interrelated in the management and pathogenesis of bronchial asthma are shown in Figure 12. All patients should be given information about features which indicate when their asthma is worsening.1. It should be made clear from the very beginning that treatment and supervision are likely to be required over a prolonged period of time. This will bring about appropriate change in behaviour only if patients and family are given adequate opportunity to express any fears or concerns. PATIENT EDUCATION Health education by the physician is a powerful tool for helping patients gain the motivation and skill to control their asthma. and time to discuss their expectations of both the disease and its treatment. Further. and . the patient should demonstrate the use of the MDI to the clinician. how the medicines work.186 Bronchial Asthma Various components of patient education plan includes: i. and if not. Encouraging adherence to the treatment plan is the next step which can be achieved by clarifying patient’s expectations for treatment and answering questions. simplifying the treatment plan. When several inhalers are prescribed. adverse effects of drugs and their prevention. Indications of immediate report to emergency include cyanosis.20 involving the patient and family in the development of a treatment plan. actions taken. If the patient is not adhering to the treatment plan. Various essentials of patient education includes the content of teaching both written and audiovisual. or dark circles under the eyes in children. Materials and guidelines for individuals and group education and support network are very helpful. Ignoring this fact is a very important cause of non-adherence to treatment prescribed. demonstrate techniques. what are the key points about the symptoms and signs of asthma. particularly during daily activity. Some patients benefit from joining asthma patient support groups or clubs. Establishing a partnership which improves the patient adherence to the treatment plan and stimulate family effort to improve control of patient’s asthma18.19 ii. the role of inflammation and the role of various medications. group education. iii. vi. These groups vary from area to area. symptoms.22 Similarly.21. cough or wheeze. The patient’s MDI technique should be reviewed during each visit. asthma triggers and how to avoid them. talking or walking. and early treatment during exacerbations. difficulty in breathing. providing the patient with diaries to record antecedents of asthma exacerbations. providing written guidelines. and then provide reinforcement by several routes. and a steady decline of PEFR. shortness of breath. failure of medications to control worsening of symptoms. The correct use of inhalers should be demonstrated to the patient. neck or ribs and nasal flaring. and peak expiratory flow rates. the need for treatment. preventive treatment. vii. alleviating patient fears concerning medications. explaining to the patient about asthma like what is it. discussions. Knowledge of the optimal use of home peak expiratory flow meter—both its recording and interpretation are now one of the essential components of asthma management. retraction of the chest. an individual pattern of early signs such as chest tightness. Evaluation of the result of treatment from time to time helps positive reinforcement plans. v. but most provide informative materials. The most effective is for the health care professional to give information verbally. labelling them is essential and also explaining when to use which one and which inhaler to be used first. and steps to manage asthma episodes at home. iv. group classes. Early warning signs include a peak flow level below 20% predicted or personal best level. then the cause for the same to be identified by asking the patient the likely problems and a possible solution for the same should be provided. an important question to be kept in mind whether that patient can afford to buy the medications prescribed. and dramas help patients learn guided self-management skills. The patient should be able to recognise the early warning symptoms or signs of airflow obstruction which will enable him to begin treatment immediately. demonstration. The education must continue in a long-term basis. alternative therapies must be considered. The specific methods should be selected on the basis of patient and cultural preferences. handle mild attacks promptly at home. PEFR indicators. a careful stepdown of the therapy can be considered as outlined below. Yellow zone This signals caution. active lives. monitor their condition. that should be doubled for 12 weeks or until PEFR improves. Emergency visits should no longer be needed. Currently asthma education worldwide websites are available. Readings in this zone indicates that an acute attack may be present for which a temporary increase in medication is needed. and takes little innovative use of technology. Frequent fluctuations into the yellow zone may indicate poor control of asthma and the green zone therapy has to be increased.23 The patient must be made to understand that there are new ways to manage their disease so that they can prevent problems. There is 20-30% variability. and live productive. identifies the earliest possible signs that day to day control of asthma is deteriorating. asthma education material contains many accessibility barriers. and reach agreement on long-term treatment. In case the patient is taking inhaled steroids. follow personalised action steps and stop attacks. The . Regular medical visits provide periodic opportunities to address concerns. and coping with the stress of a chronic disorder in the family. PEFR readings are below 60% of the personal best. The zone system helps patients understand the chronic and variable nature of asthma. PEFR are usually 80-100 percent of personal best. and prevent serious attacks. and content. If the patient has stayed for at least 3 months in this zone. recognise signs that asthma is worsening and take action. avoid triggers. monitor personal status using symptoms and if possible. These informations currently available in the web fails to meet the information needs of the patient. PEFR readings are 60-80% of personal best. Red zone This indicates medical alert. This system classifies levels of asthma control as different zones based on the frequency and severity of symptoms and peak expiratory flow measurements. The patient then follows the prearranged action steps appropriate to each of the following three zones. An asthma management zone system is effective for guided self-management and should be included in the management plan.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 187 mutual support. Asthma symptoms are present even when the patient is at rest or interfere with activity. Asthma is under control with no symptoms or interruption of activities or sleep. Also it is possible that an overall deterioration of asthma might have occurred that require further treatment. The system then indicates the appropriate therapy for each zone. When PEFR readings are available. and seek medical help at the appropriate time to stop serious attacks. making changes at home. The variability is less than 20%. A short burst of corticosteroids will be required till the PEFR comes back to the green zone. Guided self-management means a patient can take medications correctly. The patient should develop a treatment plan with the physician. Some mild asthma symptoms are present. However. understand the difference between quick-relief and long-term preventive medications. be free of symptoms both day and night. This is achieved by having the patient become actively involved as a partner in his or her care through guided self-management. Group members exchange personal tips on managing asthma. the patient’s current reading must be compared to his or her personal best—the highest PEFR value achieved when the patient’s asthma is under control—is his benchmark for asthma control. Green zone It indicates all clear. is highly variable in quality. They can learn to control their asthma. Long-term asthma control requires a written management plan that describes what to do to prevent symptoms and attacks and what to do in case an attack occurs. essentially β2−agonist inhalers for quick relief. solve problems. and act quickly to regain control. Outdoor Allergens Exposure to outdoor allergens is best reduced by remaining indoors. environmental control measures to avoid allergens is an important step in the control of bronchial asthma. which are clearly associated with asthma.24. the dander and saliva will remain for a long time even after the pet leaves. knowledge of the same is helpful. this form of therapy is still widely practiced by many physicians. Pollen particles greater than 10 microns are usually cleared in the nose and mouth and do not generally penetrate the lower airway. cat. An inhaled short-acting β-agonist should be taken immediately. The .25 particularly during the midday and afternoon when pollen and some mould spore counts are highest. If the pet cannot be removed from the house. Some fungi sporulate on worm. rodents. others in the rainy seasons. the yellow zone actions should be continued. Removal of the animal may not afford immediate relief even when followed by vigorous cleaning as allergen has been shown to remain in the home for many months. Mould spores are generally smaller than pollen grains and are more likely to penetrate the lower airway. some plants produce allergen containing particles that are in the respirable range like ragweed. cockroach allergen. and congress grass pollination.27 Residual allergen can be denatured and rendered nonallergenic by application of 3% tannic acid solution. Since allergy has a significant role in the pathophysiology of bronchial asthma.188 Bronchial Asthma patient should follow medication plan. there are allergic components in house dust. birds. Animal Allergens The best way to avoid animal allergens are just to remove the animal from the house (dog. Mould spores exist primarily out of doors and tend to be seasonal. Since there is a geographical and seasonal variation of pollens and other aeroallergens. After the attack is controlled. it should at least be kept out of the allergic person’s bedroom at all times.26 However. In general both active and passive smoking should be avoided. House dust is an important source of indoor allergens. Weekly washing of the pet may reduce the amount of dander and dried saliva deposited on carpets and furnishings. Skin prick tests and in vitro specific IgE measurements are rarely helpful in diagnosis and management and should be interpreted by a physician familiar with such tests. The most important include mites. the green zone therapy and patient adherence to the management plan should be reviewed and adjusted accordingly. The main method of identifying allergy is by clinical history. dry summer days. Keeping windows closed during seasons of high mould production will reduce exposure. Indoor Allergens Environmental control to reduce exposure to indoor allergens is a critical component of asthma management. preferably in an air conditioned environment. Use of nasal filters or masks have been tried with little success. If the animal is in the bedroom at all. and animal danders. If the PEFR improves after initial bronchodilator therapy. Although house dust per se is not an allergen. IMMUNOLOGICAL MANAGEMENT Although the benefits of immunotherapy remains unproven. etc). 35-38 If carpet removal is not possible. the pillows are also to be encased and be washed weekly. are often found on small particles that are easily airborne. measures of airflow. bedcovers. and soft toys. it is reported that use of air filtration systems in patients with asthma or allergy showed a reduction in symptoms. Washing of pets as mentioned above has given variable results and must be repeated so frequently as to be impractical in most situations. the food for the mite. carpets may be removed from the bedroom. and measures of bronchial hyperresponsiveness. the bedding should be washed in water at 130° F or 55° C weekly and dry thoroughly in a hot dryer or in the sun. Patients are often interested in alternatives to excluding the pet from the home. It is of course not possible always. They occur in environments with sufficient humidity since they are quite dependent for survival on moisture from atmosphere. upholstered furnitures.31 House-dust Mite House-dust mites are important causes of allergic asthma. In such a situation.33 Some mite allergen is associated with smaller size particles that may be in the respirable range for the lower airways. curtains and children’s soft toys are to be washed regularly. Central vacuum cleaners exhausted to the outside are also likely to be effective.28 Since there is a dose-response relationship between parameters of asthma control. but it is present in only very small amounts in undisturbed air. clothes. wherever human dander. and exposure to allergens. Cat and dog allergens. Due to small particle size of airborne allergens.32 The principal allergen is found in the mite faeces. Mite antigen is found throughout the home.room. HEPA cleaners are likely required.000 mites and 250. need for medications. is clearly associated with improvement in the parameters of asthma control like symptoms. A gram of dust may contain 1.000 faecal pellets. is found. These faecal pellets are quite large varying in size from 10-40 microns. there is hardly anything other than complete avoidance can benefit asthmatic patients with a documented pet allergy. This renders the use of air filtration devices attractive. and ascaricides may be useful in killing the mites.29 although an improvement in bronchial hyperresponsiveness has been found in cat allergic children. living room.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 189 most reliable reduction of exposure to allergens derived from furred pets is done by completely excluding the pet from the home and avoiding exposure to pets elsewhere. Settled allergens will be removed by methods of removal of house dust (see on page 191). preferably when the asthmatic patient is not present. pillows. the patient should avoid sleeping or lying on upholstered furnitures.30 In a recent meta-analysis. and no improvement in measures of peak flow. as opposed to dust mite allergen. vacuuming should be carried out with a high-efficiency particulate air (HEPA) vacuum cleaner with a double reservoir bag. High levels are obtained in dust obtained from mattresses. and play. if successful.40 . It is important to make patients aware of the choices they are making like more medications. decrease in health related quality of life and to reexamine these choices on a regular basis. and carpets laid on concrete are to be removed. it seems reasonable to keep the cat out of the bedroom.34 House-dust mite control measures include encasing the mattress in an airtight cover. carpets.39 Such a multifaceted and concerted approach to reducing levels of dust mite allergen among asthmatic subjects with positive allergy skin test results to mite allergens. Mite antigen is easily demonstrated in the air during housecleaning activities. and therefore do not easily penetrate the lower respiratory tract. if possible the indoor humidity is to be reduced to less than 50%. Significant health benefits are not documented despite the reduction in the amount of airborne particles. but not of medication use. Avoidance measures for dust mites.42 are probably effective at improving asthma control if the measures are strictly adhered to. Indoor allergens are of particular importance because of the most part of the time spent indoors. all furnaces and stoves are to be vented outside and the room is to be kept well-ventilated.42 and cockroaches. In fact. Exposure to air pollutants like oxidants and sulphur oxides and ozone has been associated with worsening pulmonary function and increased airway hyperresponsiveness in persons with asthma. Strong odours or sprays produced by cosmetics like perfumes. cockroaches. This is likely to be less effective than ridding off the pet from the home completely. Indoor Moulds These are found in environments with increased humidity. The indoor allergens most likely to be relevant are dust mites. Humidifiers are potentially harmful. household cleaning products.43 IMMUNOTHERAPY The role of specific immunotherapy in asthma management is controversial and is under continual investigation. kitchens and basements require adequate ventilation and frequent cleaning using chlorine bleach if necessary. the British Thoracic guidelines clearly mentions that the . All patients with asthma deserve an allergy evaluation to identify sensitisation to common inhaled allergens. Pillows should be encased or changed regularly. and medication sensitivities need to addressed in all patients. sulphite sensitivity. The patient should avoid tobacco smoke. If sprays are used the patient should not be present at that time. Wood smoke and other smoke from domestic cooking should be avoided as they are known to increase respiratory symptoms. Bathrooms. Other Precautions Since vacuum cleaners are prone to mobilise fine respirable allergen particles.41 The infested homes should be cleaned thoroughly and regularly. room deodorisers.190 Bronchial Asthma Cockroach Allergen It is important in warmer climates. or use a vacuum cleaner with a high efficiency particulate air filter. talcum powder. Perspiration on foam pillows may encourage mould growth. To avoid this. Other precipitating factors like gastroesophageal reflux. they should use a dust mask. Air conditioning is helpful since the windows and doors need to be closed and it reduces indoor humidity discouraging mould and mite growth. Those affected by such odours should avoid them. The unit should be cleaned regularly. and furred pets. with humidity levels for less than 50% but above 25%. These environmental exposures may interact with allergens and other triggers in the causation of bronchial asthma. Pesticides and pesticide sprays are used to eliminate cockroaches. Dehumidifiers for damp basement areas should be considered. and fresh paints irritate some patient’s airways and trigger asthma symptoms. frying. Avoidance of allergens to which a patient with asthma is sensitised is an integral and effective part of asthma management. given the characteristic distribution of these allergens at home. Air filtration devices are unlikely to be important or effective over and above the more usual measures. both active and passive. allergic patients should not vacuum or if they do so. Air filtration devices are effective at reducing levels of pet allergen in home and may improve asthma control when combined with exclusion of the pet from the bedroom. If symptoms occur frequently (more than two times a week). As asthma is a chronic inflammatory condition. Patient involvement and education should be an integral part c. The patient must have medication. Treatment may be stepped up as necessary to achieve good response e. The indications of rescue courses of steroids are as follows: • Symptoms and PEFR get progressively worse day-by-day • PEFR falls below 60% of the patient’s best . If there is no evidence of response following two allergy seasons after reaching the maintenance or the highest level tolerated by the patient. immunotherapy should be discontinued. Allergen avoidance is always the first recommendation for managing asthma symptoms. the interval between injections should be extended. adding medications as necessary to control symptoms. However.1 Allergy immunotherapy has been shown to reduce symptoms of asthma with a variety of allergens including house dust. it is recommended that once patient achieves maintenance levels of immunotherapy. Treatment is to be considered in a step-wise manner as shown in Figure 12.48 However.49 If immunotherapy is administered. A reuse course of prednisolone tablets will be necessary at any time and at any step A short “rescue” course of corticosteroid tablets may be needed at any time and at any step to gain control of asthma.45 grass pollen. The best inhaler device should be selected d.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 191 hyposensitisation or immunotherapy is not indicated in the management of chronic bronchial asthma in adults. anti-inflammatory treatment should be given to most patients. Rescue treatment itself has a step-care pattern.9 Currently available medications and avoidance strategies usually provide good control of asthma. A peak expiratory flow meter may be prescribed to monitor response to treatment. preventive therapy is necessary in addition to rescue treatment.46 and alternaria . with a goal of monthly injections.2. The patient should start treatment at the step most appropriate to the initial severity. The patient should avoid provoking factors whenever possible b. In addition to those depicted in the figure it is essential that: a. The possibility of toxicity is also increased with this approach. although under some situations more prolonged therapy at monthly intervals may be needed. when avoidance is not possible and appropriate medications fail to control symptoms of allergic asthma. If the patient’s symptoms improve. Response to allergy immunotherapy decreases with age and with lower baseline levels of pulmonary function. Allergy immunotherapy should only be administered in a physician’s office who is well versant with the therapy and where facilities and trained personnel are available to treat any life-threatening reaction that can occur. available for acute relief of symptoms.44 cat dander. which is a very rare situation. treatment is usually continued for 3-5 years.47 They also reduce the threshold for skin or lungs to the allergen employed and the late reaction to allergens in the lungs are also reduced. Increasing use of rescue treatment by the patient is an indication to review the medication plan and possibly to increase preventive therapy. PHARMACOLOGICAL THERAPY Pharmacological therapy for bronchial asthma is often described as “step care”. an inhaled β2−agonist. in which the number of medications and frequency of administration are increased or decreased as necessary. Treatment may be stepped down if control of asthma is good and f. their efficacy in the overall clinical management remains controversial. referral for allergy immunotherapy may be considered. 12. move to Step II. In an adult. The drug is then tapered. . Inhaled short acting beta agonists SOS plus beclomethasone or budesonide 100-400 mcg bd or fluticasone 50-200 mcg bd or cromoglycate or nedocromil. start inhaled steroids. This dose is to be continued in a single morning dose till two days after control is achieved.2: Step-care management of bronchial asthma (BTS) • • • • Sleep is disturbed by asthma symptoms Morning symptoms persist till midday Diminishing response to inhaled bronchodilators Emergency use is made of nebulised or injected bronchodilators.192 Bronchial Asthma Step V Regular steroid tablets added Step IV Step III Step II Regular inhaled anti-inflammatory agents Step I Occasional use of relief oronchodilator Inhaled short acting beta agonists SOS. If needed > 1 daily. Before altering a step ensure that the patient is having the treatment and having proper inhalation. If no control. High dose inhaled steroids and regular bronchodilators Inhaled shortacting beta agonists SOS plus beclomethasone or budesonide 800-2000 mcg od Inhaled shortor fluticasone acting beta 400-1000 mcg od agonists SOS + via spacer plus 1 beclomethasone or or > 1 of inhaled budesonide 400long-acting beta 1000 mcg od or agonist sustained fluticasone 400release theophyl1000 mcg od via line inhaled spacer plus 1 or > ipratropium or 1 of inhaled longoxytropium longacting beta agonist acting beta sustained release agonist tablet theophylline high dose inhaled inhaled ipratropium bronchodilators or oxytropium cromoglycate or long-acting beta nedocromil agonist tablet high dose inhaled bronchodilators cromoglycate or nedocromil High dose inhaled steroids or low dose inhaled steroids + longacting inhaled beta agonist Inhaled shortacting beta agonists SOS plus beclomethasone or budesonide 800-2000 mcg od or fluticasone 400-1000 mcg od via large volume spacer and one or more of the longacting bronchodilators plus regular prednisolone tablets in a single daily dose Stepping down Review every 3-6 months Fig. 30-60 mg of prednisolone is given immediately. use cromoglycate or nedocromil sodium. Outcome of steps 1-3: Control of asthma Outcome of step 4-5: Best possible result • Minimal or no chronic symptoms • Least possible symptoms • No nocturnal symptoms • Least need for relief bronchodilators • Infrequent exacerbations • Least possible activity limitations • Minimal need of relief bronchodilators • Least possible variation in PEFR • No activity or exercise limitations • Best PEFR • PEFR variation < 20%.3. In a very small number of patients who experience side effects with high doses of inhaled steroids. the patients management techniques including use of medicines. Any fear the patient might be having must be addressed. Cromoglycate or nedocromil may also be tried. Alternatively. peak flow measurements. If they are needed more than once daily move to step 2.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 193 The appropriate treatment with different drugs in various steps are summarised below: Step 5 Addition of Regular Steroid Tablets Inhaled short-acting beta agonists as required with inhaled beclomethasone or budesonide 800-2000 μg daily or fluticasone 400-1000 μg daily by a large volume spacer and one or more of the long-acting bronchodilators with regular prednisolone in a single daily dose. either the long-acting inhaled beta agonist or a sustained release theophylline may be added to step 2 medications. Step 1 Occasional use of relief bronchodilators Inhaled short-acting beta-agonists as required for symptom relief are acceptable. it must be ensured that the patient is having the treatment and has a good inhaler technique. For many . Step 4 High dose inhaled steroids and regular bronchodilators Inhaled short-acting β-agonists as required with inhaled beclomethasone or budesonide 800-2000 μg daily or fluticasone 400-1000 μg daily through a large volume spacer plus a sequential therapeutic trial of one or more of inhaled long-acting beta agonist or sustained release theophylline or inhaled ipratropium or oxytropium or long-acting beta agonist tablets high dose inhaled bronchodilators or cromoglycate or nedocromil. Before altering a treatment step. If control is not achieved start inhaled steroids. PEFR 80%/more • Least adverse reactions from drugs • Minimum side effects from drugs The expected line of therapy and possible outcome in different grades of asthma are depicted in Figure 12. Step 2 Regular inhaled anti-inflammatory agents Inhaled short-acting beta agonists as required plus beclomethasone or budesonide 100-400 μg twice daily or fluticasone 50-200 μg twice daily. Step 3 High dose inhaled steroids or low dose inhaled steroids plus long-acting inhaled beta agonist bronchodilator Inhaled short-acting beta agonists as required plus either beclomethasone or budesonide increased to 800-2000 μg daily or fluticasone 400-1000 μg daily through a large volume spacer or beclomethasone or budesonide 100-400 μg twice daily or fluticasone 50-200 μg twice daily. For patients who have established control of their asthma. The possible outcome with various steps of treatment are shown below. etc. regular follow up visits at approximately 1 to 3 month intervals are necessary to review the treatment plan. Periodic assessment of six domains of patient health is highlighted. find out environmental aggravators and the patient’s efforts to control them will be necessary.50 Although the basic principles of management are the same. B. The new guidelines includes additional goal of therapy to meet the expectations of the patient and its family with satisfaction. Reduction of therapy can be carefully considered if PEFR variability is less than 10% and there are no asthma symptoms for a reasonable period (2-3 days for the exacerbation in mild asthma. Skin testing or in vitro testing is now specifically recommended for at least those patients with persistent asthma .3: Step-care management of asthma and expected outcome patients with moderate to severe asthma. It is emphasised that patients of all severity levels are to monitor symptoms to recognise early signs of deterioration. and the possibility of increasing the dosage or change of medications may also need to be considered. These include signs and symptoms. Sample questions to use in periodic assessments are also added. patient-provider communication and patient satisfaction. If the morning reading is less than 80% of the personal best PEFR. The basic components of management include: A. The panel also recommends home monitoring of PEFR from twice daily to once in the morning only. evaluation of the patient’s technique in using the medication. If PEFR variability is greater than 10-20%. pulmonary function. Recently the Expert Panel Report 2 of the National Institute of Health has published guidelines for the diagnosis and management of bronchial asthma in adults and children . pharmacotherapy. can be maintained with only continuous preventive therapy. The aim of therapy should be to use the minimum medication needed to maintain control with minimum risk for adverse effects. quality of life. The possibility of concomitant upper respiratory tract disease.12. some more facts have been highlighted. Measures of assessment and monitoring. Control of factors contributing to asthma severity is important. control of the disease as reflected in normalisation of pulmonary function and activity levels without symptoms. more frequent monitoring may be required. The use of the individual patient’s personal best PEFR is emphasised. history of exacerbations.194 Bronchial Asthma Fig. several weeks for moderate or severe asthma). sinusitis. though supplement. and severe persistent asthma. .2. D. Pneumococcal vaccination is considered not important. the education by the physician. detailed questions to elicit information and educational messages for each visit are to be provided. and (b) quick-relief medications. The stepwise approach to asthma therapy emphasises initiating a higher level of therapy at the onset to establish prompt control and then stepping down. it is not intended to be a specific prescription. The stepwise approach presents general guidelines to assist clinical decision making. it is necessary to evaluate the outcome in terms of patient perceptions of improvement. long-acting β2-agonists. Stepwise management of bronchial asthma in adults and children over 5 years of age depending upon the above severity criteria as recommended by the NIH Expert Panel is shown in Table 12. Further. or a history of sensitivity to aspirin or non-steroidal anti-inflammatory drugs are to be counselled regarding the risk of severe and even fatal exacerbations from using these drugs. However. iii. Since asthma is highly variable. moderate persistent. mild persistent. prednisolone. severe to mild intermittent. moderate. The Expert Panel50 has changed the classification of the severity of asthma from mild. Annual influenza vaccinations are specifically recommended for patients with persistent asthma. C. and prednisone. medications are now categorised into two general classes. The most effective medications for long-term control are those having anti-inflammatory effects and include drugs like corticosteroids. (a) long-term control medications. Treatment of chronic persistent asthma should be considered in a stepwise manner as described above with the patients starting treatment at the step most appropriate for the initial severity of their conditions. However they do not replace. Corticosteroids are the most important anti-inflammatory drugs and include various inhaled forms as discussed earlier and systemic drugs like methylprednisolone. nasal polyps.1. ii. Patients should be treated for rhinitis.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 195 exposed to perennial indoor allergens. While the former are used to achieve and maintain control of persistent asthma. The importance of pharmacological therapy is very much there and is an important component of asthma management. Routine use of chemicals to kill house-dust mite and denature the antigen is no longer recommended as a control measure. specially quality of life and the ability to engage in desired activities. Patient education for CFC-free inhalers is gaining importance in view of the ban on the use of CFC (chlorofluorocarbons). Key messages are to be reinforced during each visit. clinicians should tailor specific medication plans to the needs and circumstances of individual patients. GENERAL PRINCIPLES OF APPROACH TO TREATMENT OF CHRONIC PERSISTENT ASTHMA i. and gastro-oesophageal reflux. the later are used to treat acute symptoms and exacerbations. To enhance the delivery of education. Education for a partnership in asthma care includes providing patients both a written treatment plan for daily self-management and a written action plan for management of exacerbations. and leukotriene antagonists. Patient education by the principal clinician as well as other members of the health care team is important. Adult patients with severe persistent asthma. The clinical features before treatment are shown in Table 12. USA.196 Bronchial Asthma Table 12. Patients at any levels of severity can have mild. Some with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of normal lung function and no symptoms. sustained release theophylline • Oral corticosteroid Step 3 Moderate Persistent Daily medications Anti-inflammatory Inhaled steroid (medium Quick relief Education Inhaled β2-agonists • • Intensity of treatment • will depend upon severity of exacerbations • Use of short-acting β2-agonists on a daily basis. Classification of severity (NIH. but < 1 day • Exacerbations may affect activity • > 2 times a month • FEV1 or PEFR 80% or more • PEF variation 20-30% Step 1 Mild intermittent • Symptoms 2 times or less per week • Asymptomatic and normal PEFR between exacerbations • Exacerbations brief • 2 times or less per month • FEV1 or PEFR 80% or more • PEF variation < 20% Note: The presence of one of the features of severity is sufficient to place a patient in that category.1. moderate. The characteristics described above are general and may overlap in view of the variable nature of asthma. Table 12. An individual should be assigned to the most severe grade in which any feature occurs. or increasing use indicates the need for additional long-term control therapy • Inhaled β2• agonists sos • • Intensity of treatment As in step 2 and 3 Individual education Step 1 action plus Individual education if available Contd. 51) Severity Step 4 Severe persistent Symptoms Night time symptoms • Continuous symptoms • Frequent • Limited physical activity • Frequent exacerbations Lung function • FEV1 or PEFR 60% or less than predicted • Variability of PEFR > 30% Step 3 • Daily symptoms Moderate persistent• Daily use of inhaled β2-agonists • Exacerbations affect activity • Exacerbation 2 or more/week • May last days • > 1 week • FEV1 or PEFR >60% > or = 80% predicted • PEF variation > 30% Step 2 Mild persistent • Symptoms > 2/week. . or severe exacerbations.2: Stepcare management of bronchial asthma50 Step Long-term control Step 4 Severe persistent Daily medications • Anti-inflammatory Inhaled steroids (high dose and long-acting bronchodilators like long-acting inhaled or oral β2-agonist... . • Review and update self manage ment plan.. especially for night-time symptoms.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) Contd. either long-acting inhaled β2-agonist. . sustained release theophylline or long-acting β2-agonist tablets If needed: Anti-inflammatory: Inhaled corticosteroids (medium-high dose) and long-acting bronchodilators. Short-acting bronchodilator: Inhaled β2agonist sos • Intensity of treatment will depend on severity of exacerbation • Use of above more than 2 times a week may need to start • Step 1 action + teach self monitoring • Group education. Leukotriene antagonists may also be tried for the patients of 12 yrs or >... Step Step 2 Mild persistent Step 1 Mild intermittent Long-term control dose) or low-medium dose and add a longacting bronchodilator. although their role in therapy is not fully established. sustained release theophylline. or longacting β2-agonist tablets Daily medications: Anti-inflammatory Either inhaled steroid (low doses) or cromolyn or nedocromil Alternatively. • Teach basic facts of bronchial asthma • Teach inhaler spacer/ holding chamber technique • Discuss role of medication management plan • Develop self management plan Contd. • Use of short acting inhaled β2-agonists daily or increasing use indicates need for additional longterm control therapy. especially for nighttime symptoms: either long-acting inhaled β2-agonist. Daily medication not needed Quick relief 197 Education will depend upon • Review and update severity of exacerself management plan bations • Use of short-acting β2-agonists on daily basis indicate need for term-control therapy Short-acting bronchodilator: • Inhaled β2agonist as needed. • Intensity of treatment will depend on exacerbation severity. sustained release theophylline. They can be used 2 puffs three to four times a day.198 Bronchial Asthma Contd. Short-acting β2-agonists are the therapy of choice for relief of acute symptoms and prevention of exercise-induced asthma. This may be especially common with exacerbations provoked by respiratory infections.. A rescue course of systemic corticosteroids may be required at any step at any time. First. A short course of systemic corticosteroids is recommended in that situation. review patient medication technique adherence. certain drugs like aspirin and non-steroidal anti-inflammatory drugs. etc. Alternatively. a higher dose of inhaled corticosteroid may be used. and environment control iv. Patients should avoid all known factors precipitating their asthma. Quick-relief Medications Bronchodilators. Patients should be encouraged to use the minimum dose to control their symptoms. vii. consider step up. Step Long-term control Quick relief long-term control therapy Step down Review treatment every 1-6 months a gradual stepwise reduction in treatment may be possible Education • Develop action plan to when and how to take rescue actions • Discuss appropriate environment control measures Step up If control is not maintained. Some patients with intermittent asthma experience severe and life-threatening exacerbations separated by long periods of normal lung function and no symptoms. Referral may be considered if the patient requires step 3 care. At each step the patient should control his environment to avoid or control factors that make their asthma worse like allergens. ix. irritants. v. A β2-agonist such as salbutamol 100-200 μg or terbutaline 250-500 μg should be used as required rather than regularly. They may be chemicals. Salbutamol is also available as rotahalers with 100-200 mcg/capsule which can .. β−blockers are contraindicated in asthma. They are the most effective medications for relieving acute bronchospasm. This requires specific diagnosis and education. viii. Gaining control may be accomplished by either starting treatment at the step most appropriate to the initial severity of their condition or by starting a high level of therapy like a short course of oral corticosteroids may be needed at any time and at any step to control their asthma as mentioned above. Referral to an asthma specialist for consultation or co-management is recommended if there are difficulties in achieving or maintaining control of asthma or if the patient requires step 4 care. The control should be gained as soon as possible and then the treatment is to be decreased to the least medications necessary to maintain control. vi. Increasing use of these drugs or roughly use of more than one canister in one month indicates inadequate control of asthma and the need for initiating or intensifying anti-inflammatory therapy. High doses of inhaled steroids. Inhaled steroids are the drugs of choice since they are the most potent and effective anti-inflammatory drugs available currently for mild. Inhaled form is used for the long-term control of asthma. The Turbohaler delivers approximately twice as much inhaled steroid to the lung. Systemic corticosteroids are used in longterm therapy to gain prompt control of the disease and also to manage severe persistent asthma. Patients with nocturnal symptoms and more severe and persistent form of disease may need more frequent and higher doses.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 199 be used 1-2 capsules every 4-6 hours as needed and prior to exercise. and nedocromil sodium (4 mg four times daily). Anticholinergic drugs like ipratropium bromide may provide additive benefit to inhaled β2-agonists in severe exacerbations. For children growth monitoring is essential. the dose should be reduced to be maintained with the minimum. Beclomethasone dipropionate or budesonide should be started in doses of 100-400 μg twice daily. The MDI dose is 20 mcg for each puff and 2-3 puffs are used every 6 hours. The patient should also be advised to rinse mouth (rinse and spit) following inhalation. a large volume spacer is recommended to reduce systemic and local effects. the doses are to be increased. Patients who need to inhale a bronchodilator more than once daily or who have night time symptoms require regular inhaled anti-inflammatory drugs. The drug is also available in solution forms for nebulisation. therefore the dose may be halved when this device is used. Inhaled corticosteroids are typically associated with a flat dose-response curve when traditional efficacy values are examined by measurement of FEV1. They may be used as regular maintenance therapy in step 4 (British Thoracic Society) patients who already require high dose inhaled steroids. Current guidelines recommend that patients should double the dose of inhaled steroids temporarily if their asthma deteriorates or at the first sign of an upper respiratory tract infection. particularly nocturnal symptoms. The small but potential risk of adverse reactions from the use of inhaled corticosteroids is well balanced by their efficacy. Although systemic corticosteroids are strictly not bronchodilators. Various drugs that can be used include corticosteroids. moderate and severe persistent asthma. a long-acting inhaled β2-agonist is to be added to a low-to medium dose of inhaled corticosteroid rather than using a high dose. As the severity increases. The delivery system is an important determinant of the systemic effects of inhaled corticosteroids. It may be an alternative bronchodilator for patients who do not tolerate inhaled β2-agonists. When the dose exceeds 800 μg. Solutions for use in nebulisers are also available (salbutamol 5 mg/ml or terbutaline 5 mg/ml) for use during acute exacerbations. by increasing the . To maintain control asthma. Once symptoms and PEFR are controlled. spacers and higher doses are needed after checking the compliance and proper use of inhalers. If control is not achieved.52 and. Regularly scheduled or daily use of these drugs are generally not recommended. Long-term Control Medications Inhaled anti-inflammatory agents. sodium cromoglycate (5-20 mg four times a day). they are used for moderate to severe exacerbations to speed recovery and prevention of exacerbations along with other medications. Thus. The lowest possible dose of inhaler should be used to maintain control. The main indication of methyl xanthines is the presence of symptoms. a trial of additional ipratropium (80 μg four times daily). Cromolyn Sodium and nedocromil These are mild to moderate anti-inflammatory medications.53 Estimated comparative daily doses for inhaled steroids are shown in Table 12. They are also available as DPI. Nedocromil has an unpleasant taste. They can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens. oral β2-agonists and xanthine derivatives are used often as the first line bronchodilators in some places.400 mcg/puff) 200-400 mcg 400-600 mcg >600 mcg Flunisolide (250 mcg/puff) 500-1000 mcg 1000-2000 mcg >2000 mcg Fluticasone (50.200 mcg/puff) (DPI same) 200-400 mcg 400-800 mcg >800 mcg Budesonide (200. in patients receiving high dose therapy (1000 mcg or more of beclomethasone or budesonide and 500 mcg or more of fluticasone per day). However in view of the cost factor.125 mcg/puff) DPI same doses 50-250 mcg 250-660 mcg > 660 mcg Triamcenolone 100 mcg/puff 400-1000 mcg 1000-2000 mcg >2000 mcg . There is no indication at present for the routine investigation of.20 mg/ capsule. supplemental calcium in the dose of 1000-1500 mg per day may be required. However. often nocturnal. There is no published trial to show that nebulised budesonide is effective in adults.54-57 At equipotent doses the drug may have the potential for producing similar systemic effects. add-on therapy should be used rather than increasing the dose of inhaled steroids. and adequate dietary calcium should be considered. Inhaled fluticasone is as effective as beclomethasone and budesonide at half the dose when given by equivalent delivery systems. Additional bronchodilators If adequate control of symptoms is not achieved with inhaled steroids 2 mg each day and standard doses of β2-agonists. osteoporosis in patients with low dose inhaled corticosteroids. or high doses of inhaled bronchodilators may be considered. hormone replacement therapy. Estrogen therapy will be required in these women when the dose exceeds 1000 mcg of inhaled corticosteroids per day.Nedocromil is not available in India yet. general measures to counteract osteoporosis such as regular exercise.200 Bronchial Asthma dose of inhaled steroids in the asthma management is not necessary and preferably. They may be used as initial choice for long-term control therapy for children. Cromolyn is available as 5 mg/puff. In addition. oral bronchodilators. or prophylactic treatment for. Table 12:3: Daily doses for inhaled corticosteroids Drug Low Dose Medium Dose High Dose Beclomethasone (100. smoking cessation. vitamin D is to be administered in a dose of 400 units a day. which are not controlled by anti-inflammatory drugs and standard doses of inhaled β2-agonists. For postmenopausal women. The dose is 1-2 puffs thrice or four times daily. Oral β2-agonists and xanthine derivatives should not be used as first line drugs.3. arthritis.59 These forms of treatment include acupuncture. They also prevent exercise-induced bronchospasm. These drugs are not yet marketed in India. Long-acting β2agonists are not to be used for the treatment of acute symptoms or exacerbations.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 201 The addition of long-acting xanthine derivatives may be good enough to control symptoms. which are tried by many but have not stood the test of controlled clinical trials. other herbal therapy including ayurvedic drugs. For control of asthma symptoms. tablets. For short-course “burst” 40-60 mgm per day as single or 2 divided doses may be given for 3-10 days. and 20 mg. Prednisolone tablets are available in 5 mg. Results of a 1998 survey indicates that 42% of adults in the United States consult alternative medical practitioners and . These patients need to be referred to a specialty clinic where additional measures can be considered. HIV infection. Usual starting dose is 10 mg/kg of body weight up to a maximum of 800 mgm per day. fish therapy.m. depression.58. For long-term treatment of severe persistent asthma. although methylprednisolone or prednisone can also be used. megavitamins. Salmeterol is currently available in India and Formoterol is being tried for clinical use in this country. and asthma. and spiritual healing. The burst should be continued till the patient achieves 80% of personal best PEFR or the symptoms resolve. High doses of inhaled bronchodilators should be considered only if the patient does not respond to standard doses. and chronic allergic disorders like allergic rhinitis. Sustained release theophylline is a mild to moderate bronchodilator used principally as adjuvant to inhaled corticosteroids for prevention of nocturnal symptoms. Long-acting β2-agonists are to be used concomitantly with anti-inflammatory drugs (lowto-medium dose corticosteroid inhalers) for long-term control of symptoms. They may have mild anti-inflammatory effect also. This usually requires 3-10 days. ionisers. These include back pain. headaches. Oral steroids Systemic corticosteroids are used in long-term therapy to gain prompt control of the disease (Rescue therapy) and also to manage severe persistent asthma. although some patients claim benefit. anxiety. either daily or on alternate days which may produce less adrenal suppression. particularly nocturnal symptoms. Daily use of long-acting β2-agonists should generally not exceed 80-100 mcg. chiropractice. The leukotriene receptor antagonist is available in USA as 20 mg tablets and the adult dose is 40 mg daily (1 tablet twice daily). The most commonly available oral corticosteroid is prednisolone. homeopathy. but may require longer. Leukotriene Modifiers These drugs may be considered as alternative therapy to low doses of inhaled corticosteroids or cromolyn or nedocromil in mild persistent asthma in patients 12 years or older. Alternative and Complementary Therapies Alternative and complementary therapies are sought most frequently for many chronic disabling conditions as a desperate (sometimes with true belief) measure as there is no definite “cure” for these conditions. High doses of inhaled steroids should always be continued in patients receiving oral steroids. a dose of 10-60 mgms daily single doses may be required. Short courses or “bursts” are effective for establishing control when initiating therapy or during a period of gradual deterioration. and antihistamines including ketotifen. Further study and clinical experience are needed to help establish their role in asthma therapy. single dose is to be administered in a. The 5-lipoxygenase inhibitor Zileuton is available as 300 and 600 mg tablets and the daily dose is 2400 mgs in four divided doses. Oral sustained release salbutamol 8 mgs tablets are available which can be used twice daily. .61 British Medical Association has recently approved acupuncture for practice. or proteinuria that might suggest associated disorders such as systemic eosinophilia or vasculitis. Real acupuncture has been shown to have an immediate effect. rash. or patient symptoms. Patients suspected to have developed complication like bronchopulmonary mycosis (i. Ascaricides may be effective in controlling number of mites but have not produce clinically relevant benefit. and • patients in whom asthma is interfering with their lifestyles despite changes in treatment.202 Bronchial Asthma spend an estimated $27 billion annually on alternative medical therapies. Hyposensitisation or immunotherapy is not indicated in the management of asthma. it was shown that a short course of acupuncture treatment in patients with moderate asthma resulted in no change in lung function.63 Traditional Chinese medicine has claimed the ability to favourably influence the course and symptoms of bronchial asthma. If these modalities of complimentary/ alternative medicine are tried. Such patients include • those who are recently discharged from a hospital • those with catastrophic severe (brittle) asthma • those with continuing symptoms despite high doses of inhaled steroids • those being considered for long-term treatment with nebulised bronchodilators • pregnant women with worsening asthma. Patients with possible occupational asthma.72 Thus. then the conventional treatment should also be continued. iii. ii. weight loss.62 and many medical schools in the USA offer elective courses in complimentary/alternative medicine. bronchial hyperreactivity. Patients in whom there is a doubt about the diagnosis for example in elderly and smokers with wheeze. iv. although homeopathy and Aurvedic forms of therapy are other forms of therapy in many countries. .58 Many physicians either practice for complimentary/alternative medicine themselves or refer patients for such treatment. In a recent randomised cross over study. Referral to a Specialist Referral to a specialist should be considered for: i. instead of the use of poisons of medicine in favour of fine needles to harmonise the blood and Qi energy. The first documented history of acupuncture is ascribed to the legendary Yelloe Emperor (Huang Di) in China (circa 2000 BC). the published data on this subject are controversial.64-66 but not a lasting effect on asthma.60 Acupuncture is one of the oldest and most widespread complimentary techniques.70. However. acupuncture may not be recommended for bronchial asthma. most studies performed to date are not controlled or cross-over in design.67-69 Methacholine challenges and exercise have been shown to be affected.e. although still thousands of patients continue to seek for this form of therapy. The first paragraph of the second part of his classic book Huang Di Nei Jing describes the desire of the benevolent emperor to relieve the suffering of his subjects affected with disease. ABPA). those with persistent unexplained persistent cough. and those with systemic symptoms like fever. However.71 Immunomodulatory changes in lymphocyte subsets and cytokines have been shown to be affected by acupuncture. Patients with difficult asthma and management problems. USA. and an optional parameter for airway inflammation assessed from induced sputum eosinophil count. systemic symptoms. Bethesda. The percentage symptom score but not the global control score of this new method correlates with patient’s global assessment of asthma control.74. profuse expectoration. BMJ 1990. Assessment of Asthma Control Once a treatment plan is established for a patient of bronchial asthma. 91-3042A. rescue bronchodilator need. but they are not currently integrated into the assessment of asthma control. Arch Dis Child 1992. Guidelines for the management of asthma in adults. Publication No. Guidelines for the management of asthma: A summary.73 As the aim of asthma treatment is to minimise symptoms. This global assessment approach may overestimate the adequacy of asthma control by the physician and even more so. Guidelines for the diagnosis and management of asthma. while optimizing pulmonary function. 6.22(Suppl):1-72. weight loss. and may consequentially contribute to the poor asthma control when current guideline criteria are used. International Paediatric Asthma Consensus Group. National Asthma Education Programme. Warner JO. National Asthma Campaign. 2.75 Studies or surveys on asthma generally use an all or none approach or a strictly qualitative evaluation of asthma control. and exacerbations. A new. Most asthma guidelines recommend assessing asthma control according to a series of criteria based on symptoms and pulmonary function. King’s Fund Center. methods for assessment of airway inflammation noninvasively have been developed. Landau LI et al. BMJ 1990. National Institute of Health. and infiltrates in chest skiagram. REFERENCES 1.9:287-92. June 1991. Guidelines for the management of asthma in adults. BMJ 1993. 4. 2-Acute severe asthma. Gotz M. Research Unit of the Royal College of Physicians of London. a follow-up statement.80 This easy-to-use asthma control scoring system is based on a percentage of optimal control. Statement by the British Thoracic Society. but they are too exhaustive to be used by the busy clinician. and Blood Institute. Arch Dis Child 1989. Recently. haemoptysis. Research Unit of the Royal College of Physicians of London. This complication may be suspected if the patient has uncontrolled symptoms. without specific quantification of its magnitude or degree compared with optimal goals. Asthma. National Asthma Campaign.64. Clin Exp Allergy 1992. King’s Fund Center.1065-79.11.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 203 These patients most often misdiagnosed as pulmonary tuberculosis.67:240-48.76-78 Quantification of control with tools such as the validated questionnaire developed by Juniper et al79 are the common ones. Management of asthma: A consensus statement. British thoracic Society and others. 3. 1-Chronic persistent asthma. 7. simple method of global assessment and quantification of asthma control has been developed. . This method provides a percentage control for symptoms. it is essential to assess the asthma control. Expert Panel Report.301:797-800. baseline expiratory flows. International Consensus report on the diagnosis and management of asthma. Maryland. Other means of assessing these parameters include evaluating or scoring each separate component of asthma control and comparing the effects of treatment or intervention on these specific parameters. by the patient. 5.301:651-53. National Heart. Statement by the British Thoracic Society. Lung. Wood RA. 30. 10. US Department of Health and human services. 23. Respir Med 1991. Bloise JR. Chest 2002.107(3 Suppl):S414-S421.83:730-34. J Allergy Clin Immunol 1980. Pediatr 1958. Crane J. 18. December 1995. Sufprenant EC. Evans D.Suppl:S47-S52. reed CE.52(Suppl 1): S2-S8. Patient education. Korsch BM. Am J Med 1980. Newman SP. 3 0 6 : 776-82. Jr Soc Med 1980. The effect of cat removal on allergen content in household-dust samples. The effects of air cleaners on hay-fever symptoms in air-conditioned homes.204 Bronchial Asthma 8. 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Active patient orientation and outcomes in hypertensive treatment. 13.5:195-205. Mellians RB. 28.85:457. Chapman MD. Clark NM. Clark NC. Eur Respir J 1994. Schulman BA.69:891-94. 27. A practical guide for public health officials and health care professionals. 21. The King’s Fund Center.288:1056-58. Clinical effects of air cleaners at homes of asthmatic children sensitised to pet allergens. 11.61:315-19. Brewis RAL. Royal College of Physicians of London. 14. Doctor-patient interaction and patient satisfaction. Gonzalez-Santos P.104(2 pt 1):447-51. Thorax 1997.95:1110-13. 16. 9. Woods RA. N Engl J Med 1973. Community based asthma care: Trial of a “credit card” asthma self-management plan.151:353-59. An evaluation of the quality and contents of asthma education on the World Wide Web. Pasch R. Williams MH. J Rev Respir Dis 1989. 26. British Paediatric Association. 22. 20. Gozzi EK. 17. 19. Gaps in doctor-patient communication.121:1301-07. J Allergy Clin Immunol 1989. Novy HS. 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The control of dust mites and domestic pets: A position paper. Eggleston PA. 49. Clin Exp Allergy 1989. Conardson TB.19:399-404. Platts-Mills TAE. Dust-mite allergens and asthma: Worldwide problem. Q J Med 1986.122:1509-10. III. Mite faeces are a major source of house-dust allergens. placebo-controlled immunotherapy with mixed grass-pollen allergoids. Arlian LG.107(3 Suppl):S406-S13. Evans CC. Cormican L. Simpson A.53:63-72.78:590-600. Moss RB.7:1839-44. Double-blind. J Allergy Clin Immunol 1993. 44. 38. Murphy M et al. Arruda LK. Ecology and elimination of cockroaches allergens in the home. Allergen avoidance in house dust mite sensitive adult asthma. 45. Buettner P. Lung and Blood Institute. J Allergy Clin Immunol 1988. Chest 2002. Eur Respir J 1994. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Seasonal asthma in northern California: Allergy causes and efficacy of immunotherapy. Double-blind. . Pediatrics 1983. 50. Colloff MJ. Hejjaoui A et al. J Allergy Clin Immunol 1989.84:546-56. Maasch HJ. 35.60:264-68. J Allergy Clin Immunol 2001. Tovey ER. Ehnert B. Wahn U. Lan JL. Carswell F et al. Ayeres J.58:199-215. J Allergy Clin Immunol 20-01. Michel FB.107(3 Suppl):S422-S29. 53.91:418-22. placebo-controlled rush immunotherapy with a standardised alternaria extract. Lau-Sehadendorf S. The biology of dust mites and the remediation of mite allergens in allergic diseases. NIH Publication No. Bousquet J. Hejjaoui A. Reducing domestic exposure to dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma. Glinert R. Asthma and Immunology. Cockroach hypersensitivity: Preliminary study of allergic cockroach asthma in Taiwan. Reid MJ. Walshaw MJ. J Allergy Clin Immunol 1984. Allergen avoidance in the treatment of asthma and atopic disorders. Chest 2002. Chapman MD. Controlled trial of hyposensitisation to house dust. Thorax 1998. Fergusson AC. Suppression of the late asthmatic reaction by hyposensitisation in asthmatic children allergic to house dust mites (dermatophagoides pteronyssiunus).22(Suppl 2):1-28. Wilson P.83:776-83.289:592-93. D1 is markedly reduced following sequential washing of cats. Thorsson L. J Allergy Clin Immunol 1990. Custovic A.85:460-72. Swanson MC. Horst V. Van Bever HP.122:1535-42. Dust free bed room in the treatment of asthmatic children with house dust mite allergy: A controlled trial. Lee DT. A systematic review of randomised trials. Effects of air filtration systems on asthma. Platts-Mills TAE. Correlation between levels of mite and cat allergens in settled and airborne dust. May 1997.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 205 31.122:1966-72. Ernst P. Bouquest J. 37. 39. Newman T et al. Weber A. Wu CH et al. Platts-Mills TA. 40. Fel. 42. Leiterman KM. Acta Pediat Scand 1971. 33.85:225. Wedner HJ. Ohman JL Jr. Findlay SR. Cook D. Aas K. 48. Effects of varying doses of fluticasone propionate on the physiology and bronchial wall immunopathology in mild-to-moderate asthma. 52. 47. 41. O’Sullivan S. Sehou C. Edsbacker S. Clin Exp Allergy 1992. 46. 36. Hsu YP. Environmental measures and asthma.82:736-40.74:230-39. J Allergy Clin Immunol 1989. J Allergy Clin Immunol 1990. J Allergy Clin Immunol 1989. American College of Allergy. 97-4051A. Campbell AR. 34. 32. Nature 1981. Immunotherapy in cat-induced asthma: Double-blind trial with evaluation of in vivo and in vitro responses. Efficacy and safety of unfractionated and high-molecularweight preparations in rhino conjunctivitis and asthma. Stevens WJ. Klauck MJ. Chapman MD et al. J Allergy Clin Immunol 1986. Chest 2002. National Heart. Horst M. Murray AB. 51. McDonald E. 43. de Weck AL. Lung deposition of budesonide from turbohaler is twice that from a pressurised metered dose inhaler p-MDI.90:135-38. National Institute of Health. Reed CE. Conolly A. Lewth GT. Courses involving complementary and alternative medicine in US medical schools. Marik PE. Berube D et al. expenditures. Silvert M. 65. Jayaram L. 70. Unconventional therapies in asthma: An overview. Primhak R. Yu DY.2:416-19. Kaptchuk TJ. Takishima T. and perceived efficacy of complimentary and alternative therapies in HIV-infected patients. 72.19:206-11.158:2303-10. Ringdal N. Chen JH. 58. Clin Sci Mol Med 1976. Eisenberg DM. Keistinen T. Can Med Assoc J 1999. Eur J Clin Res 1996.784-87. 64. Becker A. Bangha O. Eisenberg DM. JAMA 1998.121: 1387-88.39:379-85. Evaluation of asthma control by physicians and patients: Comparison with current guidelines.14:271-75. Induced sputum cell counts: Their usefulness in clinical practice. 73. 75.280. BMJ 2000. Gold M.16:150-58. Eisenberg DM. Davis RB.87:609-20. Berkman N. Pauwels RA.280:1569-75. Alexander M. McPherson K et al. O’Byrne P et al. Arch Intern Med 1998. Ettner SL et al. Tanakas J. Austin JA. Biernacki W. Monaldi Arch Chest Dis 2000. Arch Dis Child 1993. Comparison of the efficacy and safety of inhaled fluticasone pripionate 200 mcg per day with beclomethasone dipropionate 2000 mcg per day in mild and moderate asthma. 61. Gillies E.2:19-21. 63.51:503-09. The effect of acupuncture on pulmonary function in bronchial asthma. Respir Med 1998.92: 1143-45. Marie A. Ben-David G et al. et al. . Acupuncture and bronchial asthma. The bronchodilating effect of acupuncture in patients with acute asthma. A comparison of fluticasone propionate 200 mcg/day with beclomethasone dipropionate 400 mcg/day in adult asthma. 158:2257-64. Varon J. Lundback B. JAMA 1998. 69.321:11. Controlled trial of acupuncture for disabling breathlessness. Chest 2002. Short-term acupuncture therapy is of no benefit in patients with moderate persistent asthma. Leblane P. Fairfield KM. Davis RB et al. Lancet 1986. Wu JN. Kips JC. Allergy 1984. Peake MD. 67. Watkins AD. 59.206 Bronchial Asthma 54. 68. Day J et al. Wetzel MS. Paramswaran K. 1990-1997: Results of a follow-up national survey. Tamura G et al. J Altern Complement Med 1996. A review of the incorporation of complementary and alternative medicine by mainstream physicians. 76. Shapira MY. Acupuncture for asthma. Boulet LP. Virsik K. Jobst K. Tauderf E et al. Respir Med 1993.55:93-95.49:380-85. Trends in alternative medicine use in the United States. Acupuncture wins BMA approval. Allergy 1994. Effects of acupuncture on bronchial asthma. A short history of acupuncture.121:1396-1400. Phillips R. Minks S. Saaelainen PA. Payne SL.61(Suppl 11):S1-S62. Lee SP. Gustaffson P. 60. 62. Can Respir J 2003. Mue S. Fact or fiction? Chest 2002. Progr Respir Res 1980.48:44-49. Ann Allergy 1982. 71. Pelletier KR et al. Fromm RE Jr.7:15-29. Laursen LC. Eur Respir J 2000. 57. A comparison of fluticasone propionate 100 mcg twice daily with budesonide 200 mcg twice daily via their respective powder devices in the treatment of asthma. Use of induced sputum in the diagnosis and follow up of asthma and chronic obstructive pulmonary disease. Christensen PA. 56. Evaluation of fluticasone propionate (500 mcg per day) administered either as dry powder via diskhaler or pressurised inhaler and compared with beclomethasone dipropionate (1000 mcg/day) administered by pressurised inhaler. 55. Canadian Asthma Consensus Report. Patterns of use. Boulet LP. 66. Kristufek D. 74. Allergy 1996. sears MR et al. Arch Intern Med 1998.51: 761-69. 1999. Acupuncture in treatment of stable asthma. Radford M. Clinical management of asthma in 1999: The asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 1999. Soriano JB et al. 78. Where do we fall? Eur Respir J 2000. Asthma control. Guyatt GH et al. Milot J. Eur Respir J 2000. Rabe KF.122:2217-23. 79. Kips JC. Boulet V.Therapeutic Approach in Patients with Asthma (Chronic Bronchial Asthma) 207 77. How should we quantify asthma control? A proposal.14:902-07. Boulet LP.16:797-98.16:802-807. Development and validation of a questionnaire to measure asthma control. Chest 2002. Vermiere PA. O’Byrne PM. 80. Pauwels RA. . Juniper EF. 1-19 The attack can occur at any time and at any speed. Patients who develop progressive symptoms over days before finally presenting to the emergency room do so with respiratory distress.20 This form is quite different from the more slowly progressive forms of airflow obstruction.23 Both fatal and near fatal asthmatic attacks have similar features.208 Bronchial Asthma 13 Therapeutic Approach in Patients with Asthma II. if hypercapnia develops during one severe attack. Another suggested definition of an acute asthmatic attack is severe airflow obstruction that had become unresponsive to the patient’s normal bronchodilator treatment. These are accompanied pathologically by only mild inflammatory changes and little mucus plugging of the airways. meaning thereby. However. which had continued for more than 24 hours.24 Patients dying of sudden exacerbations of asthma have diminished eosinophils and increased neutrophils in the airway submucosa20 and less intraluminal mucus.22 Acute severe asthma said to “run to type”. Such episodes are called “Sudden asphyxic asthma”. In these patients. It is. all recent studies of asthma deaths have described patients who have died within hours or even minutes of the onset of symptoms. The most important aspect of such an attack is its severity. with death occurring at times within a couple of hours. All patients with bronchial asthma are at risk of developing a severe asthma attack that places them at risk of developing respiratory failure—the disorder referred to as status asthmaticus. inflammation of the airway wall and edema play a significant . therefore. it is likely to recur in a subsequent episode.21 This sudden and unexpected increased airflow obstruction results primarily from bronchial smooth muscle-mediated bronchospasm. In most cases of severe life-threatening asthma develops against a background of poorly controlled disease. Acute Severe Asthma (SA) Definition The term status asthmaticus was previously used to describe a severe attack of asthma.25 This is in contrast with the relatively slower onset disease. in 10-20% of cases of fatal or near fatal asthma the onset appears to be sudden and unexpected. An important feature of this near fatal asthma is that attacks are often recurrent and a previous life-threatening episode represents one of the most important factors predicting asthma deaths. not appropriate to include the duration of the attack in a definition of acute severe asthma. Although most severe attacks of asthma develop over days or weeks prior to presentation to medical care. Mucus plugging of both large and small airways is found at autopsy.36 In addition. Yet many patients fail to perceive the severity to treat effectively their worsening airway inflammation. inappropriate self-care. poor compliance. right ventricular volume may increase sufficiently to shift the interventricular septum towards the left ventricle compromising the volume of this chamber and resulting in incomplete filling.35 and socioeconomic factors linked to poverty.41 This may be related to hypersensitivity to foods. depressive symptoms. and disregard of asthma symptoms.44.42 Another important contributory factor may be an inadequate access to health care facilities.0% of patients with bronchial asthma die from an acute attack. Abnormal circulatory effects of severe airways obstruction result mostly from pleural pressure excursions associated with breathing.39 In a recent unmatched.43 Pathophysiology Abnormalities of gas exchange occur due to airways obstruction as a result of inflammation and bronchial smooth muscle contraction. there is a female predominance. female gender. large negative pleural pressure may directly impair left ventricular emptying by increasing left ventricular after load. the following eight variables were found to be associated with near-fatal asthma: history of seizures. These cyclical events result in pulsus paradoxus. FEV1 is reduced to almost 10-20 percent of normal and PEFR is less than 100 L/min in severe cases.37 In a case control study.1 to 7. use of inhaled beclomethasone. increases in intrathoracic pressure diminish blood return to the right heart. patients with near fatal asthma have more food allergies and onset of their episodes follows a visit to the bar. Mechanical abnormalities of the lung include marked elevation of airways resistance. In both these conditions (fatal and near-fatal asthma). more severe form of the asthma.34 psychosocial abnormalities.31. such as nuts. smoking. inspiratory transpulmonary pressure during quiet tidal breathing increases to as high as 50 cm H2O and expiration becomes active. During expiration. Despite increased work of breathing. Reduced chemosensitivity to hypoxia and blunted perception of dyspnoea perhaps predispose patients to fatal asthma.28-30 It is difficult to predict which asthma patients will have a fatal or near-fatal asthma attack. Expiratory time is prolonged and alveolar emptying is not complete at the end of expiration. During inspiration. Additionally. 33 noncompliance.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 209 role. or exposure to smoking exposure or substance abuse in this group. and more likely to have had a previous intubation.45 Further. lung hyperinflation may represent a further after load on the right ventricle by . the near fatal asthma was most often associated with the use of bronchodilators or corticosteroids during the last 12 months and these patients had nocturnal symptoms in the previous two weeks. conflict with parents and hospital staff.32 history of frequent hospital admissions and emergency department visits.40 Further.27 About 1. decrement in prednisolone dose by 50%.38 The variables associated with subsequent deaths include older age. Dead space increases as result of hypoperfusion of hyperinflated lung regions. Intrinsic or occult positive-end expiratory pressure (PEEPi) is the consequence of alveolar pressure not reaching atmospheric pressure under the condition of prolonged expiratory time. party or restaurant. a significantly decreased response to inspiration against resistance and to hypoxic hypercapnia27 and a low perception of dyspnoea are other risk factors.26 They fail to appreciate the severity of the final episode because of poor perception. case-control study. labile asthma. and psychiatric treatment for anxiety or depression. increased asthma symptoms during the week prior to discharge. Adults with status asthmaticus who assume the upright position usually has a significantly higher pulse rate. wheeze. cough. although some improving patients may remain tachycardic because of the use of drugs. respiratory rate. pulsus paradoxus and diaphoresis.51 Use of sternocleidomastoid muscle indicates severe airways obstruction. While examining a patient of status asthmaticus clue for the possible complications should be looked for. increased work of breathing due to increased airways resistance. inability to speak and use of accessory muscles are all signs severe disease.46 During quiet breathing without airways obstruction. The patient is typically anxious. which is possible in a fatigued asthmatic unable to generate significant changes in the pleural pressure. Successful therapy will reduce heart rate. a silent chest in a case of status asthmaticus indicates severe airway obstruction with little movement of air to produce respiratory sound. Thus. and is preoccupied with the task of breathing. pneumonitis or some other cause. breathless. During severe asthma this may be greater than 15 mm Hg and is used as a measure of severity of asthma. Lactate excess is thought to be due to increased muscle production. He is in apparent respiratory distress. sitting upright in bed. diaphragm failure as a force generator because of dynamic hyperinflation. wheezing. the pulsus measured as the maximal drop in systolic blood pressure during inspiration. diaphoresis. the absence of a wide pulsus paradoxus does not always mean a mild attack. ventricular or combined arrhythmias. The possible complications of bronchial asthma are shown in Table 13. Inability to lie supine.52 The rhythm is usually sinus tachycardia. All these events are responsible for respiratory muscle fatigue. tachycardia. Presence of localised wheeze and crepitations may indicate mucus plugging. and low PEFR than patients who are able to lie supine. even patients with severe obstruction and exhaustion can lie down supine giving a false impression of less severe disease. and intrinsic PEEP associated with dynamic gas trapping. atelectasis. In the period immediately preceding respiratory arrest the chest may be completely silent. The absence of wheezing does not exclude a diagnosis of bronchial asthma and the classical sign of wheezing correlates poorly with the degree of airflow obstruction. If upright patients are also diaphoretic. impaired sensorium. the PEFR is even lower. and chest tightness. or diminished clearance related to hypoperfusion. and atrial. use of accessory muscles. Rhythm abnormalities that are possible include supraventricular arrhythmias. fatigued. hyperinflated lungs.53 Patients with arrhythmias are usually older compared to patients without . Regardless of etiology.50 Rather.47 although presently this is not included as a guideline in assessing the severity of asthma.49 Further progression to ventilatory failure in status asthmaticus may result from respiratory muscle fatigue. Clinical Features The clinical presentation of a patient with status asthmaticus includes increased breathlessness.48. Successful treatment of airflow obstruction is usually associated with a decrease in heart rate. is less than 10 mmHg.1. Electrocardiogram (ECG) in such a patient will show tachycardia. the action of catecholamines used during treatment. However. Clinical signs include tachypnoea. Pulsus paradoxus may be faulty if the patient ceases making sufficient effort to cause large intrathoracic pressure swing. and pulsus paradoxus and a significantly low arterial oxygen tension.210 Bronchial Asthma increasing pulmonary artery pressure. lactic acidosis is a metabolic marker which may be used to predict an increase risk of progression to ventilatory failure. indicates a severe degree of airflow obstruction and the possible need for mechanical ventilation. the measurements are safe in most patients. in certain situations.60 This may occur more likely in men and in patients with more severe degrees of airflow obstruction and hypoxemia. the possible mechanisms are:61 .54 However. even normal PaCO2.55 High dose beta agonists.1: Complications of acute bronchial asthma Pneumothorax Pneumomediastinum Subcutaneous emphysema Pneumopericardium Myocardial infarction Mucus plugging Atelectasis Drug toxicity (theophylline) Electrolyte imbalances (hypokalemia. However. objective physiologic measurements of airflow obstruction can be made by bedside determination of FEV1 and PEFR.54.57 However. theophylline and hypoxia can further tilt this balance. hypomagnesemia) Dehydration Myopathy Lactic acidosis Hypoxic brain injury them. Such patients with status asthmaticus are in increased risk of myocardial oxygen supply/demand imbalance when large decreases in intrathoracic pressure increases left ventricular after load and possibly decreased coronary blood flow. hypercapnia alone is not an indication for intubation. In most patients PEFR can be measured more easily even if the maneuver is difficult in severely dyspnoic patients.59 On the other hand the absence of hypercapnia does not exclude the possibility of severe airflow obstruction and impending respiratory arrest. which is usually transient and which resolves within hours of therapy. Status asthmaticus can cause right ventricular strain.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 211 Table 13. Although effort-dependent. Although the pathogenesis of lactic acidosis in this setting is not clearly understood. Patients in the early stages of status asthmaticus will exhibit mild hypoxemia and respiratory alkalosis with low carbon dioxide tension. this may be deferred because deep inhalation may worsen bronchospasm56 and in rare cases. PaCO2 increases. and/or an increase in physiologic dead space.3 Metabolic acidosis can occur in as high as 28% of patients with status asthmaticus. Measurement of arterial blood gas is essential in patients with status asthmaticus. precipitate respiratory arrest.58 Presence of hypercapnia.52. hypophosphatemia. Hypercapnia has a good correlation with FEV1 and usually does not occur unless the FEV1 is less than 25% of the predicted. The possible cause is because of the elevated anion gap. inadequate alveolar ventilation. compensatory renal bicarbonate wasting may take place manifesting as a non-anion-gap metabolic acidosis. This is because of patient exhaustion. As the severity of obstruction increases. Such patients may respond to aggressive drug therapy. presence of right heart failure should suggest some other disease. If respiratory alkalosis persists for hours to days. The possibility of coronary ischaemia should be considered in older patients with coronary artery disease. The measurement is generally recommended when the FEV1 is less than 1 litre or PEFR is less than 120 L/min. In these cases. The initial assessment should consist of a brief history pertinent to the exacerbation which include the time of onset and cause of present exacerbation.62 Repeated blood gas sampling are not necessary to determine whether the patient is improving or deteriorating. Chest radiography has little role in the management of mild to moderate asthma like arterial blood gas. need serial measurement of arterial blood gas. Differential Diagnosis The differential diagnosis of severe dyspnoea with wheezing includes status asthmaticus. pneumonitis or one of the above described complications. signs or symptoms of barotrauma. It is necessary to manage a patient with acutely severe asthma with the same sense of emergency as for a 50-year old person with crushing substernal chest pain suspected of having myocardial ischaemia. atelectasis. arterial blood gas measurements. decreased lactate clearance by the liver because of passive congestion in the setting of high intrathoracic pressure. with emphasis on findings relevant to assessing the severity or identifying complications (pneumonia. intracellular alkalosis. purulent sputum. left ventricular failure or ischaemia. patients who are more comfortable on pharmacologic drug therapy are to continue with the same treatment despite an elevated PaCO2. This multifactorial analysis is necessary because no single clinical measurements have been found to predict outcome reliably. mediastinal crunch. asthma complicated by pulmonary embolism. However.212 Bronchial Asthma • Increased work of breathing resulting in anaerobic metabolism. On the contrary. The overall assessment of the patient should . pneumonia or barotrauma. and use of parenteral betaadrenergic agonists. In most cases important clinical signs described above will be sufficient to judge whether the patient is to be intubated or not. prior hospitalisation. all current medication with the time of last administered medication and any recent use of systemic corticosteroids. Patients who are deteriorating on these grounds to the point of respiratory arrest should be intubated whether or not the PaCO2 is rising. subcutaneous emphysema.64 A brief cardiopulmonary examination should be performed. physical examination. Other changes include focal/ major atelectasis. The benefits of routine chest skiagram are minimal and they contribute only 1-5% of studies where the treatment is influenced. response to initial therapy. prior episodes of respiratory insufficiency. foreign body aspiration. upper airways obstruction. cardiovascular instability. bedside monitoring of airflow obstruction. Assessment of Severity Assessment of severity of an acute asthma is very important since one has to decide whether the patient can be managed at home. a minimal increase in interstitial markings. hyperinflation. severity of symptoms including exercise limitation and disturbance of sleep. other localising chest signs. pneumothorax. acute exacerbations of COPD. History and physical findings will differentiate many of these conditions. and pneumomediastinum). suggestion of pneumonia. chest skiagram is definitely indicated in patients with fever.63 Such changes include normal. or needs to be hospitalised or he is to be admitted to an intensive care unit with or without ventilatory support. tissue hypoxia. Patients on mechanical ventilation will however. and radiographic studies. including the medical history. (chest pain. or asymmetric breath sounds). It generally requires an analysis of several factors. or when it is not clear that asthma is the cause of respiratory distress. and significant prior cardiopulmonary disease. Various clinical parameters helpful for the overall assessment of the patient are shown in Table 13. 30-50% baseline Failure of PEFR to improve at least 10% after initial treatment Arterial blood gas PO2 < 60 mmHg or O2 saturation of less than 90% PCO2 > 40 mmHg . Grade 3 Totally confined to a chair or bed. Various indices of acute severe asthma are shown in Table 13. Sherwood Jones’ index of severity of asthma Grade 1a Able to carry out house work or job with moderate difficulty. Grade 2b Confined to a chair or bed but able to get up with great difficulty. Routine laboratory studies and sputum culture are not necessary for initial management of patients. Sleep frequently disturbed.3: Indices of acutely severe asthma Symptoms/history Severe breathlessness. and wheezing Difficulty in walking for 100 feet or more Speech fragmented by rapid breathing Syncope or near syncope Physical examination Pulsus paradoxus of > 12 mmHg Use of accessory muscles of respiration Diaphoresis. A chest X-ray may be needed afterwards to identify any complication. chest tightness. No relief from inhaler. Pulse rate > 120/min. Although wheezing is a prominent finding on chest auscultation. extremely severe obstruction may be accompanied by “silent chest”. Little or no relief from inhalers. Table 13:2. Sleep disturbed. respiratory distress. Sleep occasionally disturbed. Grade 2a Confined to a chair or bed but able to get up with moderate difficulty. unable to lie supine Heart rate > 120/min Respiratory rate > 30/ min Silent chest Pulmonary functions FEV1 or PEFR . Grade 1b Able to carry out house work or job with great difficulty.2. Unable to sleep. cough. Table 13. Arterial blood gas should be obtained in all cases as far as possible.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 213 include alertness. particularly if the patient is not able to perform pulmonary function tests or for whom intubation and mechanical ventilation are being considered. Pulse rate > 120/min.3. Measurement of PEFR and FEV1 are very essential. and fluid status. Grade 4 Moribund. No asleep. colour. mild. Sits upright Phrases May be agitated Words Usually agitated Usually agitated Increased Increased Often > 30/min Accessory muscles use.4). Suprasternal retractions Usually not Commonly Usually Paradoxical thoraco-abdominal movement Wheeze Moderate Only endexpiratory Loud Throughout expiration Usually loud Throughout inspiration and expiration Absent Pulse/min < 100 100-120 > 120 Bradycardia Pulsus paradoxus Absent ± < 10 mm Hg Often present 10-25 mm Hg Present > 25 mm Hg Absence suggests respiratory muscle fatigue SYMPTOMS Breathless Talks in sentences Alertness SIGNS: Respiratory rate FUNCTIONAL ASSESSMENT: PEFR (% 80% predicted or % personal best) Respiratory arrest imminent Drowsy or confused 50-80% <50% predicted or personal best or response lasts < 2 hours PaO2 (air) Normal Test usually not required > 60 mmHg Test usually not necessary < 60 mmHg May be cyanosed and/or PaCO2 < 42 mmHg Test usually not required < 42 mmHg Test usually not necessary = or > 42 mmHg Possible respiratory failure SaO2 (on air at sea level) > 95% Test usually not required 91-95% < 91% Note: The presence of several parameters. .214 Bronchial Asthma NIH Guidelines (1997) has classified severity of asthma exacerbations into four different categories according to the symptom and signs (Table 13. Can lie down While talking. moderate. but not all. 1997) Mild Moderate Severe On walking. Prefers sitting While at rest. indicates the general classification of the exacerbations. Table 13.4: Classification of severity of asthma exacerbations (NIH. severe and imminent respiratory arrest. Interpretation of saturation in patients who are on or who have recently been on oxygen. prompt communication between the patient and the physician. There is also a difference between a patient with PEFR of 50% who has been on prednisolone for a week and a patient who has a short history and has not yet started oral steroids. especially corticosteroids. 1995). Life-threatening asthma is one where the PEFR is less than 33% of the personal best. Subcutaneous adrenaline. and removal of the allergen or irritant are important components of management.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 215 Recent data also showed that peak expiratory flow measurements must be interpreted in the light of other features of severity and the patient’s past history. Therapeutic Management The best strategy for management of asthma exacerbations is early treatment to prevent deterioration and abort the exacerbation. • Prior admission to hospital based intensive care unit (ICU). because of the availability of more β2-antagonist selective inhaled drugs recently. 1995). Similarly. is difficult. It is equally important that the patient does not delay seeking professional medical help if the asthma exacerbation is severe or if the response to therapy is not prompt and sustained. but if the value is 92% or more and there is no feature of an imminently life-threatening attack. Facilities for the monitoring of oxygen saturation should be available in all clinical areas that treat patients with acute asthma. attendance at the emergency departments and current treatment. or the patient needs hospitalisation with or without admission into the intensive care unit (ICU). and correction of hypoxaemia. and elderly individuals particularly with underlying heart disease. or salbutamol has no . arterial puncture may be deferred (BTS. as an emergency outpatient basis. their use has declined dramatically. early addition of systemic steroids. particularly previous admissions to hospital. Some acute exacerbations can be managed at home. The basic principle of care of acute asthma exacerbations is the rapid reversal of airflow obstruction with relief of accompanying respiratory distress. The primary goal of home management of acute exacerbations of asthma is to avoid delays in initiating antiasthma therapy by having the patient begin treatment at home. • Past history of syncope/hypoxic seizure due to asthma. • Hospitalisation or emergency care visit within the past month’ • Current use of systemic steroids or recent withdrawal from systemic steroids. terbutaline. This can be achieved by repetitive administration of inhaled β2-antagonists. and • Serious psychiatric disease or psychosocial problems. Although these drugs were commonly used as the first line therapy earlier. This can be repeated every 20 minutes for three times. appropriate intensification of antiasthma medication. pulsus paradoxus need not be measured as it adds nothing to the assessment and its interpretation is subject to many factors (BTS. • Three or more emergency care visits for asthma in the past year. • Two or more hospitalisation for asthma in the past year. Therefore early recognition of worsening lung function. The initial treatment should consist of subcutaneous adrenaline (1:1000) in a dose of 0. The drug should be avoided in patients with hypertension. Some patients are at increased risk for exacerbations and the category of high risk for asthma-related death includes patients who have history of : • Prior intubation for asthma.5 ml slowly. patients with cardiopulmonary arrest.69 Adrenaline is contraindicated during pregnancy because it is associated with congenital malformations and decreases uterine blood flow.5-5 mg). If parenteral β-agonists are used. In very emergency cases. Routine use of infused β-agonists are not necessary and they have no extra advantage. Salbutamol is the most commonly used drug. These situations are: i.5-5 mg. or salbutamol 2. There is no great advantage of more β2-specific drugs over subcutaneous epinephrine.65-67 These drugs can also be tried in intubated patients not responding adequately to inhaled therapy. Prior use of inhaled drugs at home does not prevent further use in hospital. Larger and more frequent doses are necessary in acute asthma because the dose-response curve and duration of action of activity of these drugs are affected adversely by the degree of bronchoconstriction.71. there are situations when these drugs are very useful. Long-acting β-agonists like salmeterol or formoterol are not indicated in acute asthma since their onset of action is very slow.74 Airway narrowing and the cooperation and breathing pattern of the patient may further reduce the dose of the drug delivered by inhalation.5 mg nebulised salbutamol and sequential doses of 2. intravenously administered β-agonists may be considered in patients below the age of 40 years who do not respond to inhaled or subcutaneous therapy. ii.68 Some patients will not need further parenteral therapy and can be stabilised with oral or inhaled bronchodilators and steroids. and cardiac arrhythmias. This dose can be used every twenty minutes for 1 hour (three doses) followed by administration every hourly during the first several hours of therapy. and iii. patients with impaired sensorium. . However.70 Terbutaline is the preferred drug in this setting. On the other hand. Rather they cause more cardiovascular side effects like tachycardia for the same degree of bronchodilatation. In a recent meta-analysis.216 Bronchial Asthma advantage over inhaled β-agonists. The onset of action is very rapid and their side effects are usually tolerated. it is shown that the clinical benefit of intravenous β-agonists appears questionable. On an individual basis however. Other injectable preparations that can be used include terbutaline and salbutamol.73 Fewer doses can be given in patients with less severe airflow obstruction who demonstrate a good response. while the potential clinical risks are obvious. Terbutaline (2.5 mg nebulised salbutamol are clinically equivalent in the treatment of patients with moderate-to-severe acute asthma and result in similar disposition from the emergency room. lactic acidosis. However. This has a slightly longer duration of action and it is more β2-selective. The only recommendations of intravenous β2-agonist use should be in those patients in whom inhaled therapy is not feasible.72 Inhalation of selective β2-agonist bronchodilators by nebulisation is favoured for both children and adults as the immediate and first-line therapy of status asthmaticus of all severity. potassium monitoring is essential to avoid hypokalemia. terbutaline or salbutamol may inhibit uterine contractility at term. or metaproterenol 15 mg or isoetharine 5 mg can be given 4-6 hourly diluted with normal saline. when the patient is unable to cooperate to inhale. epinephrine may be delivered effectively through the endotracheal tube. A single dose of 7. Lower doses are preferred initially but they can be repeated or increased if necessary. and in whom respiratory arrest is imminent or in whom persistent severe airflow obstruction is associated with alarming levels of lung hyperinflation during mechanical ventilation. inhaled treatment can be given continuously to severely obstructed patients until an adequate clinical response is achieved or adverse effects limit further use. this may result in fewer side effects.9%.84 This method of therapy has potential advantage in terms of time. Furthermore. Either 40 mgms of intravenously administered methyl prednisolone every 6 hours or prednisolone 60 mg orally every 6-8 hours for 36-48 hours depending upon the condition of the patient will be most ideal. Intravenous administration speeds up their action marginally by about an hour. optimal ventilatory settings to be used during ventilation for drug delivery.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 217 Recent studies have shown that in nonintubated patients. Corticosteroids both intravenous and oral should be started simultaneously. the dose is inadequate.75-78 Further. MDIs are more quicker action and cheaper still. treatment with corticosteroids is the most important and an integral part of managing a case of acute severe asthma. ideal site on the ventilator circuit for connection of the nebulizer. although continuous nebulisation also has been proposed.83 A recent meta-analysis supports the equivalence of continuous and intermittent salbutamol nebulisation in the treatment of acute adult asthma.79 although there are controversies regarding the optimal delivery of inhaled drugs in the intubated and/or mechanically ventilated patient. It did not matter whether steroids are given intravenously or orally even if intravenous therapy is preferred in patients at risk of intubation. However. these drugs have a slow onset of action because of their intracellular mode of action whatever their route of administration. There is a consensus that frequent intermittent nebulisation. Both MDIs and nebulizers can also be used in patients on ventilators. If not intervened early. Hydrocortisone should be administered 200 mg intravenously . cost. less coordination is required and less supervision is necessary. In comparison to systemic approach. Whether patients are using corticosteroids or not when they arrive in the emergency with severe attacks of asthma. an intensifying treatment of worsening of one’s asthma should start with aggressive use of corticosteroids. continuous salbutamol nebulisation is considered to be better than intermittent therapy. There is evidence to suggest that failure to use or under use of steroids contribute to asthma deaths.2-2. Lower doses are less effective and there will be no obvious benefit by giving higher doses. in the range of 1. as long as a minimum of 30 mg of prednisolone or its equivalent is given every 6 hourly. Moreover.80 Higher dosages are required to achieve physiologic effects than in nonintubated patients since pulmonary aerosol deposition is poor in these patients.81. Inhaled β2-agonists are the drugs of choice with which to treat patients with acute severe asthma. Ideally. are appropriate. inhalation is associated with a more rapid onset of action. and maximal acceptable drug dosage.90-92 It is recommended that 150-225 mg/day of prednisolone or its equivalent is required to reach maximal therapeutic benefit. every 20 minutes within the first hour. many prefer the use of nebulizers as they need fewer instructions. there has been considerable clinical and academic interest in the use of continuous aerosolised bronchodilators for the treatment of acute asthma. and medication delivery. In children.88 Benefits of steroids are well established in recently confirmed meta-analysis of large number of studies. both the patient and physician feel satisfied psychologically. and fewer systemic side effects. Since the late 1980s. This feature may allow deeper penetration into the airways and greater reduction of bronchoconstriction. 82 In recently extubated patients. which both the patient and many physicians do not appreciate. MDIs combined with a spacer are as useful/effective as that used by a nebulizer.85-87 Since airway inflammation is an important component of airflow obstruction of bronchial asthma. airway inflammation proceeds unchecked.89 The facts that emerge are that steroids given in the emergency room significantly reduce the rates of admission and the number of future relapses in the first 7-10 days. MDIs can be used successfully. Thus. other randomised.95 However. in adults. eight puffs twice daily is as effective as systemic corticosteroids. particularly in children with more severe acute asthma. However. It is due to the fact that locally acting inhaled corticosteroids cause local vasoconstriction and thereby decrease edema formation and plasma exudation.218 Bronchial Asthma initially followed by 100 mg every 4 hourly in place of methyl prednisolone because the later is costly.5 mg/kg/hr. which is cheap.93 The failure of steroids to influence the early course of patients with acute asthma is due to the fact that it may take up to 24 hours for the effect of corticosteroids to become evident. effective. Prednisone in a dose of 40-60 mg should be administered from the first day for several days followed by tapering of the dosage according to the response. either simultaneously or in sequence..000 mg or equivalent per day) may replace therapy with oral corticosteroids following the emergency department discharge of patients who have been treated for an acute asthma exacerbation. A meta-analysis has suggested that the administration of corticosteroids in addition to inhaled β2-agonists in patients with acute asthma on their arrival at the emergency department does not improve airflow obstruction nor reduces the need for hospitalisation.98 Addition of inhaled corticosteroid (budesonide 1600 μg/day to oral corticosteroid reduces the number of relapses. placebo-controlled trials94 have shown that high doses of inhaled glucocorticosteroids together with salbutamol in patients with acute asthma who are treated in the emergency department significantly improve pulmonary function when compared to the use of salbutamol alone. The drug augments the bronchodilating effect of β2-agonists in acute asthma. the alternatives are to add nebulised ipratropium bromide 500 μg 6 hourly. Most recent relevant reviews had proved that the use of multiple doses of ipratropium bromide are indicated in emergency department treatment of children and adults with severe acute asthma. this meta-analysis has not shown any concrete evidence to change the practice of administering oral prednisolone for a short while for 7-10 days at a dose of 40 mg per day. with beta-agonists and steroids. No apparent increase in the occurrence of side effects was observed. either in inhaled form or oral form or parenteral form are the important mode of therapy for managing a case of acute bronchial asthma.97 However. the use of high-dose inhaled flunisolide (250 μg per activation.99-101 The role for anticholinergic medications is not well-defined. number needed to treat 5-11) and significant difference in lung function favouring the combined treatment. has produced positive as well as negative results in different trials. in adults hospitalised for a severe asthma exacerbation. the use of therapy with anticholinergics and β2-agonists. and safe.95 If the patient continues to deteriorate despite treatment. there is no apparent benefit adding a single dose of an anticholinergic medication. The use of single-dose protocols of ipratropium bromide with β2-agonist treatment produced. The difference becomes evident by 90 minutes. The studies reported a substantial reduction in hospital admission (30-60%. a moderate improvement in pulmonary function without reduction in hospital admission.96 A meta-analysis indicates that there is some evidence that therapy with high-dose inhaled corticosteroids (beclomethasone dipropionate. In patients with mild-to-moderate acute asthma. > 2.102 Theophylline: Aminophylline is commonly used as an important drug in many developing countries both as a maintenance drug in chronic asthma as well for treatment during an . glucocorticosteroids. This can also be administered as an infusion in a dose of 0. the evidence showed a similar increase in pulmonary function with an approximately 35% reduction in hospital admission rate. Some studies have shown that after 48 hours of intravenous treatment with corticosteroids. theophylline continues to be an important adjunct in the management of acute asthma particularly in the setting of poor or incomplete response to treatment with beta agonists and steroids and where economy is a consideration.103 Further. other modalities may not be available at all places.104 A recent analysis of the use of theophylline had concluded that there is inadequate evidence to support or reject the use of theophylline in the emergency setting. Obstruction of peripheral airways will result in V/Q mismatch and hypoxemia.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 219 acute attack of bronchial asthma in the form of a continuous drip in many countries because of its lower cost and if given in proper doses. Only a small proportion of patients below the age of 45 years develop hypoxaemia. and protection against the modest fall in PaO2 often seen after β2-agonist administration resulting from pulmonary vasodilatation and increased blood flow to low V/Q units.105 However.118 Several trials in paediatric patients demonstrated a benefit from IV magnesium. and 500 mg 8 hourly will be required for a small.5% of the pulmonary blood flow. Theophylline can be. Although there is a good correlation of FEV1 or PEFR with that of arterial oxygen tension. the drug is not all that unsafe. There are reports supporting the usefulness of magnesium sulphate107-111 or heliox in the treatment of refractory bronchial asthma.113 It has since been shown to be a bronchodilator. Since the attack is frightening reassurance to the patient is essential. Adequate hydration should be maintained. However.112 Magnesium was first reported as a treatment for acute bronchial asthma in 1936. although hypomagnesemia has been reported in 50% of patients with acute asthma. Periodic assessment of progress of disease or the effect of therapy is very essential.106 Therefore. Moreover.114-116 Many case reports showed clinical benefits in patients with respiratory failure complicating bronchial asthma. 400 mg. Oxygen therapy improves oxygen delivery to the peripheral tissues including respiratory muscles. and has been used. Sedatives of all kinds should be avoided. there is no cut-off value for either measurement to accurately predict hypoxaemia.117. sputum that looks purulent. Use of theophylline confers additional benefit on beta agonists and parenteral steroid therapy. safely if attention is paid to the possible side effects. High concentrations of oxygen (35%) will increase arterial PO2 and will not lead to carbon dioxide retention unless there is some other associated problem. This benefit has been described in patients with normal magnesium levels. true shunt in acute asthma is only 1.120 Many . airway bronchodilatation. The routine administration of low flow oxygen is an entirely safe practice that is recommended if routine pulse oxymetry is not available and if there is co-morbid condition such as coronary artery disease. However. The usual loading dose and maintenance dose is shown in the table below. correction of hypoxemia requires only modest flow of oxygen. Routine use of antibiotics is not necessary unless there is evidence of bacterial infection in form of fever. and to factors that increase serum levels. 1-3 L/min through a nasal cannula. Serum levels should be checked within 6 hours of intravenous loading to avoid toxic levels. the ready availability of beta agonists and their safety and quick onset of action has replaced theophylline therapy in acute asthma. 119. administration of theophylline results in fewer hospitalisations. purulence of sputum or radiological evidence of consolidation. reverses hypoxic pulmonary vasoconstriction. However. may be due to abundant eosinophils and not polymorphonuclear leukocytes. In most situations roughly 250 mg. serum drug levels. medium or large person respectively for maintenance. Serum theophylline level should be obtained whenever possible. or 60:40) with a gas density less than that of air. care should be taken to monitor renal function. Magnesium also reduces histamine-induced and methacholine-induced bronchoconstriction in asthmatics and affects respiratory muscle force generation. However patients having the following problems should be admitted and observed for treatment in the intensive care unit. These groups of patients require ongoing treatment either in the emergency room or in the medical ward where facilities are available. Further. • Use of accessory muscles of respiration. and loss of deep tendon reflexes can result from magnesium intoxication. hypotension.121-123 A recent multicentric trial has shown that administration of 2g of IV magnesium sulphate improves pulmonary function when used as an adjunct to standard therapy in patients with very severe.125.126 Drugs used in the treatment of status asthmaticus are shown in Table 13. Observation for a minimum period of 30 minutes after the last dose of β-agonist is administered is necessary to ensure stability before discharge.5. • Pulsus paradoxus of > 12 mmHg • Diaphoresis • Inability to recline • Hypercapnia • PEFR < 40% predicted . This decreases the work of breathing and delays the inspiratory muscle fatigue until definite bronchodilator and anti-inflammatory therapy becomes effective. The drug is not recommended for routine use. Because the mixture is lighter than air. One hypothesis is that magnesium inhibits calcium channels of airway smooth muscle and thus. which may interfere with bronchoconstriction. Follow-up schedule should be made before the patient is sent home. acute asthma. airways resistance is decreased in bronchi with turbulent flow. Magnesium decreases acetylcholine release at the neuromuscular junction.70:30. these patients should be provided with a detailed follow-up plan which includes written medical instructions and a written plan of action to be followed if there is worsening of symptoms.220 Bronchial Asthma randomised trials of IV magnesium in acute asthma in adults have shown mixed results. Indications for Admission in the Intensive Care Unit Each patient should be assessed for response to treatment instituted initially in the emergency room. These are: • Patients with severe airflow obstruction. Before discharge. Patients who can be discharged include:127 • Significant improvement in shortness of breath • Improved air entry on clinical examination • PEFR or FEV1 greater than or equal to 70% predicted. An incomplete response to treatment may be defined as the persistence of wheezing or shortness of breath and a PEFR or FEV1 between 40-70% of predicted. interferes in calcium-mediated smooth muscle contraction. Heliox is a mixture of helium and oxygen (80:20. It can be delivered through a tight fitting nonrebreathing face-mask in nonintubated patients and through the inspiratory limb of the ventilator circuit in mechanically ventilated patients. Mild complications include flushing and mild sedation.124 The mechanism of action of magnesium is not known. Although 1-2 gm of the drug is safe. 5 × 50 × (18 mg/L -8 mg/L) = 250 mg. then Vol. for three doses.2 As discussed in section under theophylline 1-3 l/min by nasal canula. dose sulfate adjusted to normalize serum levels.9-1. The intravenous drugs are to be continued for at least for a period of 24-48 hours. followed by 100 mg every 6-8 hourly. with Cs of 8 mg/L and desired Cs of 18mg/L.4 0. Hydrocortisone can also be given 200 mg start. • Poor response to initial therapy • Less than 10% improvement in PEFR • Those deteriorate despite therapy • Respiratory arrest . Theophylline . Maintenance dose: Adults Smokers Liver disease Severe COPD CCF Viral illness Children drug interactions Oxygen Infusion Rate (mg/kg/hr) 0.5L/kg × Wt (kg) Loading dose = Vd × desired change in serum level (mg/L) = Vd × (Cs desired -Cs known) For a patient of 50 kg Wt.5% solution (2.4 0. intubated patients can also given this drug. The drug is to be avoided in patients with hypertension.Loading dose: No previous drug -6mg/kg of aminophylline (lean body weight) infused over 30 minutes or can be given slowly diluted with 25% of glucose over 20 minutes Already on theophylline: Reduce according to serum level as follows: If serum level is Cs mg/L.4 0. they can take-over. Salbutamol 0. Oral prednisolone is to be substituted as soon as possible. older patients.5: Drugs used in status asthmaticus Drug Dosage/Mode of use Adrenaline 0. Corticosteroids Methyl prednisolone 60-125 mg given intravenously every 6 hours or prednisolone 30-40 mg orally every 6 hours.8 0.5/5 mg) in 3 ml normal saline by nebulisation or 4 puffs by MDI with spacer every 20 min. oral drugs are to be started simultaneously so that when the injectable steroids are withdrawn.5 0.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 221 Table 13. Titration by pulse oxymetry Unproved alternatives Magnesium 1 gm intravenously over 20 minutes (Total dose 2 gm). In fact.5 ml of 0.5 mg by nebulisation hourly or 4-10 puffs by MDI with Spacer every 20 minutes for three doses. Anticholinergics Ipratropium bromide 0. Loading dose = 0. or 60:40 helium:oxygen mixture by tight-fitting. Terbutaline is favoured in pregnancy. 70:30. Heliox 80:20.2 0. and those with coronary artery disease. Higher helium concentrations are needed for maximal effect.3 ml of 1:1000 solution subcutaneous every 20 minutes 3 times. of distribution (Vd) = 0. If hypomagnesemic. nonrebreathing face mask. Near cardiopulmonary arrest (patients unable to speak and/or gasping for air) g. facial pressure necrosis. Various advantages of noninvasive ventilation are. Changes in posture. Altered mental status despite PaCO2 levels d. decreased incidence of nosocomial infections. decreased need of anaesthesia. b. Potential disadvantages of this mode of ventilation include aspiration of gastric contents due to gastric insufflation. and better patient comfort. confusion. patients whose condition is deteriorating and PaCO2 is rising need to be monitored in an intensive care unit. but not all. PaCO2 is not an important predictor for intubation since patients who are more comfortable. decreased incidence of sinusitis and otitis. drowsiness. Intubation Once it is decided to ventilate the patient intubation should be done quickly by an experienced person as manipulation of the upper airways may precipitate laryngospasm. Fatigued patient despite PaCO2 levels c. Significant obtundation A. Similarly. and ii. and paralysis. which has . B. and less control of the patient’s ventilatory status. Non-invasive Ventilation Non-invasive ventilation through face mask mechanical ventilation is an option used by some clinicians as a short-term ventilatory support in patients with hypercapnic ventilatory failure who are not i.128-131 Usually a nasal CPAP of 5-7. Oral intubation allows insertion of larger bore endotracheal tubes (8 mm or more). of these patients will need ventilatory support. speech.5 cm H2O will be necessary. Responding adequately to drug therapy. Mechanical Ventilation Many.222 Bronchial Asthma • Altered mental status • Cardiac toxicity • Tachyrrhythmias. Patients presenting with cardiopulmonary arrest f. Patients with encephalopathy or with a need of airway protection are not suitable for this form of therapy. hypoxia (PaO2 < 60 mmHg despite 60% oxygen) or patients with a raised PaCO2 should be admitted into the ICU. Where immediate intubation and mechanical ventilation is not indicated/required. Indications for intubation will depend upon: a. alertness. These signs do not need any arterial blood gas measurement or peak flow documentation. use of accessory muscles. Myocardial infarction Further. all of which indicates worsening respiratory failure. better able to speak. Patients receiving pharmacological therapy needs to be watched closely for the need for intubation in patients showing clinical deterioration. patients with imminently life-threatening features such as unconsciousness. Immediate intubation: e. and respiratory rate. and less respiratory distress can continue medical therapy despite a rise in PaCO2. sedation. Angina. Coma h. Paralysis Muscle paralysis is required in patients fighting with the ventilator despite sedation and in those who continue to have asynchronous breathing which is a grave risk factor for generation of high airway pressure and loss of airway access. Further. and decreases oxygen demand and consumption and decreased carbon dioxide production besides decreasing the risk of barotrauma. C.5 mg/kg/h IV Drug accumulation Ileus As described above Seizures. Nasal intubation is safe in most patients particularly if he is awake. sedation improves patient comfort. These are nondepolarising agents and are free of cardiovascular side effects. Hypotension. hypertriglyceridemia . will be based on the clinician’s own judgment whether to use neuroparalytic agents or not to achieve a therapeutic strategy to maintain stable respiratory parameters. The paralytic drugs of choice are vecuronium and atracurium. Sympathomimetic effects. there is less airway collapse. facilitates various procedures. The drugs are either given intermittently by bolus injection or by continuous Table 13. Sedation Sedation will invariably be required in awake patients to prepare for intubation and to allow for effective mechanical ventilation (to avoid fighting the ventilator). breathless and in obese patients with short necks. D.5 mg/kg/min. Because the expiratory effort is eliminated. and lactic aciodosis in addition to decreasing the risk of barotrauma with an overall augmentation of sedatives already used. Fibre optic guided intubation may be helpful in difficult cases.6: Sedatives that can be used in status asthmaticus Drug Dose Comments 1 mg IV push slowly. as needed. Various sedatives that can be used in status asthmaticus are shown in Table 13. delirium Propofol 60-80 mg/min IV up to 2 mg/kg followed by an infusion of 5-10 mg/kg/hr as needed Respiratory depression Before intubation Midazolam After intubation for prolonged ventilation: Lorazepam Morphine sulphate Ketamine Propofol 1-5 mg/hr IV continuous infusion or bolus 1-5 mg/h IV continuous infusion 0. can be repeated every 2-3 min.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 223 advantage of better suction and a decrease in airway resistance beneficial at high airflow. mood change.6. carbon dioxide production. however. respiratory depression. The decision. Paralysis further helps to reduce oxygen consumption.5 mg/kg IV 1-4.1-0. respiratory depression Ketamine 1-2 mg/kg IV at a rate of 0. The disadvantage with the nasal route is that a smaller endotracheal tube can only be used and there is a high incidence of nasal polyps and sinusitis in them. although larger doses may cause hypotension. sedatives. As airway pressures fall. This is preferable to the risk of barotrauma during an attempt to bring the PCO2 to normal. Mechanical ventilation should be initiated with a tidal volume of 8 ml/kg. Once this begins. A . the expiratory limb of the ventilator is occluded at end expiration while omitting the subsequent breath. tidal volume can be varied in 100-ml increments with corresponding changes in rate and flow in an attempt to optimize peak airway pressure (Ppk).133 If peak airway pressures exceed 55 cmH2O and PEEPi is greater than 15 cmH2O despite full sedation and muscle relaxation. Measurement of PEEPi in the sedated patient who has also received muscle relaxant. disuse muscle atrophy and myopathy. Dynamic hyperinflation is often seen in these patients if an attempt is made to make them eucapnic. If this occurs a fluid bolus of 0. and inspiratory flow rate of 60L/min. • Low levels of PEEPi. Weaning from mechanical ventilation of the patient of status asthmaticus requires good planning. more typically the patient will require 24-48 hours of aggressive bronchodilator therapy until airway pressures and PEEPi fall. The proximal airway pressure rises to a plateau (PEEPi). rate of 12-15/min. The patient should initially be fully sedated and adequate muscle-relaxation be achieved to minimize airway pressures.2). improvement is usually rapid. muscle relaxants. Mechanical Ventilation Hypotension and hypoperfusion often follow intubation and positive pressure ventilation. bicarbonate infusion can be given to achieve a serum pH of approximately 7. This is known as “controlled hypoventilation”. Slowly bagging (4-6 breathes/min) with 100% oxygen for about 1 min will allow for prolonged expiratory time to decrease PEEPi which will result in a rise of blood pressure. While some patients with very labile asthma may respond to therapy within hours. a high level of PCO2 in the range of 70-90 mmHg is the only way to bring Ppk below 55 cm H2O and PEEPi below 15 Cm H2O. and bicarbonate infusions can be reduced to prepare the patient for a brief period of spontaneous ventilation and then extubation. The paralytic agents should be discontinued briefly every 4 hours and readministered only if evidence of muscle activity is seen. The goals of mechanical ventilation in status asthmaticus are: • To achieve adequate alveolar ventilation. In some patients. E.132 The last complication is more pronounced in the presence of concomitant use of high dose steroids. If the patient has adequate muscle strength and no sign of respiratory failure emerge during the brief period of spontaneous breathing.25. If associated acute respiratory acidosis is severe (pH < 7. and PCO2.5-1L of normal saline should be given every 10-20 minutes until adequate circulation is restored. • Minimal circulatory compromise. greater danger of developing deep vein thrombosis. PEEPi. extubation should be performed since the endotracheal tube itself can perpetuate bronchospasm. with resolution of all dynamic hyperinflation by 12 hours. External PEEP should not be used during ventilation of a patient of status asthmaticus as it can result in dangerous increases in lung volumes and pressures.224 Bronchial Asthma intravenous infusions. attempt to achieve this should never be tried. This can be prevented by using small tidal volumes and high inspiratory flow. The disadvantages of neuroparalytic agents in acute asthma are: difficulties in assessing the mental status. Assessment of respiratory muscle strength should be made by determination of negative inspiratory pressure. • Low risk of barotrauma. Recently. Strategies of mucus removal short of bronchodilators or steroids. F. At present.Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 225 quick return to spontaneous breathing can be achieved through a T-piece or by decreasing the respiratory rate on SIMV. Inhalation of these drugs has significant cardiovascular side effects including myocardial depression.139-143 Although there is improved airflow in intubated patients. These have bronchodilatation activity that can acutely reduce Ppk. frequency.137. etc. nitric oxide has been used to induce bronchodilatation. This will increase the expiratory airway resistance and may lead to high levels of lung hyperinflation. any oral medication required is to be told to the patient in writing. however. When inhaled corticosteroids are prescribed. a careful programme for education should be implemented to help the patient identify signs of worsening asthma and optimize the drug regimen to reduce/obviate future episodes of life-threatening asthma. the procedure is not without risk in intubated patients which further compromises the airway lumen. the above strategy fails to allow adequate ventilation at a safe level of lung inflation. particularly for inhalers. BAL is not recommended as part of a routine management of patients with status asthmaticus. like chest physiotherapy or mucolytics are not efficacious.138 Bronchoalveolar lavage using saline or acetylcystine. in the general ward itself the question of prevention and treatment of subsequent asthma attacks should be addressed.135 But the effect lasts as long as the drugs are in use. and PaCO2. Inhalant Anaesthetics Rarely. and when to contact a physician or to visit the emergency department.134. the experience is limited and at a dose of 80 ppm it exerts a weak bronchodilator effect in asthmatics. In that situation inhalation of general anaesthetic is—halothane and enflurane—can be considered. all attempts should be made to remove the same from the respiratory tract to improve airflow. Bronchoalveolar Lavage Since mucus plugging is one of the notable features of status asthmaticus. patients must be told not to expect immediate . The proper agents like inhaled medications with or without spacer as per the need. The importance of airway inflammation and use of anti-inflammatory drugs needs special explanation to the patient. Hospital Discharge and Future Plan of Action After the patient has come out of the ICU. Similarly. The use of 5-8 cm H2O of pressure support helps overcome endotracheal tube resistance. quick extubation is done. This process starts with extensive patient education. During this period and following discharge from the ICU. It is important to explain also the purpose of such medication plans and the techniques are to be taught. Inhalation of these drugs are.136 G. Their doses. is being tried to remove mucus plug. Once the patient tolerates a trial of spontaneous breathing. how to recognise the worsening of asthma and what to do at home in such an eventuality. and arrhythmias. should be clearly explained. Patients should be provided with written medication instructions as well as a written plan of action to be followed in the event of worsening of symptoms. arterial vasodilatation. The bronchodilating effect are lost once the drugs are stopped. Vigorous bronchodilator and chest physiotherapy should be continued in the ICU until the next day. • Signs and symptoms correlate poorly with severity • Accessory muscle use and suprasternal retractions suggest severe exacerbations. 13. Possible side effects of various drugs are to be told. The patient should be given the date. double dose for 7-10 days • If distress is severe and non-responsive. Most important is to tell the patient what is the best for him and at what level of reading (severity) he should report to the physician. Appointments are to be made for followup care with primary clinician or asthma specialist. . The purpose and importance of peak flow measurements is to be explained. time and location of appointment within seven days of hospital discharge. Good response Incomplete response Poor response Mild episode Moderate episode severe episode PEFR > 80% predicted or 50-80% predicted or personal best personal best < 50% predicted or personal best No wheezing or shortness Persistent wheezing and of breath shortness of breath Marked wheezing and breathlessness Response to β2-agonist sustained for 4 hours Add oral steroid Add oral corticosteroid May continue above every Continue β2-agonist 3-4 hours for 24-48 hrs Repeat β2-agonist immediately For patients on inhaled corticosteroids.1: Home treatment of asthma exacerbations relief of respiratory symptoms as they are not bronchodilators. The technique of the manoeuvre. frequency of measurement maintaining a diary. The patient or its caregiver should be instructed on simple plan of action to be taken for symptoms. Follow up with physician Contact physician urgently the same day Visit emergency department Fig. Before or at discharge the action plan has to be decided. consult physician and report to emergency. and PEFR values suggesting recurrent airflow obstruction. up to three treatments of 2-4 puffs by MDI at 20-minutes intervals or single nebuliser treatment. signs. timings of measurements are to be told. Initial treatment: • Inhaled short-acting β2-agonist.226 Bronchial Asthma Assessment of severity: • PEFR measurement— < 50% personal best or predicted suggests severe exacerbation. The patient should be told that it is to be measured at am and pm and the best of three readings each time is to be noted as the representative PEFR. The presence of any one should alert the physician. cyanosis. . • Nebulised beta. feeble respiratory effort • Bradycardia or hypotension • Exhaustion.5 mg to nebuliser and repeat every 6 hrly until patient is improving. ABG personal best measurement is essential • Cannot complete sentence in one breath Severe. • If patient is still not improving: • Aminophylline infusion (750-1500 mg/24 hrs for a small and large framed individual). confusion.5 mg to the nebulised beta-agonist • IV aminophylline 250 mg over 20 min or Salbutamol or Terbutaline 250 mcg over 10 min. 1. if— • Respiration 25/min or more • Pulse > 110/min • Normal (36-45) or high PaCO2 • PaO2 < 60 mmHg irrespective of treatment with oxygen • A low pH Life-threatening features No other investigation is required for management • PEFR < 33% predicted or best • Silent chest. serum level monitoring essential if continued for more than 24hr • Salbutamol or Terbutaline infusion as an alternative to aminophylline. Immediate treatment • Oxygen 40-60%(CO2 retention is not a problem) • Salbutamol 5 mg or Terbutaline 10 mg by a nebuliser • Prednisolone tablet 30-60 mg or IV Hydrocortisone 200 mg or both if very ill • No sedatives of any kind • Chest radiograph to exclude pneumothorax If life-threatening features are present:• Add ipratropium 0. life-threatening. Contd. No bolus aminophylline to patients already taking oral theophylline. or coma IMP: Patients with severe or life-threatening attacks may not be distressed and may not have all these abnormalities. • Add ipratropium bromide 0.agonist 4 hourly • If patient not improving after 15-30 min: • Continue oxygen and corticosteroids • Beta-agonists more frequently. Subsequent management: • If patient is improving: Continue • 40-60% oxygen • Prednisolone 30-60 mg orally daily or Hydrocortisone 200 mg 6 hrly...Therapeutic Approach in Patients with Asthma (Acute Severe Asthma) [SA] 227 ASSESSMENT IN HOSPITAL Acute severe asthma If SaO2 < 92% or if the patient has • PEFR 50% or less of predicted or any life-threatening features. up to every 15-30 min. 2. drowsiness • Coma or respiratory arrest 4. these alone are not sufficient to treat more severe forms of asthma. The guidelines of the NHLB Institute Expert Panel for management of acute exacerbations of bronchial asthma at different levels are summarised in Figures 13. • Follow-up visit to respiratory clinic within 4 weeks.. warning signs of worsening airflow obstruction include: a 20% drop in PEFR below predicted or personal best. • Treatment with oral and inhaled steroids in addition to bronchodilators. patient should have: • Been on discharge medications for 24 hours and have had inhaler technique checked and recorded. When discharged from hospital.228 Bronchial Asthma Contd. Accelerated use of β2-agonists should be a warning sign that airway wall inflammation has worsened and corticosteroid therapy should be initiated. Fig. chest tightness. In general. Transfer to ICU accompanied by physician prepared to intubate if: • Deteriorating PEFR.. • • • • Monitoring treatment: Repeat measurement of PEFR 15-30 min after starting treatment Oxymetry Maintain SaO2 > 92% Repeat ABG within 2 hrs after treatment if: • initial PaO2 < 60 mmHg • PaCO2 normal or more than normal • Patient deteriorates • Record PEFR before and after treatment and at least 4 times daily throughout hospital stay. 3. Patients with a history of sudden asphyxic asthma should also be given a kit of epinephrine for the immediate subcutaneous epinephrine. • Cause of exacerbations is also to be determined. • Patient should be given details of record.2.139 . feeble respiration. • PEFR > 75% of predicted or personal best and diurnal variability of < 25% unless discharge is agreed with respiratory physician. • Worsening or persisting hypoxia • Hypercapnia • Exhaustion. • Own peak flow meter and written self management plan • Physician follow-up planned within one week.1 and 13. 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Safety and possible efficacy of Fibre optic bronchoscopy with lavage in the management of refractory asthma with mucus impaction. Smith DL. 133. Kamolhz SL. Non-invasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure. Inhalation of nitric oxide modulates adult human bronchial tone. Stevensopn DD. 136. Heurich AE. Am Rev Respir Dis 1982. Am Rev Respir Dis 1980. Melmed A et al.38:183-92. 139. Yazdi N. Tims RM. Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma. Mansel JK. Wunderink RG. Bronchoalveolar lavage in asthma. 140. National Asthma Education Programme.89:153-54. Pollard BJ. 130. US Department of Health and Human Services. Leeper KV. Lang DM.8:87-92. Durocher AV. Bethesda. Shuman JF. Zubrow AB. Enflurane and halothane in status asthmaticus. Mathison DA. Millman M. 129. Rogers RM. Ellis EF. and antimicrobial aerosols. 141. J Crit Care 1993. Abou-Shala N. Bronchoalveolar lavage in bronchial asthma. Ann Allergy 1991. Goldstein IM.67:324-30. 142. Am J Respir Crit Care Med 1995. The less is the underlying bronchial hyperresponsiveness and higher the pre-exercise level of expiratory airflow. eucapnic voluntary hyperventilation can be substituted for physical exertion. the condition must be mimicked as closely as possible in the laboratory by having the patient exercise with a stationary bicycle or treadmill to the levels of ventilation and with inspired air temperature and humidity that simulates the actual exercising condition. Testing worldclass athletes in an otherwise well equipped pulmonary laboratory becomes still difficult because of difficulty in providing a sufficiently strenuous exercise work load. it means to compete at extremely high levels of physical activity and ventilatory performance. However. In athletes failing to respond to conventional prophylactic treatment. For highly trained athletes with asthma.Management of Asthma with Special Problems 235 14 Management of Asthma with Special Problems EXERCISE-INDUCED ASTHMA (EIA) The term “exercise-induced asthma” (EIA) is often used to describe the asthma of persons in whom exercise is the predominant or at times the only identified trigger to airflow limitations. While for other. Therefore. and the target level of ventilation to be sustained can be set without limit. Some difficulty is encountered when the exercise cannot readily be performed in the laboratory. thereby objectively assessing their success. The goal of EIA is to enable patients to participate in any activity they choose without experiencing asthma symptoms and to enable the patient to achieve a normal exercise capacity. Bronchoconstriction induced by exercise are generally rapidly eliminated by administration of inhaled β2-agonists. For some asthmatics. the goals of managing asthma in relation to exercise are: (i) to maximise lung function prior to exercise. identical exercise challenges can be performed following administration of various medications in varied doses and combinations. like children and young adults. Formal pulmonary evaluation before and after exercise can also be used effectively to evaluate the impact of preventive therapies. The presence or absence of bronchospasm induced by exercise can be established by spirometry before and after the exercise task in question. it implies the freedom to run about and to compete in sports without respiratory disability. the less likely it is . In this setting. In that situation. Optimised control of asthma in general as outlined is the first step towards prevention. the bigger problem is preventing the development of significant airflow obstruction during and following exercise so as to minimise the impact of asthma on athletic participation and performance. this goal means an ability to walk short distances and to work regularly without limitation due to breathlessness. (ii) to protect bronchoconstriction during exercise. Fenoterol is an exception as its metabolite parahydroxyamphetamine.2 Cromolyn sodium (2 puffs) before exercise is another acceptable pre-treatment. In these patients. Many other drugs have been shown to inhibit the bronchoconstrictive effect of exercise. Inhaled corticosteroids are currently approved by the International Sports authorities for this purpose. it takes several weeks for its effect. theophylline and inhaled steroids. Patients who experience a refractory period during continuous exercise may benefit from a warm-up period before exercise utilising submaximal exercise and may not need repeated medications during periods of continuous exercise.6 Medications that are approved by the US Olympic Committee for use in competition include β2-agonists (aerosol or inhalant forms of salbutamol. However.236 Bronchial Asthma that a particular exercise task will provoke asymptomatic airflow obstruction. which is not allowed for athletes. inhaled frusemide4. PREGNANCY AND ASTHMA The natural history of asthma during pregnancy is variable. and inhaled heparin5 are some of the conventional and newer therapies active in modifying the response to exercise. a single dose prior to exercise is effective. used prior to exercise. They should avoid a sudden change to a warm.3 The small percentage of patients who still encounter difficulty are helped by an increase in the dosage of β2-agonist or use of both this and Cromolyn. They are ipratropium bromide. The newer. inhaled β2-agonists. calcium channel blocking agents. Regular use of the drug does not enhance the protective action. Most patients with EIA are otherwise asymptomatic. will prevent EIA in more than 80% of subjects. salmeterol and formoterol. Specially designed low-resistance “heat and moisture exchange” face mask has been shown to help asthmatics in cold environments. and terbutaline). offer effective prevention of exercise-induced symptoms for as long as 8 hours following a single. They provide excellent protection for 2 hours. longer-acting β-agonists. But as a prophylactic in EIA. Because they do not enhance exercise performance in any way other than prevention of air-flow obstruction. it is not clear which are the factors that will decide the ultimate course.10 Exacerbations of asthma symptoms usually occurs during the . the disease worsened during pregnancy in 35%. This drug is virtually devoid of any side effect.9.8 Other studies suggest that 11-18% of pregnant women with asthma will have at least one emergency department visit for acute asthma and of these.7 In a perspective cohort study of 366 pregnancies in 330 women with asthma. regular use of inhaled corticosteroids will be needed to achieve these goals. Their use can be considered when conventional therapy with β-agonists and cromolyn fails. particularly in those who cannot tolerate beta-agonists. pre-exercise dose. leukotriene D4 antagonists and lipoxygenase inhibitors. It is reported that symptoms of asthma worsens during pregnancy in 43% of patients and improves in 14%. These may be taken from less than 10 to 20 minutes prior to exercise in standard doses (1-2 inhalations) and are helpful for up to several hours. In some asthmatics. nedocromil. use of many of these are rarely required. theophylline. The peculiarity of the drug is that when used as an anti-inflammatory agent for chronic asthma. Several physiological changes occur during pregnancy that could worsen or improve asthma. moist environment immediately after exercise which will help in modifying the post-exercise response. terfenadine.1. However. 62% will require hospitalisation. they are permitted and approved for use in world-class competitions. Cromolyn sodium. bitolterol. 19 and also with increased morbidity during infancy. pregnancy and delivery related complications could be avoided.14 A cohort study comparing 198 pregnant women with asthma with 198 women without asthma observed that non-atopic patients with asthma tend to have more severe asthma. On the other hand. Pre-eclampsia was also more common in this group. some patients with severe asthma may experience improvement. In a large cohort study the most severe symptoms were experienced by patients between the 24th and 36th week of pregnancy. Theophylline at term did not influence labor or delivery. clear documentation of teratogenic effects is lacking. especially in patients with severe asthma. vaginal hemorrhage. including hyperemesis.18 Obstetric complications have been observed more often in asthmatics than in control subjects. The risk of prematurity and low birth weight were higher in women with severe asthma necessitating admission.11 Some other reports suggest that there is no change in the course of asthma during pregnancy.16 During pregnancy 40% of the patients managed with the same asthma medications as before pregnancy.17 Bronchial asthma in the mother has been associated with increased perinatal morbidity and mortality. Hypoglycemia occurred more often in infants of mothers with severe asthma than in infants of mothers with less severe disease.18 Pre-eclampsia occurred more often in asthmatics than controls.24 In contrast. resulting in increased perinatal mortality. Only two patients required additional medications beyond bronchodilators.20-23 A large Swedish population based study using record linkage data demonstrated increased risks for preterm birth. severe asthma or systemic corticosteroid treatment or both during pregnancy seems to increase the incidence of mild pre-eclampsia in the mother and hypoglycaemia in the newborn.Management of Asthma with Special Problems 237 last trimester. Thus. Thus all drugs can be used without increased . However. hypertension. if asthma is well controlled throughout pregnancy there is little or no increased risk of adverse maternal or fetal complications. 18% needed less.18.10 Pregnancy. Thereafter symptoms decreased significantly in the last four weeks and 90% had no asthma symptoms during labor or delivery. and one-third remains the same. pre-term birth. the use of drugs to obtain optimal control of asthma is justified even when their safety in pregnancy has not been unequivocally proven. 8 Women with extrinsic (atopic) asthma tend to have fewer symptoms during pregnancy than patients with intrinsic asthma. complicated labor. therefore. A systematic review has shown that baseline asthma severity does determine what happens to asthma in pregnancy and asthma may affect the risk of adverse outcome.19 Poorly controlled asthma has adverse effect on the fetus.8 Another study has also confirmed that during the last months of pregnancy asthma is least likely to exacerbate.9.13. For this reason. A meta-analysis of 14 studies concluded and agreed with the commonly quoted generalisation that during pregnancy about one-third of asthma patients experience an improvement in their asthma. and low birth weight. Uncontrolled asthma is associated with many maternal and fetal complications. and neonatal hypoxia. increased prematurity. pre-eclampsia. perinatal mortality.8 However. whilst symptoms may deteriorate in some with mild asthma.15 Severe asthma is likely to worsen during pregnancy than mild asthma. For most antiasthma drugs. intrauterine growth retardation. one-third experience a worsening of symptoms. and pre-eclampsia in women with asthma. and in 42% the need was more. low birth weight. should be an indication for optimisation of therapy and maximising lung function in order to reduce the risk of acute exacerbations. with proper surveillance and treatment. these drugs have not yet been proved to be safe. increased perinatal mortality.12 Women tend to follow the same pattern during all pregnancies with respect to the course of their asthma. It is important to avoid fetal hypoxia during acute exacerbations. systemic steroids should not be withheld when the need arises. although the direct effects of systemic steroids on the fetus appears to be small.34 No significant association has been demonstrated between major congenital malformations or adverse outcome and exposure to methylxanthines. Risk of postpartum exacerbation of asthma is increased in women undergoing caesarean section. their indirect effects (hypertension. drug therapy should be the same as for the non-pregnant patient. During acute attacks.36 Leukotriene antagonists should not be started during pregnancy. some having short-term and some long-term systemic corticosteroids. corticosteroid inhalers are to be used as normal during pregnancy. There are concerns about animal data on zyleuton. No special treatment is required for asthma during labor except for those who have received daily parenteral steroids for a week or three separate courses in the preceding year. showed no complications attributable to steroid treatment. In the absence of acute severe asthma. Continuous fetal monitoring is recommended for severe asthma. as an acute exacerbation of asthma carries even greater risks for the mother and child. Higher theopylline concentrations in the mother might be associated with complications of labor and delivery due to uterine atony. The women should continue their usual asthma medications in labor. they were unfounded and steroid tablets are to be used as normal when indicated during pregnancy for severe asthma and they should not be withheld because of pregnancy. Terbutaline and salbutamol can cause delayed/poor uterine contraction during labor. In women with poor control of asthma. However. inhaled steroids may be quite safe in recommended doses. the medicines used to treat patients of asthma are quite safe in pregnancy.31 Thus. the alarming findings in these studies may be a part of the underlying severe disease rather than the treatment. Reports on the adverse effects of corticosteroids during pregnancy are contradictory.30.28 However.35 Although there were some concerns of use of oral steroids during early pregnancy. This may be related to the severity of asthma rather than caesarean section per se. Apgar reported an increased incidence of cleft palate in two series of pregnancies in women treated with systemic corticosteroids in early pregnancy. In women receiving steroid tablets there is a theoretical risk of maternal hypothalamic-pituitaryadrenal axis suppression.26 except alpha-adrenergic compounds. if that is considered.32. In some studies there is an association between asthma and an increased caesarean section rate. preeclampsia. Acute attacks of asthma are very rare in labor due to endogenous steroid production. On the other hand. They may be continued in women who have demonstrated significant improvement in asthma control with these agents prior to pregnancy not achievable with other medications. β2-agonists. hypoglycemia) may still form a risk for the infant. In general. in whom hydrocortisone supple-mentation (100 mg every 8 hours) should be given for the stress of delivery unless there is documentation of normal adrenal responsiveness.29 However. Women with asthma may safely use all forms of pain relief in labor.32 The risk of harm to the fetus from severe or chronically under treated asthma outweighs any small risk from the medications used to control asthma. Data regarding the safety of leukotriene antagonists are limited.238 Bronchial Asthma risk to the fetus25. Immunotherapy should not be started during pregnancy.33. there should be close liaison between the respiratory physician and obstetrician. two other studies of pregnant asthmatic women.27 The incidence of stillbirths was eight times higher in women having continuous steroid treatment than in a corresponding group of untreated women with the same diseases. caesarean section should be .. which may not be conjectural. Oxygen should be delivered to maintain saturation above 95%. Animal studies and postmarketing surveillance for zafirlukast and monteleukast are reassuring. and mucus hypersecretion. Severe airflow obstruction along with postoperative pain. can impair the effective cough. the evaluation should begin several days prior to surgery. Thus. thus. Prednisolone is secreted in breast milk. the patient should be hospitalised for a day or more prior to surgery for optimisation of lung function. Other factors that influence the rate of postoperative complication include the type of surgery (thoracic and upper abdominal surgery have the greatest risk) and type of anaesthesia (general anaesthesia with endotracheal intubation carries the greatest risk). therefore. physical examination. Antiasthma drugs may pass into the breast milk. frequent or . and earlier. been advised not to breastfeed. but milk concentrations of prednisolone are only 5-25% of those in serum. Less than 1% of the maternal dose of theophylline is excreted into the breast milk. is to be encouraged.15 There is less data with newer agents.19 All medications used to treat asthma including steroid tablets have been shown in early studies to be safe to use in nursing mothers. However. Women receiving steroid tablets at a dose exceeding prednisolone 7.5 mg per day for more than two weeks prior to delivery should receive parenteral hydrocortisone 100 mg 6-8 hourly during labor. and spirometry. and the amount of mucus plugging at the time of surgery. Increased airway obstruction may result due to suppressed cough and mucus plugging following surgery. Further. the nursing infant is exposed to minimal amounts of steroid with no clinically significant risk. asthma drugs should be used as normal during lactation.16. These variables can be assessed by history.37 Breastfeeding. The likelihood of these complications will depend upon the severity of the patient’s airway hyperresponsiveness. SURGERY AND ASTHMA Possible intraoperative and postoperative complications can occur in patients of bronchial asthma because of bronchial hyper-reactivity. The proportion of an oral or intravenous dose of prednisolone recovered in breast milk is less than 0. Patients having frequent nocturnal awakening. airflow obstruction. mothers have. All patients with active asthma should undergo preoperative respiratory evaluation. in line with manufacturer’s recommendations. regional blockade is preferable to general anaesthesia in women with asthma. Even asymptomatic patients with bronchial asthma should undergo evaluation as they may have significant airflow obstruction and bronchial hyper-responsiveness. If anaesthesia is required.01%. Patients with moderate to severe disease. Acute attacks may be triggered during intubation which stimulates sensory receptors in the upper airway that can lead to reflex efferent neurotransmission via the vagus nerve. no evidence has shown that inhaled drugs or moderate doses of theophylline or systemic steroids taken by mouth by the lactating mother would be harmful to the infant. For maternal doses of at least 20 mg once or twice daily. Prostaglandin F2α should be used with extreme caution in these women with asthma because of the risk of induction of bronchoconstriction. When the asthma is uncontrolled. This will result in ventilation-perfusion mismatching and may contribute to impaired gas exchange resulting in hypoxaemia and possibly hypercapnia during and following surgery. resulting in bronchial smooth muscle contraction.38-40 Possible complications are many and may include the following. the degree of airways obstruction. Retained airway secretion can further impair airflow and gas exchange.Management of Asthma with Special Problems 239 reserved for usual obstetrics indications. mucus impaction can cause atelectasis and associated diminished respiratory excursion will result in respiratory infection and further impairment of gas exchange. morbidity and mortality is particularly high in the elderly. sensitisation to indoor allergens may play a particularly significant role. or dyspnoea should receive intensified treatment of their asthma prior to elective therapy. Asthma patients experiencing wheezing.4 Whereas many factors contribute to the urban asthma problem. The usual dose of replacement corticosteroid therapy during stress is 300 mg of hydrocortisone per day. Intravenous aminophylline can be used to maintain therapeutic levels who are taking this drug. The presence of cockroach-specific serum IgE in a population of elderly urban patients with asthma. as reflected by an increase in airway obstruction and hyperinflation. intraoperative and postoperative steroid supplementation should be given to patients who have received systemic steroids for more than 2 weeks within the last 6 months or more than two courses of systemic steroids within the last 12 months. Patients receiving daily medications for asthma should generally be maintained on these drugs. even if this necessitates delay of surgery. To prevent depressed adrenal-pituitary response to stress. Modification of anaesthetic approach may be possible in some at increased perioperative risk. large volume of sputum production.240 Bronchial Asthma continuous use of steroids. Patients who have been taking high-dose inhaled corticosteroids more than the conventional recommended doses. Clearance of airways is an important aspect of postoperative care. Even in the asymptomatic or minimally symptomatic patient. and underreporting of symptoms. Spirometry is the best way to assess the degree of airflow obstruction and all attempts should be made to achieve a normal or near normal lung function prior to surgery. In New York City. epidural. The usual maintenance dose of theophylline is intravenous aminophylline of 0. intraoperatively. prior perioperative complications related to asthma.46 Increased asthma mortality is more common in elderly patients . and postoperatively.42 Asthma is frequently under diagnosed in the elderly because of a number of differential diagnosis. difficulty in measurement of lung function. Frequently a brief course of corticosteroids will be required to achieve this goal. Inhaled bronchodilators can be maintained during surgery even patients receiving general anaesthesia and mechanical ventilation. or local anaesthesia may in some cases be substituted for general anaesthesia and postoperative pain control may be achieved with epidural analgesia rather than parenteral narcotics. should also be considered at risk of relative adrenal-pituitary suppression and should be given perioperative steroid replacement therapy.6 mg/kg/hour by continuous infusion. is associated with more severe asthma.44 A similar age related difference in the physical signs associated with severe asthma may lead to underestimation of severity and under treatment. it is useful to administer an inhaled β2agonist bronchodilator immediately prior to surgery. chest tightness. Hydrocortisone of 100 mg each should be given intravenously on the day of surgery in the morning. An attempt should be made to improve lung function in patients with an FEV1 or PEFR < 80% of predicted or < 80% of their recent best value. but are not permitted to take anything by mouth. productive cough. The dose is then tapered over the next few days. and co-morbid cardiovascular disease are associated with a high risk for perioperative complications.45 Simple tests of mental functioning may be necessary to ensure that elderly people with asthma are capable of acquiring the necessary skills for treating and monitoring their condition. asthma-attributable mortality rates in adults > 65 years of age are six times higher than those in adults < 40 years of age. Spinal.43 The later may occur because of reduced expectations or because of an age related reduction in perception of breathlessness. OLDER PATIENTS WITH ASTHMA Although asthma affects all age groups. hypokalemia. Older individuals are more prone for depression.Management of Asthma with Special Problems 241 above the age of 55 years. aspirin and other nonsteroidal anti-inflammatory drugs). All patients of asthma above the age of 55 years old should be evaluated for coexisting disease conditions. which may require special devices such as a spacer to assist actuation. Some other family member may be helpful in this situation. Monitoring of hematocrit and blood sugar periodically is essential to rule out hyperglycemia. Although . Eye examination is to be conducted annually to rule out cataract and glaucoma.47 Oxygen should also be used with caution if there is associated COPD to avoid precipitation of carbon dioxide retention. Some cases asthma diagnosed in older individuals may actually be a combination of asthma and COPD or of asthma and congestive heart failure. and gastrointestinal bleeding. and other psychosocial problems are more common in this age group. coexistence of other diseases (myocardial ischaemia). Depression and other associated serious psychiatric illness needs detail assessment. Anticholinergic bronchodilator therapy may have a greater role in this age group than in the younger patients. which in turn is identified as a risk factor for fatally-prone asthma. Although treatment of chronic and acute asthma exacerbations should be the same as per the recommended guidelines. if the patient takes aspirin and other non-steroidal anti-inflammatory drugs may cause sudden and severe asthma exacerbations. These patients should carefully be monitored for steroid side effects. Frequent intake of drugs by people of this age are known to aggravate asthma (beta blockers for hypertension and eye drops. OCCUPATIONAL ASTHMA The diagnosis should be suspected in all adults with airflow obstruction and with a positive history of high-risk occupations or exposures. Asking the patients to state the information and/or instructions in their own words will help ensure understanding. These include arthritis. ischaemic heart disease in a case of bronchial asthma may be more dangerous because of associated hypoxaemia which could result in decreased myocardial oxygenation followed by myocardial infarction or rhythm disturbances. The subject is usually better on days away from work and better on holidays. Patients with memory difficulties might forget to adhere to medical regimens that require several drugs and frequent schedules. Patients with hearing difficulties may not tell the health provider that they have not heard or understood the instructions. Family loss and disruption. For example. epinephrine and theophylline have the potential of precipitating the underlying heart disease. Evaluation of possible alterations in calcium homeostasis is essential particularly in whom there is a greater concern of bone loss as in postmenopausal women. Patients with visual impairment may be unable to read the numbers on the peak flow meter in which colour codes might help. Particular attention should be given to the monitoring of hypoxemia if he has concomitant heart disease. Further. This may be due to difficulty in diagnosis (COPD and congestive cardiac failure). Further. there may be difficulty in reading instructions either on the drug or prescriptions given by the physician. can cause additional problems. Further. difficult adjustments to retirement. Nebulisers might be more useful. The precise cause of severe airflow obstruction is difficult to diagnose at times. certain special considerations are necessary in elderly individuals. Theophylline may increase the risk of urinary retention in older men with prostatism apart from its potential cardiac side effects. Certain other impairments more common in older individuals may interfere worth treatment. Since arthritis is a known disease of this age. Patients with pre-existing asthma aggravated non-specifically by dust and fumes at work (work aggravated asthma) should be distinguished from those with pre-existing asthma who become additionally sensitized to an occupational agent. Eliminating exposure should be tried. These symptoms are also present in asthmatics due to sensitizing agents at home and in those who do much less physical exertion. and at work. (b) At least three series of consecutive days at work with three periods away from work (usually about three weeks). These include serial measurements of PEFR at home. • Confirmation of the relationship between asthma and work exposures. IgE measurements are possible for most biological agents and a few low molecular weight chemicals. Measurements of PEFR should be made every two hours from working to sleeping for four weeks keeping treatment constant and documenting times at work. These include latex in health care workers. An accurate history taking is important which should include exposures to chemicals. rodent urine extracts. There should be information about the sources of exposure (risk assessment). and reversibility testing. Most people with occupational asthma have to be retained for a job with another employer in a different field. measurements of non-specific airway hyper reactivity after days at and away from work.242 Bronchial Asthma they are not specific for occupational asthma. but are important clues for investigation for an occupational agent. COPD and non-respiratory causes of breathlessness should be excluded. Recovery. In some instances. The next step is the establishment of a relationship between asthma and work exposure. attempt should be made to see if . However. The decision of making a case of occupational-induced asthma remains a matter of clinical judgment. and specific bronchial provocation testing. Carefully controlled exposure to workplace agents and suitable controls is the gold standard for diagnosis. The diagnostic sensitivity. if occurs may take months to years after removal from exposure. which is substantially worse than serial PEFR measurements.50 Tests are difficult to do and are not widely available. Nonspecific responsiveness measurements with methacholine or histamine can be undertaken after a period at end away from work exposure. reducing exposure by improving ventilation or providing a respirator may allow a person to return to the same job. however. Once well established. The diagnosis and management of occupational asthma are difficult and can be divided into three parts: • Confirming the diagnosis of asthma.48 Minimum standards for diagnostic sensitivity of > 70% and specificity of > 85% are (a) at least three days in each consecutive work period. and animal epithelia in laboratory animal workers and veterinary surgeons. and are not always possible for some types of workplace exposures. once sensitisation occurs. bronchoconstriction will often be triggered by subsequent minimal exposure. lung function tests.2-fold changes in PC20 indicates a significant change outside the 95% confidence intervals for repeat measurements. organic dusts and other possible agents both at the current time as well as in the past.49 The third step is identification of the cause of occupational asthma. is only 40%. and • Finding the specific cause The first step is to confirm that the patient is having asthma by using standard measures like peak expiratory flow measurements. The ideal treatment for patients with occupational asthma with a latency period is removal from exposure. A more than 3. occupational asthma may not be completely reversible. A worker might be transferred to a job without exposure in the same company. and (c) at least four evenly spaced readings per day. measurements of specific IgE to an occupational agent. Early diagnosis and removal from exposure is associated with a favourable prognosis. flour and enzymes in bakers. and acid anhydrides in exposed workers. which is often difficult. Before advising the worker to leave the job. If the patient returns to the same job. DRUG-INDUCED ASTHMA Even an initial reaction to aspirin or other nonsteroidal anti-inflammatory drug (NSAID) may be severe and an adverse reaction can occur at any time. Patients should be evaluated for temporary impairment and disability when their asthma is under good control. If the patient has severe asthma requiring steroids or has severe asthma with compromised pulmonary function. the initial dose in the form of a rapid graded challenge should be given in the presence of a physician. medical and surgical treatment of gastro-oesophageal reflux has resulted in improvement in symptoms of oesophagitis and also a decrease in asthma symptoms.51 If the patient is avoiding these drugs.53 In some studies. when improvement in asthma has plateaued. The physician should advise the patient regarding compensation as per the law of the particular country. and steroid dependency. RADS is diagnosed by the presence of non-specific responsiveness and a compatible history. a more conservative treatment approach is indicated and should be undertaken by a physician familiar with the technique. The prognosis varies. chronic rhino sinusitis. If there is a concern regarding the use of aspirin in these patients. although most people now believe that this is an important precipitating factor for asthma. Worsening of asthma should lead to immediate removal from exposure. GASTRO-OESOPHAGEAL REFLUX AND ASTHMA The relationship of asthma to gastro-oesophageal reflux is a matter great debate. . sodium salicylate.52. a sensitivity challenge should be conducted. Although removal from the source of exposure lead to improvement. in which a wheezing illness starts within 24 hours. Evaluation for potential permanent impairment and disability should take place after two years. employer should make every effort towards reasonable accommodation by improving the workplace as required. Patients should be referred to compensation boards or similar other agencies. typically following years of employing these drugs without difficulty. patients may continue to require medication and have airflow limitation or bronchial hyperresponsiveness for many months or years. Therefore. but there is a good likelihood of improvement. Reaction to aspirin or an NSAID produce a refractory state lasting 2-7 days and do not occur if patients ingest the drugs on a daily basis. of a single large exposure to an irritant. or disalcid. or work-aggravated asthma.Management of Asthma with Special Problems 243 changing the job process or activities can be changed to reduce exposure or if protective equipment is useful. The condition is inflammatory and does not involve immunological recognition of the irritant. continuing monitoring is important.51 Aspirin use may be a special problem in patients with nasal polyps. However. or if the patient reports a previous bronchoconstrictive reaction to these drugs. should have close medical follow-up. all patients of asthma should avoid this group of drugs. and usually less than that. Irritant-induced asthma (Reactive airway dysfunction syndrome—RADS) is another form of asthma associated with the workplace. so that continued low levels of exposure to the causative agent can be tolerated without problems. Pharmacological treatment of occupational asthma is similar to the treatment of patients with other forms of asthma. When the employees have irritant-induced asthma. Usually safe and alternative drugs are acetaminophen. Sims CD. 5. Stenius-Aarniala B. Am J Respir Crit Care Med 1995. caffeine. Rodwell LT. Henriksen JM. The course of asthma during pregnancy. Schatz M. 12.89: 1176-82. Thorax 1988.329:90-95. Am J Obstet Gynecol 1996.37:164-68.43:12-18. 1993.47:446-50. ethanol. The effects of pregnancy on asthma: A prospective study. Thorax 1996. J allergy Clin Immunol 1988. 8. Effect of pregnancy on asthma: a systematic review and metaanalysis. Interrelationship between asthma and pregnancy. et al. Wandel OJ. Acute asthma during pregnancy. Schatz M. Barnett-Hamm C et al. a literature review.175:150-54. avoiding food or drink between dinner and bed time. Vaghi A. Lancet 1988.100:1254-60. On the other hand. Ramin SM. 11. J Allergy Clin Immunol 1986. Anderson SD. 17. Zeiger RS. Juniper EF. . Spence DPS. spices. Chest 1991. Medical management of the reflux include elevation of the head of the bed 6-8 inches. Pasorgikliom. Zeiger RS. 9. postpartum and with successive pregnancies: A prospective analysis.151:1170-74.401-27. de Swiet M. Ahmed T. Siegel SC. Bianco S. Thorax 1992. Ann Allergy 1987. Agertoff L. 16. theophylline.83:434-37.51: 411-14. Robuschi M.81:509-17. Gluck JC. Schatz M. for complications like stricture. Asthma and pregnancy. REFERENCES 1. New York. 10. Toit JD. N Engl J Med 1993. In Schatz m. and avoiding drugs like metoclopromide that increase lower oesophageal sphincter pressure. Ann Allergy 1976. Katz RM et al. Rohr AS. other studies have failed to document similar benefits.63:521-23. 3.59:107-09. Harden K. Claman HC (Eds). Hedman J. Lung function tests in bronchial asthma during and after pregnancy. Nisar M. 13. A prospective study of 198 pregnancies.244 Bronchial Asthma particularly those occurring in the night. N Z Med J 1964. 15. Forsythe A et al. Potential outcome in the pregnancies of asthmatic women: A prospective controlled analysis. Br J Obstet Gynaec 1976. Harden K. Surgery is indicated for severely symptomatic oesophagitis that is not responsive to medical therapy. Schtz M. Gluck PA.103:5330-35. eating smaller but frequent meals. 6. Piirila P. 14. A prospective analysis (Abstract). Hiddlestone HJ. Asthma and immunology of diseases in pregnancy and early infancy. Pederson S. Danta I. Forsythe A et al.2:252-55. Young IH. Marcel Dekker. Course of asthma post-partum (PP) and during successive pregnancies. Garnigo J. Teramo K. and for established pulmonary complications of nocturnal reflux. Since surgery is extensive and is not successful for everyone. Preventing bronchoconstriction in exercise induced asthma with inhaled heparin. Prevention of exercise induced bronchial asthma by inhaled frusemide. A comparison of inhaled albuterol and cromolyn in the prophylaxis of exercise induced bronchospasm. J Allergy Clin Immunol 1992. Duration of protection by inhaled salmeterol in exercise-induced asthma. Chamberlain GVP. emphasis should be on medical management. 2. Asthma treatment in pregnancy: A randomized controlled study. 7. Stenius-Armiala B. inhibition of gastric acid production using H2-antagonists and maintenance of lower oesophageal sphincter pressure by avoiding fatty meals. Protective effect and duration of action of inhaled fenoterol and salbutamol in exercise-induced asthma in children. Terano KA. Newhouse MT. 4. West D. A mask to modify inspired air temperature and humidity and its effects on exercise induced asthma.77(Suppl):161. Hoffman CP et al. J Allergy Clin Immunol 1999. Bronchial asthma and pregnancy. NY: New York City Department of Health. Prescribing in pregnancy. Greenberger PA. 32.158:1091-95. Berendes H. VII. Rydhstroem H.294:103-05. 28. Surgery in corticosteroid-dependent asthmatics. Rikonen S. Asthma facts.106:421-29. JAMA 1975. 31. Thom E. 42. Clark FR. Cassino C. Melam H. Montogomery D. Am J Obstet Gynecol 1992.98:478-80. Beclomethasone dipropionate for severe asthma during pregnancy. Terano K. Rhods GG. The interaction between immunoglobulin E and smoking in airflow obstruction in the elderly. Lancet 1968. Barnes PJ. Asthma during pregnancy: A population based study. Am Rev Respir Dis 992. Am J Respir Crit Care Med 1998. Hoffman CP. 37. Berger KL et al.103:5356-59. Demissie K. Schatz M.78:349-53. The safety of asthma and allergy medications during pregnancy. The course and outcome of pregnancy in women with bronchial asthma. Maternal Fetal Medicine Units (MFMU) studies of inhaled corticosteroids during pregnancy. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Apgar V. Kaiser-Permanents Asthma and Pregnancy Study Group. The treatment of the asthmatic during pregnancy and lactation.53:345. Pregnancy in patients on long-term corticosteroid therapy.171:770-73. O’Rourke J. Infant and maternal outcomes in the pregnancies of asthmatic women. Schatz M. Patterson R. Breckbridge MB. Morgan MA et al. McNellis D. Greenberger PA.233:804-07. Br Med J 1987. Fitzsimons R. Chest 1990. Chung KF. Chest 1995. Acta Allergol 1972. 23. Atkinson BD.107:642-47. Gordon M.12:302-06. Perioperative management of the patient with asthma. Bahna SL. Anaesthesia for the asthmatic.16:167-71. Am J Obstet Gynaecol 1970. Taylor R. J Allergy Clin Immunol 1997.98:389-92. Oh SH. Severity of asthma and perinatal outcome. New York. Aberg A. Niswander KR. Walsh SD. S Afr Med J 1981. 41. 24. 35. Cockroach sensitization and severity of airway obstruction in elderly nonsmokers. 20. Kantor AG. Ann allergy 1983. Harden K et al. Perlow JH. Outcome of pregnancy in women requiring corticosteroids for severe asthma.122:1580-86. Kallen B.Asthma in the elderly. Dombrowski M. Outcome for the fetus of mothers receiving prednisolone during pregnancy. Greenberger PA. Banatar SR. New York City department of Health. Patterson R. Bjerkedahl T. The drug problem during pregnancy. Patterson R. Warrell DW. Zeiger RS. Asthma and Immunology (ACAAI). Slow-release theophylline in pregnant asthmatics. 29.78:349-53. Short term effects of inhaled albuterol on maternal and fetal circulation. J Allergy Clin Immunol 1986. Schatz M. 30.146:402-07. 26. 2000. Scot Med J 1967. Hirshman CA. Am J Obstet Gynecol 1994. Bronchial asthma.9:623-30. Ann Intern Med 1983.100:301-06. Outcome of pregnancy in women requiring corticosteroids for severe asthma. Spector SL. 40.167:964-67.51:173-77. Chest 2002. Rogers L. 36. 25. Eur J Epidemiol 2000. Ormond C. Treatment of asthma. Gilbert K et al. Corticosteroid therapy for the pregnant asthmatic patient. 21. Rayburn WF.Management of Asthma with Special Problems 245 18. J Allergy Clin Immunol 1986. Fetal morbidity following potentially anoxigenic obstetric conditions. 39. The use of newer asthma and allergy medications during pregnancy. 19.84:475-80. Stenius-Armiala B. Kingston HG. 43. . 34. J Allergy Clin Immunol 1999.i:117-18. Zitz S.63:844. Zieger RS. Clin Obstet Gynec 1966.59:409. 38. 33. Patterson R.27:397-406. Anaesth Analg 1984. Patterson R. 27. J Allergy Clin Inmmunol 1974. Fitzsimons R. Dow L. Ann Allergy Asthma Immunol 2000. The American College of Obstetricians and Gynaecologists (ACOG) and the American College of Allergy. Holgate ST. Campbell MJ. Coggon D. 22. Petheram IS. Ellis EF et al (Eds): Allergy Principles and Practice. 51. . Report of the Subcommittee on Bronchoprovocation for Occupational Asthma.36:523-29. 52. What determines whether an elderly patient can use a metered dose inhaler correctly? Br J Dis Chest 1986. Occup Med 1999. Saunders KB. Malo JL. Cartier A. Chatran NB. Pope CE. Perrin B. Midlands Thoracic Society Research Group. Crowley JJ. Newman GB. Connoly MJ. 53. St. Thorax 1981. Carrasco E. Medical and surgical treatment of nonallergic asthma associated with gastroesophageal reflux. Burge PS. 48. (3rd Ed). Simon RO: Aspirin sensitivity: Respiratory and cutaneous manifestations. J Allergy Clin Immunol 1989. Guidelines for bronchoprovocation on the investigation of occupational asthma. Postgrad Med J 1982. Reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measure in a simple awareness scale. Worsening asthma: is reflux esophagitis to blame? J Rev Respir Dis 1990. Thorax 1992. Burge PS et al. Reed C. Stevenson DD. 50.58:149-52. Allien AC. Louise. Galleguillos F. Development of an expert system for the interpretation of serial peak expiratory flow measurements in the diagnosis of occupational asthma.84:823-29.11:827-44. Newton DT et al. Sepulveda R. 1988.47:410-13.99:1330. Larrin A. Nelson HS. Influence of age on response to ipratropium bromide and salbutamol in asthma. Vestel RE. Bernstein IL. Assessment and management of acute asthma in the elderly: a comparison with the younger asthmatic.80:45-59.56:758-64. In: Middleton E. Chest 1991. Pantin CF. CV Mosby.246 Bronchial Asthma 44. Comparison of monitoring of peak expiratory flow rates and bronchial responsiveness with specific inhalation challenges in occupational asthma. Ullah MI. Collins JV. 45. 46. Jones DA. Nielson CP.141:A79. 47. 49. Prior A. l’Archeveque J et al. Am Rev Respir Dis 1990. addition of a long acting β2-agonist to the regimen is a better option than merely increasing the dose of inhaled corticosteroids. and corticosteroids along with other supplementary drugs. About ~5% of asthma patients are steroid-resistant. Thus. there are concerns about side effects particularly tremor.13 Combination therapy of inhaled corticosteroid and long-acting β2-agonist. There are still concerns about side effects of corticosteroids. A number of studies have demonstrated that in patients on moderate doses of inhaled corticosteroids. In general there is a corticophobia in the mind of many. including long acting β2-agonists and leukotriene antagonists.1-10 The most recent one is the British Thoracic Society Guidelines-(2003).12 The addition of a long acting β2agonist is also effective in reducing the number and severity of exacerbations. although effective bronchodilators. There are also concerns about the osteoporosis and fracture which is in direct correlation with the overall drug intake. and • Anti-interleukin-5 antibodies. The basis of these therapeutic strategies are depicted in Figure 15.15 Currently. They do not respond to high doses of corticosteroid therapy. tachycardia.14 Although. Inhaled β2-agonists. and tachyphylaxis. This group of patients will need some other forms of therapy. . are clearly a better option for asthmatic persons receiving lower doses of inhaled corticosteroids than merely increasing the dose.1.11 The main therapy consists of inhaled β2-agonists.New Treatment Modalities/Newer Drugs for Bronchial Asthma 247 15 New Treatment Modalities/Newer Drugs for Bronchial Asthma A number of advances had taken place in the management of bronchial asthma and a number of national and international guidelines have been developed on this regard. there are certain limitations. similarly has potentially serious side effects. salmeterol or formoterol delivered simultaneously by a single device may be beneficial. which include: • Anti-immunoglobulin E (IgE) antibodies • Soluble interleukin-4 receptors (sIL-4Rs). Theophylline. All these guidelines emphasize that ‘add-on’ or adjunctive therapies to inhaled corticosteroids. there is a need for the development of newer drugs for the treatment of asthma. by which new treatment options are being provided. current asthma therapy is effective and well-tolerated. particularly in children and in patients requiring very high doses of the drug. This knowledge has been harvested through advancement in biotechnology. and in some stages of clinical trial. Many patients are also reluctant to take steroids because of the fear of side effects. It is now firmly established about the cellular and mediator basis of the inflammatory processes in bronchial asthma. a number of different therapies are under investigation. are developed by grafting the variable immunoglobulin region of murine origin onto a backbone of the constant region of human IgG1. It forms antiIgE-IgE complexes. 15. The half-life of the hexamer.17 This reduced the immunogenicity of the monoclonal antibody and thus.1: Therapeutic basis of anti-IgE antibody. They lower serum free IgE in rodents and block passive sensitisation of lung fragments by serum from sensitised individuals. Humanised version of murine monoclonal anti-IgE antibodies . enabled examination of the role of IgE in human disease. The drug had protective effects on both the early and late responses to allergen challenges. Fcε receptors). The effects were then examined to see the preventive effect on the allergen provoking bronchoconstriction. it does not bind to IgE on the IgE receptors (both low-affinity and high-affinity types. and also has a role in antigen presentation.16 However.19. Soluble IgE has a half-life of only a few days. like mast cells and basophils. which consist of three molecules of soluble IgE and three molecules of anti-IgE.21 The treatment also inhibited production of IL-4 and IL-5.248 Bronchial Asthma Anti-immunoglobulin E (IgE) antibodies-(E25) Anti-IgE is a specific monoclonal antibody that inhibits IgE activity by binding both to circulating IgE and to IgE on the surface of B cells. They block the binding of IgE to its receptors on effector cells. The safety and efficacy profile of the anti-IgE antibody – E25. IL-4 and IL-5 . and it acts as a sump for the allergen. was studied by repeated injections of the antibody to allergic human subjects which did not provoke anaphylaxis and lowered the serum IgE levels by > 99%. which are central to the action of the drug.20 E25 treatment also reduced the number of circulating eosinophils and the increases in bronchial reactivity and in sputum eosinophilia provoked by allergen challenge. The molecule is nonanaphylactogenic.18 The treatment also reduced basophil receptor density and histamine release by > 96% and 90% respectively.rhuMab-E25 and CGP 51910. on the other hand. The drug also reduced the eosinophilic-inflammation of the airways provoked by antigen challenge in sensitised mice. Antigen B-cell IgE IL-4 Mast cell Th2 IL-5 Acute symptoms (early asthma reaction) Eosinophil (Late asthma reaction) Fig. The maximum demonstrable size of these complexes is as hexamers. but do not trigger the activation of these cells. is considerably longer. inhaled or oral. E25.26-41 anti.40. Further. the need for rescue treatments. Another large study also has shown E25 to be effective in adults and children with ragweed allergic rhinitis. and mucus gene expression and hypersecretion. significantly improves asthma. but also as a novel therapeutic tool in the treatment of bronchial asthma. Apart from a slight increase in urticaria.IL-antibody is an important target for asthma therapy. but does not cure asthma. The most important of all these is the biological activity of its ability to drive the differentiation of Th-0 lymphocytes into Th-2 cells. Treatment with . There was no side effect of the drug.5 μg /kg/ngIgE/ml) or a high dose E25 (5. In view of a wide variety of important contribution of IL-4 in asthma pathogenesis.New Treatment Modalities/Newer Drugs for Bronchial Asthma 249 The first large scale clinical trial of the efficacy of the humanised. basophils. and peripheral blood mononuclear cells produce IL-4 in response to dust mite antigen. It shares a number of activities with IL-13 and because of its ability to prevent apoptosis of T lymphocytes. examined the effects of repeated dosing on the severity of allergic rhinitis. serum free IgE dropped rapidly. were randomised to placebo or IL-4R at doses of 0. Soluble Interleukin-4 Receptors (sIL-4Rs) Interleukin-4 plays a number of important roles in the allergic process and is critically important for the development of allergic inflammation.24 Other studies of E25 in adults and asthma with moderate severity confirm the safety and efficacy in terms of a significant reduction in the frequency of exacerbations as an adjunct or during tapering off of steroids.41 Preclinical studies in mice has shown prevention of the development of allergenspecific IgE and reduction of eosinophilic inflammation. and especially eosinophils to the site of inflammation. Important functions include secretion of IgE by B lymphocytes. The drug is proved to be safe and effective in patients of bronchial asthma. A soluble IL-4 receptor is currently under investigation for the treatment of bronchial asthma. E25 showed safety and efficacy. monoclonal anti-IgE antibody. neither there was development of any antibody. When given as regular treatment to patients with moderate to severe asthma requiring regular treatment with corticosteroids. induction of VCAM-1 expression on vascular endothelium in promoting cellular inflammation by which it directs the migration of T lymphocytes. and the severity of asthma symptoms.22 and showed beneficial results. The IL-4 levels are increased in the BAL fluid of allergic individuals. there is altered regulation of IL-4 in atopic individuals as well atopic individuals have higher number of T cells. inhibition of eosinophil apoptosis. apparently safe anti-IgE monoclonal antibody holds great promise not only as a research tool for defining the role of IgE in health and disease.5 mg once by nebuliser42 and their steroid therapy was discontinued. In 25 patients of mild to moderate persistent asthma on inhaled corticosteroid therapy. prospective study of 317 patients compared the effects of placebo with that of a low dose E25 (2. Aerosolised IL-4 significantly increases airway hyper-responsiveness in patients with mild asthma. it is important in allergic immune responses. thus shows that the monoclonal antiIgE antibody. There was a significant reduction in the reduction in dose for corticosteroid treatment.23 The double blind. and remained low throughout the study period. Development of more selective.8 μg /kg/ngIgE/ml) as adjuvant therapy every two weeks for 20 weeks. Other mechanisms of eosinophilic inflammation are increasing eotaxin expression. In both active IgE treatment groups.25 The above clinical studies. quality of life scores.5 or 1. monocytes. adverse events were not more than those in the placebo group. significantly improved the morning PEFR. E25 treatment. 5. and airway remodelling in animal models of pulmonary disease. Bronchial reactivity to methacholine was reduced in 6 of the 8 patients tested.46 b. mucus formation.5 mg IL-4R resulted in significantly better FEV1 at 2 hrs after treatment.48 . Interleukin-13 antagonism. or 3. No effect. These findings suggest the possible role of IL-13 antagonists in the treatment of bronchial asthma. TNF Antagonism. Asthma symptom score also improved significantly. Animal studies have shown that endogenous IL-10 suppresses excessive inflammation in the lung. IL-10 therapy. TNF seems to play an important role in determining the severity of asthma. There is an increased production of IL-13 in atopic and non-atopic asthma. double blind. treatment was given with 0.75. Two different monoclonal antibodies against IL-5 in clinical trials have shown that single intravenous infusion with 2.44 Another study using a single dose of anti-IL-5 provided only a small increase in FEV1 in noneosinophilic bronchial asthma. In further phase I/II randomised. The results were similar to that of the earlier study. Its antiinflammatory effect was obvious by a reduction of exhaled NO scores. placebo-controlled study in 62 patients with moderately severe persistent asthma. it is apparent that IL-4 receptor is potentially a safe and effective treatment for asthma without the use of corticosteroids. Based on findings from experimental animals and the presence of elevated TNF levels in patients with bronchial asthma. Recent human genetic data also show association of genes of the IL-13 signalling pathway to allergic disease and bronchial asthma. Interleukin-5 is thought to be associated with the late stages of maturation and release of eosinophils that occur within the bone marrow in different allergic diseases.5 or 10 mg/kg reduced the eosinophil levels to low normal values in the blood and sputum from patients with asthma. IL-10 deficiency is associated with several inflammatory diseases like bronchial asthma and cystic fibrosis. IL-13 plays an important role in the induction of airway hyperreactivity. The effect of IL-10 may thus. however was noticed on bronchial hyperresponsiveness. allergic rhinitis.47 c. there is a rationale for TNF antagonism to be deployed in asthmatics. provide a physiological form of anti-inflammatory therapy. Il-4R was safe and well tolerated. Clinical studies have shown that constitutive IL-10 protein concentrations are reduced in BAL fluid from asthmatic compared to normal subjects and the IL-10 production by monocytes is reduced.0 mg of IL-4R twice weekly by nebulisation or placebo administration.43 The steroid inhalation was discontinued. 1.45 Other Cytokine-directed Therapy a. Antibodies to IL-4R developed in <3% without any symptom. Thus. Long-term disease progression can be prevented by IL-4 as it inhibits the central inflammatory process.41 Anti-interleukin-5 Antibodies Eosinophils are important in the inflammatory pathophysiology of bronchial asthma. which is maintained up to 4 months. TNF antagonism may be useful in treating cases of severe persistent asthma as well as acute severe asthma. and chronic sinusitis. atopic dermatitis. Once-weekly dosing targeting the lungs will improve patient compliance. and the improvement persisted till 2 weeks.250 Bronchial Asthma 1. ii. Asthma is not curable by the currently available drugs. the potency of the drug is relatively poor at therapeutic concentrations. theoretically there is a wide scope of manipulating these products.51-53 This suggests that vaccination with allergens. particularly in combination with H1-antihistamines. iv. degranulation. airway hyperreactivity. some investigators believe that the disease is potentially curable through strategies that prevent or reverse the immunological abnormalities in atopy. Phosphodiesterase inhibition increases the intracellular levels of cyclic AMP. Because of the role of a large number of cytokines and other mediators in the pathophysiology of bronchial asthma. and leukotriene synthesis. However. macrocyclic immunosuppressants. ribozyme therapy and gene therapy. Thus. astemizole. Therapies acting on transcription and viii. Mediator inhibitors and agonists like kinin receptor antagonists. are useful for the treatment of allergic rhinitis. selective iNOS inhibitors. mycobacterial immunisation. and P2Y receptor antagonists. There are several approaches to reduce the preponderance of Th2 cells in atopy by switching the balance in favour of Th1 cells. Vaccines for bronchial asthma. azelastine. which is important for regulation of cell function.New Treatment Modalities/Newer Drugs for Bronchial Asthma 251 d. mizolastine etc.56 PDE4 inhibitors reduce eosinophil survival. which can be used as anti-asthma therapy.49 Similarly. which includes antisense therapy. v. Genetic therapy. Other functions of PDE4 inhibitors include attenuation of proliferation of mononuclear cells in atopic individuals and Th1 and Th2 cells. or unmethylated cytosine-guanosine dinucleotidecontaining oligonucleotides (CpG ODN).55. H3–antihistamines. endothelin antagonists.) are useful drugs for associated conditions like allergic rhinitis. PDE4 inhibition suppresses various characteristic features of inflammation including recruitment of inflammatory cells to the lungs. This can be achieved in animals by exposure to bacterial products such as BCG. Chemokine receptor inhibition. loratadine. vi. Antihistamine drugs like H1. This combination provides a better treatment approach for allergic nasal congestion without the hypertensive liability of current alpha-adrenergic agonist decongestive therapy. A number of highly selective PDE4 inhibitors have been developed to overcome this problem. One of the mechanisms of action of theophylline for bronchodilatation is inhibition of PDE4. Adhesion molecule inhibitors.antihistamines (cetirizine.54 PDE4 Inhibitors Phosphodiesterase 4 (PDE4) is present in a number of inflammatory cells responsible for the development of asthma. tachykinin antagonists. inhibit eosinophil chemotaxis. . f. terfenadine. immunomodulators and adjuvants may be a future strategy for the prevention or cure of asthma. They do not have any direct effect on bronchial asthma. Inhibition of cell signalling. mucus regulation. vii. iii. However. Allergen-and IgE-directed therapy.50 e. Other future targeted therapeutic approaches. They also inhibit cytokine generation. and airway edema. fexofenadine. adhesion molecule expression. T-cell immunomodulation like GATa-3. These are i. Mycobacterium vaccae. Guidelines for the management of asthma in adults. International Consensus report on the diagnosis and management of asthma.9:287-92. King’s Fund Center. Apart from the potential anti-inflammatory action.1065-79. National Asthma Campaign. attenuates the development of the late asthmatic response in mild asthmatics while showing effect on the acute response and with no significant side effects.63 REFERENCES 1. British Paediatric Association. Single oral administration of the drug is without any significant bronchodilator activity. it is suggested that a mixed PDE3/4 inhibitor would seem to be a better option provided that they have minimal side effects. 9. National Asthma Campaign. British thoracic Society. Thorax 1997. 1-Chronic persistent asthma. Statement by the British Thoracic Society. BMJ 1990. Hence. 2.48:S1-S24. Research Unit of the Royal College of Physicians of London. 8.67:240-48. British Paediatric Association.306: 776-82. • Cilomilast . Arch Dis Child 1989. a follow-up statement.252 Bronchial Asthma The drugs of this class include: • Rolipram. British thoracic Society and others. The King’s Fund Center. Clin Exp Allergy 1992. national asthma Campaign et al.64. suppresses the development of bronchial hyper-responsiveness following antigen challenge in asthma. and also various features of allergic rhinitis62 and improves various pulmonary function parameters. The King’s Fund Center. Arch Dis Child 1992. King’s Fund Center. another orally active PDE4 inhibitor attenuates bronchoconstriction following exercise.301:651-53. Guidelines for the management of asthma in adults. Guidelines for the management of asthma: A summary. The orally active PDE4 selective inhibitor CDP840 when administered orally for 9. Research Unit of the Royal College of Physicians of London.52(Suppl 1): S2-S8. A practical guide for public health officials and health care . Landau LI et al. Global Initiative for Asthma. Statement by the British Thoracic Society. and improves various indices of lung function. National Asthma Campaign et al. British thoracic Society. Asthma. 5.57 The inhibition of the late asthma response is due to their anti-inflammatory property and not due to bronchodilator action per se. 6. Warner JO. 4. BMJ 1990. 10. BMJ 1993. 7. The drug is well tolerated up to a dose of 15 mg bid. they perhaps act by suppression of neural reflexes by suppressing neuropeptide release from sensory C-fibres and inhibition of bronchoconstriction by vagal nerves. 2-Acute severe asthma.5 days. Gotz M. 3. and effective in allergic rhinitis. and • Roflumilast These drugs suppress various aspects of allergic inflammation. Royal College of Physicians of London.59-61 Cilomilast.58 Roflumilast is more potent than CDP840 acts against late asthma response. Summary charts.22(Suppl):1-72. BMJ 1993. The major side effect of this class of drugs is gastrointestinal disturbances. Management of asthma: A consensus statement.301:797-800. Thorax 1993. Another PDE4 inhibitor RP73401 has also no acute effect. 1995 Review and Position Statement. 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Bruijnzeel P.176:1091-98. Lofdahl CG. Barnes PJ (Eds).2001. Am J Respir Crit Care Med 1994. Huber BT.106:1131-1136.34:987-94. Bachmann M et al. Barnes PJ (Eds). In: Progress in Respiratory Research. Interleukin-4 and soluble CD23 serum levels in asthmatic atopic children. ten Brinke A. Gruber C et al. et al. Xie H.22:1615-20. 48. et al. Allergy and COPD. Borish L.31: 256-59. Cuss FM et al. 35.31:28132. . placebo-controlled trial. Khan J. Gerhold K. Seward RJ. Lanz MJ. Rihoux JP H-antihistamines. Wills-Karp M. Chan SC. Nature 1993. volume 31. Deng JM. Allergy and COPD. Ihle J et al. Barnes PJ (Eds). New drugs for Asthma. 50. 39. 36. Interleukin-4 antagonism. 47.362:245-48. Braun RK. In: Hansel TT. Kopf M. Allergy and COPD. Walker C.31:260-64. a humanised anti-IL-5 antibody in severe persistent asthma (Abstract). Disruption of the mucin IL-4 gene blocks Th2 cytokines responses. Nelson H. In: Hansel TT. 41. et al. Abnormal IL-4 gene expression by atopic dermatitis T lymphocytes is reflected in altered nuclear protein interactions with IL-4 transcriptional regulatory element. Am J Respir Crit Care Med 2000. 42. J Allergy Clin Immunol. In: Progress in Respiratory Research. McDonnell N. In: Progress in Respiratory Research. Cytokine rescue from glucocorticoid induced apoptosis in T cells is mediated through inhibition of I kappa-Balpha. TNF antagonism. Basel: Karger. Donaldson DD. 31:269-73. New drugs for Asthma. Manetti R. Shi HZ.157:1818-21. Interleukin-10. Parronchi P.254 Bronchial Asthma 32. Barnes PJ (Eds).2001. Borish LC. Teague TK. Bauer W. De Vos C. Allergy and COPD. 44. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. In: Hansel TT. Brown MA. Am J Respir Crit Care Med 1999. Kipa JC. Aberrant interleukin(IL)-4 and IL-5 production in vitro by CD4+ helper T cells from atopic subjects. In: Hansel TT.2001. O’Conner BJ.17:368-75.2001.2001. Am J Respir Crit Care Med 1998. 43. et al. Am J Respir Cell Mol Biol 1997. 40.160:1816-23. In: Progress in Respiratory Research. Interleukin-4 receptor in moderate atopic asthma: A phase I/II randomised. Results of a phase I trial with SCH55700. 49. New drugs for Asthma. Vella A. Histamine H3 antagonists. In: Progress in Respiratory Research. Basel: Karger.186:325-30. 37. Le Gros G. Eur J Immunol 1992.111 (2 Suppl):S460-75. Allergy and COPD.356:2144-48. Lecki MJ. Cuss F. J Allergy Clin Immunol 1998. In. Mohler KM et al. New drugs for Asthma. Basel: Karger. Egan RW. Lancet 2000. Sole D. Interleukin-13 antagonism. Allergen-induced cytokine production in atopic disease and its relationship to disease severity.31. New drugs for Asthma.150:1038-48. 31:247-50. Burke C. Abbott NN. Narula S. 2. Hertz U. Allergy and COPD. 2003. Effect of inhaled interleukin–4 on airway hyper-reactivity in asthmatics. J Exp Med 1997. Santos IM. Agosti JM. J Invest Allergol Clin Immunol 1995. 51. Haher S. McLeod RL. 46. 34. 31:133-36. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils. Xu H. Basel: Karger. New drugs for Asthma. 38. airway hyper-responsiveness and the late asthmatic response. Steinke JW. In: Progress in Respiratory Research. et al. Mol Immunol 1997.2001. Elias JA. Interleukin 4 (IL-4) or Il-7 prevents the death of resting T cells: stat 6 is probably not required for the effect of IL-4. Hansel TT. Borish LC. Tormey V. BCG infection suppresses allergic sensitisation and development of increased airway reactivity in an animal model. Langley SJ et al. Barnes PJ (Eds). Leonard C. Basel: Karger. 45. Cytokines and chemokines. In: Hansel TT.5:251-54. et al. Barnes PJ (Eds). 33. J Invest Dermatol 1996.161:A505.102:867-74. Basel: Karger. De Carli M. Wilcox TM et al. et al. 62. Louw C.108:530-36. a new. 59. Phosphodiesterase isoenzymes: Molecular targets for novel anti-asthma agents. Immunology 1998. 61. Holt PG. J Allergy Clin Immunol 2001.12:131-35. J Allergy Clin Immunol 2001. The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced response in asthmatic subjects. 54. et al. 63. 60. Lancet 1994. Schmidt BM.165:A85. Wang CC.New Treatment Modalities/Newer Drugs for Bronchial Asthma 255 52. 57. Acute anti-inflammatory effect of the novel phosphodiesterase 4 inhibitor roflumilast on allergen challenge in asthmatics after a single dose (abstract) Am J Respir Crit Care Med 2000.161:A200. Rook GA.108:671-80.344:456-58. A potential vaccine strategy for asthma and allied atopic diseases during infancy. orally active. McLeod D. Spina D. Kusma M. Eur Respir J 1996. RP73401 (a phosphodiesterase IV inhibitor) single dose does not prevent allergen induced bronchoconstriction during the early phase reaction in asthmatics.157:325-32. Hawksworth R.10:1008-14. Feuring M. Inhibition of an established allergic response to ovalbumin in BALB/c mice by killed Mycobacterium vaccae. et al. Eur Respir J 1997.9:82S. J Immunol 1999. et al. 53. Pulm Pharmacol Ther 1999. Dose-related efficacy of once-daily roflumilast. Barmette MS. Chaudhury BK. Theophylline and PD4 inhibitors in asthma. Underwood DC. Cyclic nucleotide phosphodiesterases. Torphy TJ.93:307-13. de Monchery JGR. Leichtl S. et al. The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis.162:6284-93. Tijhuis GJ. Curr Opin Pulm Med 2003. 56. 58. Leichtl S. Nell H. 55. Bredenbroker D.. Torphy TJ. Wild JS. selective phosphodiesterase 4 inhibitor. Essayan DM. et al. Sur S.9:57-64 . Harbinson PL. et al. Schmid-Wirlitsch C. in asthma (abstract) Am J Respir Crit Care Med 2002. Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG oligodeoxynecleotides. Airflow (SB 207499): A second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: From concept to clinic. Jonker GJ. Am J Respir Crit Care Med 1998. 2++. which was strengthened by collaboration with the National Asthma Campaign. well-conducted meta-analysis.2-12 The Scottish Intercollegiate Guidelines Network (SIGN) published its first asthma guidelines in 199613 and has subsequently published on primary care management of asthma in 199814 and management of acute asthma in 1999. it is emphasised that the grade of recommendation relates to the strength of the evidence and not necessarily the clinical importance of the recommendation in patient management. The panel of experts have taken into account the evidence-based medicine. The two organisations jointly produced the comprehensive new guideline. a more scientific way of expressing a particular conclusion . High quality case control or . the Royal College of Paediatrics and Child Health. The recommendations levels are graded into 8 subtypes (1++. 1-. the Royal College of Physicians of London. RCTs with low-risk bias. the International Consensus Report and the WHO. systemic reviews. 3. meta-analyses. this should be seen as a stimulus for further research. High quality systemic reviews of case-control or cohort studies. and the British Association of Accident and Emergency Medicine.16 However.1 The first British Guidelines on Asthma Management in adults were first published in 1990 after a joint initiative between the Thoracic Society. General Practice Airways Group.15 Further. systemic review of randomised controlled-trials (RCTs). and 4) depending on whether the inference from high-level meta-analyses. Where there are only low grade recommendations in important clinical areas. These guidelines are already discussed earlier. by the Global Initiative for Asthma (GINA). RCTs with a very low-risk of bias.1 One important and new feature in this new guideline is the levels of evidence and grades of recommendations used in these guideline.256 Bronchial Asthma 16 New Guidelines for Asthma Management (Non-pharmacological Management) The British Thoracic Society has recommended the new guidelines for the management of bronchial asthma in 2003. 2+. 2-. the King’s Fund Center. using evidence-based methodology to cover all aspects of asthma care. or RCTs with high-risk of bias. the Royal College of Physicians of London. systemic reviews. Simultaneously Guidelines were also developed by the American Physicians. both the British Thoracic Society and the SIGN have recognised the need to update their asthma guidelines. 1+. The outcome is the new British Guideline on the Management of Asthma. These were updated in 1993 when the addition of childhood asthma and further updated in 1995. and the National Asthma Campaign. A number of epidemiological studies suggest that close contact with a cat or dog in very early infancy reduced subsequent prevalence of allergy and asthma. Allergen Avoidance There is a strong correlation between allergic sensitisation to common aeroallergens and the subsequent development of asthma. if avoided might facilitate the management of asthma. Two trials in progress are investigating the consequences of introducing house dust mite reduction in early pregnancy. a more recent study in 1246 patients found that breastfeeding was associated with a reduced . There is also a strong association between allergen exposure in early life and sensitisation to these allergens. A number of potential strategies are suggested. However. Breastfeeding A systematic review and meta-analysis involving 8183 subjects followed for a mean of four years revealed a significant protective effect of breastfeeding against the development of asthma. The grades of recommendations are from A-D depending on the levels of evidence. Good practice points are also given based on clinical experience of the guideline development group. case series. Primary Prophylaxis Primary prophylaxis is employed before there is any evidence of disease in an attempt to prevent its onset. There appears to be a transient reduction in the prevalence of atopic eczema in the first two years of life but no evidence of sustained benefit in relation to asthma. However.New Guidelines for Asthma Management (Non-pharmacological Management) 257 cohort studies with a very low-risk of confounding or bias or a high probability that the relationship is causal. well conducted case control or cohort studies with low-risk of confounding or bias and a moderate probability that the relationship is causal. evidence has been difficult to obtain for many approaches and more studies are required. In contrast. outcomes at one year of age indicate a modest but significant reduction in wheezing illnesses. and which may have the potential to modify fundamental causes of asthma. reducing the requirement for pharmacotherapy. The effect was greatest in children with a family history of atopy. and are following up the children born to the participating mothers. Allergen avoidance after birth has been studied in a number of controlled (but no double blind) trials. although it has not been possible to demonstrate an association between allergen exposure and the development of asthma. no recommendations on prenatal or postnatal allergen avoidance can be made in relation to primary prevention of asthma. Although accurate asthma phenotyping is not possible in infancy. and expert opinion. case control or cohort studies with a high-risk of confounding or bias and a significant risk that the relationship is not causal. NON-PHARMACOLOGICAL MANAGEMENT There is increasing interest in factors which. This may be a consequence of high allergen exposure inducing tolerance. non-analytical studies like case reports. Majority of allergen avoidance studies focus on dietary manipulation to prevent atopic eczema and have paid little attention to aeroallergen avoidance. No double blind placebo controlled trials of immunotherapy as primary prevention have been conduced. Children given ketotifen (206 infants. and at present immunotherapy cannot be recommended for primary prevention. Small sample size and early outcome age limit the interpretation of this study.258 Bronchial Asthma risk of infant wheeze. increasing susceptibility to wheeze. in two trials) showed significantly less asthma at one . co-interventions and outcome definition make meta-analysis problematical. reported a reduced incidence of atopic eczema but no effect on IgE antibody sensitisation. A double blind placebo trial of the probiotic. but also with an increased risk of asthma at six years. Variation in study design. Avoiding Pollutants No evidence was found to support a link between exposure to environmental tobacco smoke and other air pollutants and the induction of atopic asthma. Modified Infant Milk Formulae Trials of modified milk formulae using partial and extensive hydrolysates of whey or casein or soy formulae compared with conventional formulae have not shown any consistent significant long-term benefits in relation to asthma. Pharmacotherapy There are some pharmacological trials of treatments designed to prevent onset of the disease. no recommendation can be made at present. Preliminary results from an ongoing parallel group study using contemporaneous untreated children as the control group for pollen immunotherapy in children with allergic rhinitis suggest a lower rate of onset of asthma in the treated group. Thus. breastfeeding should be encouraged and its benefits include a protective effect in relation to early life wheezing. Trials of lipid supplementation during pregnancy and postnatally to prevent atopic disease are in progress. but this has not been brought out in larger studies. Microbial Exposure The “hygiene hypothesis” suggests that early exposure to microbial products will switch off allergic responses preventing allergic diseases such as asthma. Pregnancy smoking affects an infant’s airway function. Other Dietary Modifications Limited epidemiological evidence suggests that fish oil consumption may protect against asthma in childhood. Immunotherapy and Primary Prevention Three observational studies. In the absence of good quality intervention studies. Epidemiological studies comparing large populations who have or have not had such exposures support the hypothesis. have shown that immunotherapy in individuals with a single allergy reduces the numbers subsequently developing new allergies over a three to four years follow-up compared with contemporaneous untreated controls. intervention used. Increased risk of infant wheeze is associated with smoking during pregnancy and maternal postnatal smoking. An early meta-analysis suggested an association between gas cooking and respiratory illness. lactobacillus CG. in over 8000 patients. There are many other adverse effects on the young child of such exposures. Cetirizien had additional benefits for atopic dermatitis alone and reduced the frequency of urticaria. Evidence that reducing allergen exposure can reduce morbidity and mortality is tenuous. The reviewed studies used various chemical. children and adults have both shown benefit from exposure to a very low allergen environment. using cetirizien. The first concluded that current chemical and physical methods were ineffective and could not be recommended as prophylactic treatment for asthma patients with sensitivity to house dust mites. In uncontrolled studies. the major cat allergen • 10 μg/g dust of Can f l. An amendment concluded that physical reduction methods may reduce asthma symptoms. bronchial reactivity and deterioration in lung function. In the third study.New Guidelines for Asthma Management (Non-pharmacological Management) 259 and three years follow-up compared with those receiving placebo. The combined meta-analysis showed no difference in improvement in asthma between patients in experimental groups compared with controls. There was heterogeneity between studies with regard to intervention. Increasing allergen exposure in sensitised individuals is associated with an increase in asthma symptoms. • Complete barrier bed covering systems • Removal of carpets • Removal of soft toys from bed • High temperature washing of bed linen • Acaricides to soft furnishings • Dehumidification . Treatment requirements. At present. the benefits in such circumstances cannot be necessarily attributed to the allergen avoidance. Larger and more carefully controlled studies are required to demonstrate any clear benefit from house dust mite avoidance. Threshold concentrations of allergens that can be regarded as risk factors for acute attacks include: • 10 μg/g dust of group l mite allergen • 8 μg/g dust of Fel d l. 18 months’ treatment had no effect in the intention to treat population but significantly reduced asthma in children with atopic dermatitis sensitised to either grass pollen or house dust mite. the major dog allergen • 8 μg/g dust of cockroach allergen. House dust mite control measures There have been two Cochrane reviews on house dust mite control measures and the management of asthma. physical or combinations of methods to reduce mite exposure. hospital attendance and respiratory arrest are associated with increased exposure to high concentrations of indoor allergens. In committed families with evidence of house dust mite allergy and who wish to try mite avoidance. and in some studies intervention allocation was not adequately concealed. the following are recommended. Secondary Prophylaxis Allergen Avoidance Allergen avoidance measures may be helpful in reducing the severity of existing disease. this does not appear to be a cost-effective method of achieving benefit. However. The independent contributions of prenatal and postnatal maternal smoking to the development of asthma in children are difficult to distinguish. Starting smoking as a teenager increases the risk of persisting asthma.1 for the development of asthma over six years in 14 years old children who have started to smoke. resulted in no differences between groups with regard to symptoms. Maternal pregnancy smoking has been shown to have an adverse influence on lung development. Although fungal exposure has been strongly associated with hospitalisation and increased mortality in asthma. No studies were identified that directly related to the question of whether smoking affects asthma severity. Alternatively. peak flow. One controlled cohort study suggested that exposure to passive smoke at home delayed recovery from an acute asthma attack. There is no conclusive evidence regarding the impact of cockroach allergen reduction on asthma symptoms. Environmental Factors Smoking The association between passive smoking and respiratory health has been extensively reviewed. There is little evidence that maternal pregnancy smoking has an effect on allergic sensitisation. Observational studies have not found that removing a pet from a home improves asthma control. Exposure to tobacco smoke in the home contributes to the severity of childhood asthma. Smoking cessation should be encouraged as it is good for general health and may decrease asthma severity. Parents who smoke should be advised about the dangers for themselves and their children and offered appropriate support to stop smoking. to date no controlled trials have addressed fungal exposure reduction and asthma. In a study in adults with cat sensitivity. lung function of bronchial reactivity. Cockroach allergy is not a common problem in some countries like UK. are a potent cause of asthma symptoms. randomisation to either bedroom air cleaner and covers for bedding or no active intervention with restriction of cats away from the bedroom. there is a suggestion that maintaining a high exposure to cat allergen in the domestic environment might actually induce some degree of tolerance. but important in some other areas. This showed a relative risk of 2. One small study suggests that by stopping smoking. Studies of interventions designed to reduce environment tobacco smoke exposure in the home have been largely ineffective in reducing the degree of exposure and none were designed with primarily clinical (as opposed to smoking outcomes. Many experts still feel that removal of pets from the home of individuals with asthma who also have an allergy to that pet should be recommended.260 Bronchial Asthma Other allergens Animal allergens. Air pollution There is evidence that changing from a high particulate sulphur dioxide (coal burning) environment to a low sulphur dioxide/high diesel particulate environment . Only one study was identified that examined the incidence of asthma related to taking up smoking. A US Institute of Medicine review identified a causal relationship between environmental tobacco smoke (ETS) exposure and exacerbations of asthma in pre-school children. There is a direct causal relationship between parental smoking and lower respiratory illness in children up to three years of age. Infants whose mothers smoke are four times more likely to develop wheezing illnesses in the first year of life. Average exposure is associated with a 30% increased risk of symptoms. particularly cat and dog. In one observational study giving up smoking in adults was associated with improved severity of asthma scores. parents decrease the severity of asthma in their children. Binding was a common problem. recognised in traditional Chinese medicine to be of benefit in asthma) or sham acupuncture (i. However. More rigorous research methodology and attention to outcomes other than lung function are required. and only achieved for those making the observations. Only seven trials (174 patients) achieved randomisation to active (i. Nine of the 17 trials reported some improvement in lung function. Seventeen trials were identified but the combined results are inconclusive. but this has not been formally tested. such as volatile organic compounds. The Cochrane review found no evidence for a clinically valuable benefit from acupuncture. No evidence was identified regarding asthma and indoor air pollutants. Air Ionisers Ionisers are widely advertised and marketed as being of benefit to patients with asthma. In the UK. Further research in this area is required. and could be incorporated into a coordinated allergen avoidance programme. there is no evidence that they are of value in ameliorating the symptoms of asthma or improving lung function.e. points with no recognised activity) for the treatment of persistent or chronic asthma.New Guidelines for Asthma Management (Non-pharmacological Management) 261 increases the incidence of asthma and atopy. There was wide inconsistency in methodology. but this is less in magnitude than that achieved by inhaled bronchodilators or cromones. Complementary and Alternative Medicine Herbal and Traditional Chinese Medicine Currently available evidence does not allow any firm judgment to be made on herbal remedies in general or individual preparations in particular. although the effects are minimal in comparison with factors such as infection. many differences between environments might explain the variation in asthma and allergy risk. The short-term fluctuations in levels of air pollution currently encountered in the UK may be responsible for small changes in numbers of hospital admissions and emergency attendances for asthma. however. The difficulty in making sham acupuncture convincing and part of the holistic approach of traditional Chinese medicine was emphasised. Time series studies suggest that air pollution may provoke acute asthma attacks or aggravate existing chronic asthma. but there is no firm epidemiological evidence that this has occurred in the UK or elsewhere. but it is not clear that the results reported would be generalised.e. asthma is more prevalent in 12-14 years olds in non-metropolitan rather than metropolitan areas. Demonstrating that this effect can be transferred to persistent asthma using regular treatment was achieved in one RCT reported in the Cochrane review. There is some laboratory evidence that various pollutants can enhance the response of patients with asthma to allergens. One study has raised concerns that ionisation may . with no statistically significant improvement in lung function being demonstrated. They do reduced mite allergen levels in the room in which they are used. formaldehyde or nitrogen oxides. Acute trials show that acupuncture has a beneficial effect. Acupuncture A Cochrane review of 21 trials raised many methodological concerns. oxygen consumption. maximum heart rate. No conclusions can be drawn on massage therapy. poorly reported. FVC or VEmax. Small study size limits the recommendations. A Cochrane review found no change in routine measures of lung function. in 55 children showing that family therapy may be a useful adjunct to medication in children with asthma. Physical Exercise Training A Cochrane review has shown no effect of physical training on PEF. Most studies discussed the potential problems of exercise-induced asthma. The two trials of chiropractice suggest that there is no place for this modality of treatment in the management of asthma. Homeopathy A Cochrane review identified only three methodologically sound randomised controlled trials. trial demonstrated an increase in lung function in patients receiving the active preparation. Hypnosis Studies of hypnosis in patients with asthma are generally poorly controlled and patient characteristics and outcome measured vary enormously. Breathing Exercise Including Yoga and Buteyko The underlying principle of Yoga and Buteyko is to reduce hyperventilation by lowering respiratory frequency. FEV1. At present it is not possible to make an evidence-based recommendation about breathing exercises for asthma. There is insufficient information regarding the value of homeopathy in the treatment of asthma. as there is no evidence of benefit and a suggestion of adverse effect. nut none made any observations on this phenomenon. Family Therapy A Cochrane review identified two trials. In the first trials (24 patients). homeopathy improved symptom scored and forced vital capacity (FVC) but had no effect on FEV1 or bronchial reactivity. The second study demonstrated improvements in both active and placebo groups. with appropriate precautions advised about exerciseinduced asthma. and two a reduced frequency of attacks. Large well designed trials using defined remedies and a spectrum of patients are warranted.262 Bronchial Asthma produce an increase in nocturnal cough. The third. . it should be seen as part of a general approach to improving lifestyle and rehabilitation in asthma. but more randomised and appropriately controlled studies are required. Manual Therapy including Massive and Spinal Manipulation A Cochrane review identified four relevant randomised controlled trials. However. and work capacity all increased significantly. The conclusions from a critical review were that hypnosis may be effective for asthma with the biggest effect in susceptible subjects. As physical training improves indices of cardiopulmonary efficiency. Two studies reported a reduction in use of medication. The use of ionisers cannot be encouraged. et al. Summary charts. 1-Chronic persistent asthma. 11. Statement by the British Thoracic Society. Management of Asthma: A consensus statement. British Paediatric Association. International Paediatric Asthma Consensus Group. 2-Acute severe asthma. Thorax 1993. 12. Guidelines for the Management of Asthma in Adults. The British Guidelines on Asthma Management.301:651-53. Royal College of Physicians of London. BMJ 1990. The King’s Fund Center. NIH Publication No. National Asthma Campaign. Controlled clinical studies in small numbers have on the whole been negative. Clin Exp Allergy 1992. British Thoracic Society.52(Suppl 1): S2-S8. Weight Reduction in Obese Patients with Asthma A small randomised parallel group study has shown improved asthma control following weight reduction in obese patients with asthma. King’s Fund Center. et al. REFERENCES 1. Fish Oils and Fatty Acids In vitro studies suggest that supplementing diet with the omega n-3 fatty acids found predominantly in fish oils might reduce the inflammation associated with asthma. Bethesda. British Thoracic Society. King’s Fund Center.306:77682. Royal College of Physicians of London. Guidelines for the management of asthma: A summary. 9. 1997. BMJ 1993. Research Unit of the Royal College of Physicians of London. Statement by the British Thoracic Society. 4. Guidelines on the management of asthma. 2. British Thoracic Society and others. The King’s Fund Center. 3. BMJ 1993. MD: National Institute of Health. British Paediatric Association. Arch Dis Child 1992. et al.64. 1995 Review and Position Statement. Guidelines for the Management of Asthma in Adults.67:240-48. a follow-up statement. Warner JO. with a Cochrane review concluding that there was little evidence to recommend fish oil supplements in asthma. An intervention study of magnesium supplementation has suggested a reduced rate of bronchial hyperresponsiveness and wheeze. National Asthma Education and Prevention Program.1995. National Asthma Campaign. A practical guide for public health officials and health care professionals. New British Guidelines on Management of Asthma.1065-79. Studies of sodium and antioxidant supplements such as selenium and vitamin C have produced little or no evidence of benefit amongst patients with asthma. Asthma.58(Suppl 1):1-94. 6. Thorax 1997. Global Initiative for Asthma.. Landau LI. National Asthma Campaign. Gotz M. 7.9:287-92. 5. Thorax 1993. .48:S1-S24. US Department of Health and human services. Expert Panel Report II: Guidelines for the diagnosis and management of asthma.96:3659A. 8. BMJ 1990. 10. Research Unit of the Royal College of Physicians of London. Arch Dis Child 1989. International consensus report on the diagnosis and management of asthma.301:797-800. National Asthma Campaign.22(Suppl):1-72.New Guidelines for Asthma Management (Non-pharmacological Management) 263 Dietary Manipulation Minerals Low magnesium intakes have been associated with higher prevalence of asthma. Miller J. SIGN. SIGN Publication No. 1996. SIGN Publication No. A new system for grading recommendations in evidence based guidelines. 16. Harbour R. SIGN. SIGN Publication No. Scottish Intercollegiate Guidelines Network (SIGN).264 Bronchial Asthma 13. Edinburgh. . 33. Scottish Intercollegiate Guidelines Network (SIGN). 38. 1998. 15. Scottish Intercollegiate Guidelines Network (SIGN). 14. 6. SIGN. Edinburgh.323:334-36. Edinburgh. BMJ 2001. Hospital inpatient management of acute asthma attack. Emergency management of acute asthma. Primary care management of asthma. 1999. New Guidelines for Asthma Management (Pharmacological Management) 265 17 New Guidelines for Asthma Management (Pharmacological Management) The aims of pharmacological management of asthma are: • The control of symptoms. The aim is to achieve early control and to maintain control by stepping up treatment as necessary and stepping down when control is good. inhaler technique and eliminate trigger factors. It is not appropriate to define a fixed level of lung function or symptom control which must be achieved. In general terms. including nocturnal symptoms and exercise-induced asthma • Prevention of exacerbations • Achievement of best possible pulmonary function • With minimal side effects. Adjustment may be necessary for fluticasone and/or other devices. Patients should start treatment at the step most appropriate to the initial severity of their asthma. as individual patients will have different goals and may also wish to balance these aims against the potential side effects or inconvenience of taking the medication necessary to achieve “perfect” control. STEP 1: MILD INTERMITTENT ASTHMA The following medicines act as short acting bronchodilators: • Inhaled short acting β2-agonists • Inhaled ipratropium bromide . All doses of inhaled steroids in this section refer to beclomethasone (BDP) given via a metered dose inhaler (pMDI). control of asthma is assessed against these standards: • Minimal symptoms during day and night • Minimal need for reliever medication • No exacerbations • No limitation of physical activity • Normal lung function (in practical terms FEV1 and/or PEF>80% predicted or best) A stepwise approach aims to abolish symptoms as soon as possible and to optimise peak flow by starting treatment at the level most likely to achieve this. Before initiating a new drug therapy practitioners should check compliance with existing therapies. but patients with lower inhaler requirements may also benefit. or • Use of inhaled β2-agonists more than once a day. treatments have been judged on their ability to improve symptoms. In adults. Starting Dose of Inhaled Steroids In mild to moderate asthma. The dose is to be titrated to the lowest dose at which effective control of asthma is maintained. starting at very high doses of inhaled steroids and stepping down confers no benefit. • Nocturnal asthma. STEP 2: INTRODUCTION OF REGULAR PREVENTER THERAPY For steps 2. Frequency of Dosing of Inhaled Short Acting β2-Agonists There is no consistent evidence of any benefit or harm from regular (four times daily) use of short acting β2-agonists compared with “as required” (sos) use. Using two or more canisters of β2-agonists per month or > 10-12 puffs per day is a marker of poorly controlled asthma. and prevent exacerbations. In children under 5 years of age. They are the recommended preventer drug for adults and children for achieving overall treatment goals. Start patients at a dose of inhaled steroids appropriate to the severity of disease. • Recent exacerbations. There is little evidence of benefit for dosage frequency more than twice daily. The threshold for introduction of inhaled steroids has never been firmly established. Initially. Unless individual patients are shown to benefit from regular use of inhaled short acting β2-agonists. a reasonable starting dose will usually be 400 μg per day and in children 200 μg per day. Inhaled steroids should be started for patients with.266 Bronchial Asthma • β2-agonist tablets or syrup • Theophyllines Short acting inhaled β2-agonists work more quickly and/or with fewer side effects than the alternative. Frequency of Dosing of Inhaled Steroids Current inhaled steroids are slightly more effective when taken twice rather than once daily. 3 and 4. improve lung function. then “as required” use is recommended. An inhaled short acting β2-agonist should be prescribed as short-term reliever therapy for all patients with symptomatic asthma. Patients with high usage of inhaled short acting β2-agonists should have their asthma management reviewed. Inhaled Steroids Inhaled steroids are the most effective preventer drug for adults and children for achieving overall treatment goals. . with an acceptable safety profile improvement of quality of life while important is the subject of two few studies to be used to make recommendations at present. higher doses may be required if there are problems in obtaining consistent drug delivery. • Impaired lung function. There is strong evidence that patients requiring short acting β2-agonists more than two to three times a day should be treated with inhaled steroids. Cross-sectional studies have shown possible dose related reduction in bone density. However. • Antihistamines and ketotifen are ineffective. All comparison used BDP-CFC (chlorofluoro-carbons) as the reference.New Guidelines for Asthma Management (Pharmacological Management) 267 the inhaled steroids are to be given twice daily. • Sodium cromoglycate is ineffective in children. Beclomethasone dipropionate (BDP) and budesonide are approximately equivalent in clinical practice although there may be variations with different delivery devices. Account should be taken of other topical steroid therapy when assessing systemic risk. The smallest dose of inhaled steroids required to maintain adequate asthma control must be used. • Long acting inhaled β2-agonists have some beneficial effects but they are not recommended as first line preventive therapy. The evidence that it causes fewer side effects at doses with equal clinical effect is limited. In view of the clear differences between normal volunteers and asthma patients in the absorption of inhaled steroids. Safety of Inhaled Steroids The safety of inhaled steroids is of crucial importance and a balance between benefits and risks for each individual needs to be assessed. • Nedocromil sodium is of benefit in 5-12 years old. less effective preventive therapies in patients taking short acting β2-agonists alone are: • Cromones (have an inconvenient dosing frequency). Non-blinded studies also has to be considered because of the problems of obtaining competitors’ delivery devices. and adrenal suppression. data from normal volunteers have not been taken into account. the possibility of long-term effects on bone has been raised. Other studies have shown effects on adrenocortical function of uncertain significance. at present a 1:1 ratio should be assumed when changing between BDP and budesonide. In children. The height of the children should be monitored on a regular basis. Fluticasone provides equal clinical activity to BDP and budesonide at half the dosage. Only studies in which more than one dose of at least one of the inhaled steroids or both safety and efficacy has been studied together in the same trial were evaluated. Comparison of Inhaled Steroids Many studies comparing different inhaled steroids are of inadequate design and have been omitted from further assessment. There is little evidence that doses below 800 μg day cause any short-term detrimental effects apart from the local side effects of dysphonia and oral candidiasis. However. Once a day inhaled steroids at the same total daily dose can be considered if good control is established. Other Preventive Therapies Inhaled steroids are the first choice preventive drugs. There is limited evidence from two open studies of less than ideal design that budesonide via the turbohaler is more clinically effective. The later may manifest as hypoglycaemic episodes. add-on therapy like long acting β2-agonists should be considered. Alternative. . inhaled stereoids of 400 μg day of beclomethasone dipropionate or equivalent may be associated with systemic side effects like growth retardation. • Leukotriene receptor antagonists have some beneficial effect (side effects are common and monitoring of plasma levels is required). At higher doses. If there is a response to LABA. one should carry out a trial of other treatment before increasing the inhaled steroid dose above 800 μg/day in adults and 400 μg/day in children. If. Many patients will benefit more from add-on therapy than from increasing inhaled steroids above doses as low as 200 μg/day. • Theophylline improves lung function and symptoms. the correct dose at which to add another therapy. no intervention has been consistently shown to decrease inhaled steroid requirement in a clinically significant manner compared to placebo. as may happen occasionally. . If there is no response to treatment the drug should be discontinued. inhaler technique and eliminate trigger factors. which improves lung function and symptoms. leukotriene receptor antagonists. The duration of a trial of add-on therapy will depend on the desired outcome.1. theophyllines. whereas preventing exacerbations of asthma or decreasing steroid tablet use may require a longer trial of therapy (weeks or months). but control remains poor. a decrease in exacerbations. and decreases exacerbation. at doses of inhaled steroid above 800 μg/day side effects become more frequent. one may consider a sequential trial of add-on therapy.268 Bronchial Asthma STEP 3: ADD-ON THERAPY Before initiating a new drug therapy one should recheck compliance. An absolute threshold for introduction of add-on therapy in all patients cannot be defined. preventing nocturnal awakening may require a relatively short trial of treatment (days or weeks). The addition of other treatment options to inhaled steroids has been investigated at doses from 200-1000 μg in adults and up to 400 μg in children. the LABA should be stopped and the dose of inhaled steroid to be increased to 800 μg/day (adults) or 400 μg/day (children) if not already on this dose. there is no response to inhaled long acting β2-agonist. Thus. but side effects occur more commonly. i. In patients on inhaled steroids whose asthma is stable.e. Furthermore. CRITERIA FOR INTRODUCTION OF ADD-ON THERAPY No exact dose of inhaled steroid can be determined. and an improvement in symptoms. Addition of cromones is of marginal benefit. First choice would be the addition of an inhaled long acting β2-agonists (LABA). If control is still inadequate after a trial of LABA and after increasing the dose of inhaled steroid. In adult patients taking inhaled steroids at doses of 200-800 μg/day and in children taking inhaled steroids at a dose of 400 μg/day the following interventions are of value. Addition of anticholinergics is generally of no value. but side effects occur more commonly. • Leukotriene receptor antagonists provide improvement in lung function. For instance. The first choice as add-on therapy to inhaled steroids in adults and children (5-12 years) is an inhaled long acting β2-agonists. Add-On Therapy Option for add-on therapy are summarised in Figure 17. • Slow release β2-agonists tablets also improve lung function and symptoms. slow release β2-agonist tablets in adults. one should continue with the LABA and increase the dose of inhaled steroid to 800 μg/day (adults) or 400 μg/day (children 5-12 years). 17. If control remains inadequate on 800 μg daily in adults and 400 μg/day in children. of an inhaled steroid plus a long acting agonist. usually a long acting β2-agonist. 5-12 years) If control still inadequate. (caution needs to be taken in patients on long acting β2-agonist) . the following interventions are to be considered: • Increase the inhaled steroids to 2000 μg/day in adults or 800 μg/day in children of 5-12 years of age. STEP 4: POOR CONTROL ON MODERATE DOSE OF INHALED STEROID + ADD-ON THERAPY: ADDITION OF FOURTH DRUG In a small proportion of patients asthma is not adequately controlled on a combination of as required short acting β2-agonist. inhaled steroid (800 μg/day).New Guidelines for Asthma Management (Pharmacological Management) 269 Inadequate control on lowdose inhaled steroids Add inhaled long-acting β2agonist (LABA) Assess control of asthma Good response to LABA and good control: • Continue LABA Benefit from LABA. β2-agonist. and an additional drug.1: Summary of step 3: add-on therapy Combination Inhalers There is no difference in efficacy in giving inhaled steroid and long acting β2-agonist in combination or in separate inhalers. but control still inadequate: • Continue LABA and • Increase inhaled steroid dose to 800 µg/day (adults) and 400 µg/ day (children. The following recommendations are based on extrapolation from trials of add-on therapy to inhaled steroids and on previous guidelines. go to step 4 No response to LABA: • Stop LABA • Increase inhaled steroid dose to 800 µg / day (adults) and 400 µg/day (children 5-12 years) Control still inadequate: Trial of other add-on therapy. • Leukotriene receptor antagonists • Theophyllines • Slow release β2-agonist tablets. There are very few clinical trials in this specific patient group to guide management. e. leukotriene receptor antagonist or theophylline If control still inadequate go to step 4 Fig.g. In children of aged 5-12 years.g. Before proceeding to step 5.g. Their risks and benefits should be discussed with the patient and their side effects carefully monitored.270 Bronchial Asthma There is no control trial indicating which of these is the best option. three to four per year) will be at risk of systemic side effects • Blood pressure should be monitored • Diabetes mellitus may occur • Osteoporosis commonly occurs and should be monitored and treated. cyclosporin and oral gold) may be given as a three month trial. Inhaled steroids are the most effective drug for decreasing requirement for long-term steroid tablets. There is no evidence of persisting beneficial effect after stopping them. STEP 5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS Prevention and Treatment of Steroid Tablet-induced Side Effects Patients on long-term steroid tablets (e. the drug is to be stopped. the dose is to be reduced to the original dose). once other drug treatments have proved unsuccessful. the recommended method of eliminating or reducing the dose of steroid tablets is inhaled steroids. theophyllines. They should be stopped if no improvement in steroid dose. or in case of increased dose of inhaled steroid. There is limited evidence for the ability of long acting β2-agonists. or leukotriene receptor antagonists to decrease the requirements for steroid tablets. especially children. Continuous subcutaneous terbutaline infusion has been reported to be beneficial in severe asthma but efficacy and safety have not been assessed in randomised controlled trials. There is a role for a trial of treatment in adults with long acting β2-agonists. cyclosporin and oral gold) decrease long-term steroid tablet requirements but all have significant side effects. Although popular in . In adults. to specialist care. • Growth should be monitored in children • Cataracts should be screened for in children Steroid Tablet—Starting Medication The aim of treatment is to control the asthma using the lowest possible dose. leukotriene receptor antagonists. Immunosuppressants (methotrexate. Steroid Formulations Prednisolone is the most widely used steroid for maintenance therapy in chronic asthma. symptoms or lung function is detected. doses above 1000 μg/day should be added cautiously. Treatment should be in a center with experience of using these medicine. Immunosuppressants (methotrexate. longer than three months) or requiring frequent courses of steroid tablets (e. but they may improve symptoms and pulmonary function. and there is marked variability in response. or if possible. If a trial of an add-on treatment is ineffective. at doses of up to 2000 μg/day if required. to stop long-term steroid tablets completely. Colchicine and intravenous immunoglobulin have not been shown to have any beneficial effect in adults. and theophyllines for about six weeks. the physician should consider referring the patient with inadequately controlled asthma. There is no evidence that other formulations offer any advantage. doubling the dose at the time of an exacerbation is of unproven value. decreasing the dose by approximately 25-50% each time. Regular review of patients as treatment is stepped down is important. The following medicines give protection against exercise-induced asthma: • Inhaled steroids • Short acting β2-agonists • Long acting β2-agonists • Theophyllines • Leukotriene receptor antagonists • Cromones • β2-agonist tablets The following medicines do not give protection against exercise-induced asthma at normal doses: • Anticholinergics • Ketotifen • Antihistamines Long acting β2-agonists and leukotriene antagonists provide more prolonged protection . the severity of asthma. there are no studies to show whether alternate day steroids produce fewer side effects than daily steroids. Reductions should be considered every three months. In adult patients on a low dose (220 μg) of inhaled steroids. the side effects of the treatment. When deciding which drug to step down first and at what rate. but often not implemented leaving some patients over treated. the beneficial effect achieved. including eye drops. There is little evidence regarding the most appropriate way to step down treatment. recommended for both adults and children in previous guidelines and as part of asthma action plants.New Guidelines for Asthma Management (Pharmacological Management) 271 paediatric practice. Exercise-induced Asthma For most patients exercise-induced asthma is an expression of poorly controlled asthma and regular treatment including inhaled steroids should be reviewed. Stepping Down Stepping down treatment once asthma is controlled is recommended. Patients should be maintained at the lowest possible dose of inhaled steroid. SPECIFIC MANAGEMENT PROBLEMS Onset of Exacerbation Asthma Although. β-Blockers β-blockers. Reduction in inhaled steroid dose should be slow as patients deteriorate at different rates. a five-fold increase in dose at the time of exacerbation leads to a decrease in the severity of exacerbations. are contraindicated in patients with asthma. This five-fold increase should not be extrapolated to higher doses of inhaled steroids. and the patient’s preference should all be taken into account. inhaled short acting β2-agonists are the drug of choice.272 Bronchial Asthma than short acting β2-agonists. is recommended. Tiotropium Bromide Tiotropium bromide is a once daily long acting anticholinergic agent. Allergic Bronchopulmonary Aspergillosis In adult patients with allergic bronchopulmonary aspergillosis (ABPA). Its value in the treatment of asthma has not been evaluated. the following therapies are to be considered: • Leukotriene receptor antagonists • Long acting β2-agonists • Cromones ` • Oral β2-agonists • Theophyllines Immediately before exercise. apart from the rigorous avoidance of non-steroidal antiinflammatory medications. Aspirin Intolerant Asthma There are theoretical reasons to suggest that leukotriene receptor antagonists might be of particular value in the treatment of aspirin intolerant asthma. No tolerance has been demonstrated with leukotriene receptor antagonists. However. Rhinitis Patients with asthma often have rhinitis. but a degree of tolerance develops with LABA particularly with respect to duration of action. there is little evidence to justify managing patients with aspirin intolerant asthma in a different manner to patients tolerant of aspirin. Treatment of allergic rhinitis has not been shown to improve asthma control. particularly hepatic dysfunction. NOVEL THERAPIES Anti-IgE Monoclonal Antibody In highly selected patients an anti-IgE monoclonal antibody has some beneficial effect. a four-month trial of itraconazole should be considered. If exercise is a specific problem in patients taking inhaled steroids who are otherwise well controlled. Careful monitoring of side effects. In adult patients with ABPA. At present this drug does not have a license in many countries. but its role in the stepwise treatment of asthma is unclear. The relative safety of mometasone is not fully established. Mometasone Mometasone is a new inhaled steroid and the relatively limited number of studies suggests it is equivalent to twice the dose of BDP-CFC. . The most effective therapy is intranasal steroids. itraconazole may decrease steroid tablet dose and improve asthma control. g. 400 μg /day is an appropriate starting dose in many patients Start at dose of inhaled steroids appropriate to severity STEP1: MILD INTERMITTENT ASTHMA Inhaled short acting β2-agonist as required Inhaled steroids indicate beclomethasone dipropionate or equivalent Step care management of bronchial asthma in adults. e. leukotriene receptor antagonist. .g. 2. institute trial of other therapies. SR theophylline. β2-agonist tablet STEP3: 1.New Guidelines for Asthma Management (Pharmacological Management) 273 STEP5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS Use daily steroid tablet in lowest dose providing adequate control • Maintain high dose inhaled steroid of 2000 μg /day • Consider other treatments to minimize the use of steroid tablets STEP4: PERSISTENT POOR CONTROL Consider trials of: • Increasing inhaled steroid up to 2000 µg/ day • Addition of a fourth drug. e. leukotriene receptor antagonist or SR theophylline STEP2: REGULAR PREVENTER THERAPY Add inhaled steroid 200-800 μg /day . • • • ADD-ON THERAPY Add inhaled long acting β2-agonist (LABA) Assess control of asthma: Good response to LABA – continue LABA Benefit from LABA but control still inadequate – continue LABA and increase inhaled steroid dose to 800 μg /day (if not already on this dose) No response to LABA-stop LABA and increase inhaled steroid to 800 μg /day if control still inadequate. (Other preventer drugs if inhaled steroid cannot be used) 200 µg/day is an appropriate starting dose in many patients Start at dose of inhaled steroids appropriate to severity STEP1: MILD INTERMITENT ASTHMA Inhaled short acting β2-agonist as required Inhaled steroids indicate beclomethasone dipropionate or equivalent Step care management of bronchial asthma in children. • • • ADD-ON THERAPY Add inhaled long acting β2-agonist (LABA) Assess control of asthma: Good response to LABA—Continue LABA Benefit from LABA but control still inadequate – continue LABA and increase inhaled steroid dose to 400 μg /day (if not already on this dose) No response to LABA-stop LABA and increase inhaled steroid to 400 μg /day if control still inadequate.g. . leukotriene receptor antagonist or SR theophylline STEP2: REGULAR PREVENTER THERAPY Add inhaled steroid 200-400 μg /day . 2. e. institute trial of other therapies.274 Bronchial Asthma STEP5: CONTINUOUS OR FREQUENT USE OF ORAL STEROIDS Use daily steroid tablet in lowest dose providing adequate control • Maintain high dose inhaled steroid of 800 μg /day • Refer patient for specialist care STEP4: PERSISTENT POOR CONTROL Consider trials of: • Increase inhaled steroid up to 800 µg/ day STEP3: 1. aged 5-12 years. Step care management of bronchial asthma in children less than 5 years.New Guidelines for Asthma Management (Pharmacological Management) 275 STEP4: PERSISTENT POOR CONTROL • Refer to Paediatrician with respiratory specialization STEP 3: ADD-ON THERAPY In children aged 2-5 years consider trial of leukotriene receptor antagonist In children under 2 years consider proceeding to Step 4. . or Leukotriene receptor antagonist if inhaled steroid cannot be used Start at dose of inhaled steroids appropriate to severity STEP 1: MILD INTERMITTENT ASTHMA Inhaled short acting β2-agonist as required Inhaled steroids indicate beclomethasone dipropionate or equivalent. Higher nominal doses may be required if drug delivery is difficult. STEP 2: REGULAR PREVENTER THERAPY Add inhaled steroid 200-400 µg/day . A small proportion of patients with asthma were sensitive to nonsteroidal anti-inflammatory agents. Deaths have continued to be reported following inappropriate prescription of β-blocker therapy or heavy sedation.276 Bronchial Asthma 18 New Guidelines for Asthma Management (Acute Asthma) Confidential enquires into over 200 asthma deaths in the UK have concluded that three important factors associated with the disease—the medical management and the patient’s behaviour or psychosocial status-contributed to the death. Medical Management Many of the deaths occurred in patients who had received inadequate treatment with inhaled steroid or steroid tablets and/or inadequate objective monitoring of their asthma. There was widespread underuse of written management plans. Most deaths occurred before admission to hospital. previous ventilation or respiratory acidosis • Previous admission for asthma especially if in the last year • Requiring three or more classes of asthma medication . e. Heavy or increasing use of β2-agonist therapy was associated with asthma death. A combination of severe asthma: • Previous near fatal asthma. Disease Factors Most patients who died of asthma had chronically severe asthma. In a minority the fatal attack occurred suddenly in a patient with only mild or moderately severe background disease. Follow up was inadequate in some and others should have been referred earlier for specialist advice. all asthma patients should be asked about past reactions to these agents. Adverse Psychosocial and Behavioural Factors Behavioural and adverse psychosocial factors were recorded in the majority of patients who died of asthma.g. The most important are: I. Compared with control patients with asthma in the community. financial or employment problems. are significantly more likely to have had a previous near fatal asthma attack. and more likely to have ready access to acute medical care. repeatedly failed to attend appointments or discharged themselves from hospital. For those with near fatal asthma. and noncompliance. those with near fatal asthma are significantly younger. poor medical management. In the UK there is a peak of asthma deaths in young people (aged up to 44 years) in July and August and. are less likely to experience delay in receiving medical care. more likelihood or a previous near fatal attack. obesity. and similar seasonal deaths might also be true for other countries. or a previous near fatal attack. failure to measure pulmonary function. Patients who have had near fatal asthma or brittle asthma should be kept under specialise supervision indefinitely. psychosis or prescribed antipsychotic drugs. more likelihood or a hospital admission or visit to emergency department for their asthma in the previous year. Not all patients with near fatal asthma require intermittent positive pressure ventilation. in December and January in older people. are less likely to have concurrent medical conditions. those who died were significantly more likely to have learning difficulties. and that these contribute to the near fatal asthma attack. it is always wise to involve a close relative when discussing future management. Compared with patients who die. . patients who died had more severe disease. marital or legal stress Case control studies support most of these observations. Patients with brittle asthma should also be identified. Studies comparing near fatal asthma with deaths from asthma have concluded that patients with near fatal asthma have identical adverse factors to those described above.New Guidelines for Asthma Management (Acute Asthma) 277 • Heavy use of β2-agonist • Repeated attendances at emergency for asthma care especially in the last year • Brittle asthma. II Adverse behavioural or psychological features: • Non-compliance with treatment or monitoring • Failure to attend appointments • Self-discharge from hospital • Psychosis. drug or alcohol abuse. adults as well as children. Compared with control patients admitted to hospital with asthma. depression. Health care professionals must be aware that patients with severe asthma and one or more adverse psychosocial factors are at risk of death. other psychiatric illness or deliberate self-harm • Current or recent major tranquilliser use • Denial • Alcohol or drug abuse • Obesity • Learning difficulties • Employment problems • Income problems • Social isolation • Childhood abuse • Severe domestic. 0 kPa) • Exhaustion • Silent chest • Confusion • Cyanosis • Coma • Feeble respiratory effort Acute severe asthma Any one of • PEF 33-50% best or predicted • Respiratory rate > 25/min • Heart rate > 100/min • Inability to complete sentences in one breath Moderate asthma exacerbation • Increasing symptoms • PEF >50-75% best or predicted • No features of acute severe asthma Brittle asthma • Type 1: Wide PEF variability (> 40% diurnal variation for 50% of the time over a period > 150 days) despite intense therapy • Type 2: Sudden severe attacks on a background of apparently well controlled asthma. over 80% developed over more than 48 hours.6-6. In one study.278 Bronchial Asthma PREDICTION AND PREVENTION OF A SEVERE ASTHMA ATTACK Most (88-92%) attacks of asthma severe enough to require hospital admission develop relatively slowly over a period of six hours or more. They should know when and how to increase their medication and when . A respiratory specialist should follow up patients admitted with severe asthma for at least one year after the admission. Self Treatment by Patients Developing Acute or Uncontrolled Asthma Many patients with asthma and all patients with severe asthma should have an agreed written action plan and their own peak flow meter. ACUTE ASTHMA IN ADULTS Recognition of Acute Asthma Definitions of increasing levels of severity of acute asthma exacerbations are as follows: Near fatal asthma Raised PaCO2 and/or requiring mechanical ventilation with raised inflation pressures Life threatening asthma Any one of the following in a patients with severe asthma: • PEF<33% best or predicted • Bradycardia • SpO2<92% • Dysrhythmia • PaO2<60 mmHg • Hypotension • Normal PaCO2 (4. There are many similarities between patients who die from asthma. patients with near fatal asthma and asthmatic controls who are admitted to hospital. Predicted PEF values should be used only if the recent best PEF (within two years) is unknown. with regular checks of inhaler technique and compliance. I. There should therefore be time for effective action and the potential to reduce the number of attacks requiring hospitalisation. Systolic paradox (pulsus paradoxus) has been abandoned as an indicator of the severity of an attack for pragmatic reasons. cyanosis or collapse.g. Where possible the same or similar type of peak flow meter should be used. PEF or FEV1 are both useful and valid measures of airway caliber PEF is more convenient and cheaper. None of these singly or together is specific and their absence does not exclude a severe attack PEF or FEV1 Measurements of airway caliber improve recognition of the degree Or severity. PEF as a percentage of predicted gives a rough guide in the absence of a known previous best value. should be aware that asthma patients complaining of respiratory symptoms may be at risk and should have immediate access to a doctor or trained asthma nurse. the appropriateness or intensity of therapy. Chest X-ray Chest X-ray is not routinely recommended in patients in the absence of: • Suspected pneumomediastinum or pneumothorax • Suspected consolidation • Life threatening asthma • Failure to respond to treatment satisfactorily • Requirement for ventilation. the severity of the attack and the nature of treatment required are detailed above as well as follows: It may also be helpful to use a systematic recording process. e. Initial Assessment All possible initial contact personnel. tachycardia. and decisions about management in hospital or at home. symptoms and respiratory and cardiovascular signs are helpful in recognising some patients with severe asthma. Pulse oximetry Measurement of oxygen saturation (SpO2) with a pulse oxymeter is necessary in acute severe asthma to determine the adequacy of oxygen therapy and the need for arterial blood gas (ABG) measurement. Proformas have proved useful in the emergency settings. Blood gases (ABG) Patients with SpO2<92% or other features of the threatening asthma require ABG measurement. silent chest. PEF expressed as a percentage of the patient’s previous best value is more useful clinically. Different peak flow meters give different readings. The aim of oxygen therapy is to maintain SpO2 > 92%. The assessments required to determine whether the patients is suffering from an acute attack of asthma. tachypnea. Systolic paradox . Clinical features Clinical features. Asthma action plans have been shown to decrease hospitalisation for and deaths from asthma. severe breathlessness (including too breathless to complete sentences in one breath).New Guidelines for Asthma Management (Acute Asthma) 279 to seek medical assistance. Criteria for Admission One should refer to a hospital if one comes across any patients with features of acute severe or life threatening asthma. Criteria for Admission Patients with any feature of a life threatening or near fatal attack should be admitted. Treatment of Acute Asthma in Adults Oxygen Patients with acute severe asthma are hypoxaemic. Other factors.280 Bronchial Asthma Prevention of Acute Deterioration A register of patients at risk may help primary care health professionals to identify patients who are more likely to die from their asthma. social circumstances or concomitant disease. A system should be in place to ensure that these patients are contacted if they fail to attend for follow up. In view of the theoretical risk of oxygen desaturaion while using air driven compressors to nebulise β2-agonist bronchodilators. This should be corrected urgently using high concentrations of inspired oxygen (usually 40-60%) and a high flow mask such as a Hudson mask. Oxygen saturations of at least 92% must be achieved. Hypercapnia indicates the development of near fatal asthma and the need for emergency specialist/anaesthetic intervention. Outside hospital. unless they meet any of the following criteria. ambulances and primary care. nebulised β2-agonist bronchodilators should be driven by oxygen. Also patients with any feature of a severe attack persisting after initial treatment need to be admitted. (in order to generate the flow rate of 61/min required to drive most nebulisers. In hospital. Unlike patients with COPD there is little danger of precipitating hypercapnia with high flow oxygen. high dose β2-agonist bronchodilators may be delivered via large . a high flow regulator must be fitted to the oxygen cylinder). when admission may be appropriate: • Still have significant symptoms • Concerns about compliance • Living alone/socially isolated • Psychological problems • Physical disability or learning difficulties • Previous near fatal or brittle asthma • Exacerbation despite adequate dose steroid tablets pre-presentation • Presentation at night • Pregnancy Criteria for admission in adults are summarised subsequently. ambulance and primary care. Patients whose peak flow is greater than 75% best or predicted one hour after initial treatment may be discharged from emergency. such as failure to respond to treatment. The absence of supplemental oxygen should not prevent nebulised therapy from being administered where appropriate. may warrant hospital referral. oxygen-driven nebulisers are the preferred method of delivery in hospitals. There is no evidence for any difference in efficacy between salbutamol and terbutaline. Higher bolus doses. 10 mg of salbutamol. In acute asthma with life threatening features the nebulised route (oxygen-driven) is recommended. inhaled β2-agonist given in high doses act quickly to relieve bronchospasm with few side effects. β2-agonist can be administered by repeated activations of a pMDI via an appropriate large volume spacer or by wet nebulisation driven by oxygen. relapses. Whilst supplemental oxygen is recommended. Inhaled β2-agonist are at least as efficacious and preferable to intravenous β2-agonist (meta-analysis has excluded subcutaneous trials) in adult acute asthma in the majority of cases. Following recovery from the acute exacerbation steroid tablets can be stopped abruptly and doses do not need tapering provided the patient receives inhaled steroids (apart from patients on maintenance steroid treatment or rare instances where steroids are required for three or more weeks). if available.New Guidelines for Asthma Management (Acute Asthma) 281 volume spacers or nebulisers.g. however there is limited evidence to support this. Continuous nebulisation of β2-agonist is at least as efficacious as bolus nebulisation in relieving acute asthma. subsequent hospital admission and requirement for β2-agonist therapy. continuous nebulisation may be considered. although rarely patients may express a preference. Inhaled steroids do not provide benefit in addition to the initial . in addition to inhaled β2-agonist may have a role in ventilated patients or those patient in extremes in whom nebulised therapy may fail. are unlikely to be more effective. In acute asthma without life threatening features. its absence should not prevent nebulised therapy being given if indicated. The earlier they are given in the acute attack the better the outcome. β2-Agonist Bronchodilators In most cases of acute asthma. Doses of prednisolone of 40-50 mg daily or parenteral hydrocortisone 400 mg daily (100 mg sixhourly) are as effective as higher doses. The duration of prednisolone 40-50 mg daily is for at least five days or until recovery. Most cases of acute asthma will respond adequately to bolus nebulisation of β2-agonist. Intravenous β2-agonist should be reserved for those patients in whom inhaled therapy cannot be used reliably. steroid tablets may be given as 2 × 25 mg tablets daily rather than 8-12 × 5 mg tablets. Steroid Therapy Steroid tablets reduce mortality. Steroid tablets are as effective as injected steroids. There is no evidence to suggest that inhaled steroids should be substituted for steroid tablets in the treatment of patients with acute severe. or life threatening asthma. Further randomised controlled trials to determine the role of inhaled steroids in these patients are required. provided tablets can be swallowed and retained. High-dose inhaled β2-agonist are to be used as first line agents in acute asthma and should be administered as early as possible. Steroid tablets are to be given in adequate doses in all cases of acute asthma. Repeated doses of β2-agonist should be given at 15-30 minute intervals or continuous nebulisation of salbutamol at 5-10mg/hour (requires appropriate nebuliser) used if there is an inadequate response to initial treatment. For convenience. Parenteral β2-agonists. e. In severe asthma (PEF or FEV1 <50% best or predicted) and asthma that is poorly responsive to an initial bolus dose of β2-agonist. Side effects such as palpitations.5 mg 4-6 hourly) should be added to β2-agonist treatment for patients with acute severe or life threatening asthma or those with a poor initial response to β2-agonist therapy.5-0. Such patients are probably rare and could not be identified in a meta-analysis of trials involving 739 subjects. arrhythmias and vomiting are increased if IV aminophyline is used. Leukotriene Receptor Antagonists There is no published study of the use of leukotriene receptor antagonists in the management of acute asthma. Intravenous Aminophylline In acute asthma. . Anticholinergic treatment is not necessary and may not be beneficial in milder exacerbations of asthma or after stabilisation. Levels should be checked daily for all patients on aminophylline infusions.2. Nebulised ipratropium bromide (0. The safety and efficacy of repeated doses have not been assessed in patients with asthma. then infusion of 0.282 Bronchial Asthma treatment. leading to a faster recovery and shorter duration of admission.2g IV infusion over 20 minutes) should only be used following consultation with senior medical staff. on oral aminophylline or theophylline. Intravenous aminophylline is to be used only after consultation with senior medical staff. Indications of giving a single dose of IV magnesium sulphate for patients are: • Acute severe asthma who have not had a good initial response to inhaled bronchodilator therapy • Life threatening or near fatal asthma IV magnesium sulphate (1. If IV aminophylline is given to patients. Intravenous Magnesium Sulphate A single dose of IV magnesium sulphate has been shown to be safe and effective in acute severe asthma. Repeated doses could give rise to hypermagnesaemia with muscle weakness and respiratory failure. More studies are needed to determine the optimal frequency and dose of IV magnesium sulphate therapy. Some individual patients with near fatal asthma or life threatening asthma with a poor response to initial therapy may gain additional benefit from IV aminophylline (5mg/kg loading dose over 20 minutes unless on maintenance oral therapy. blood levels should be checked on admission. the use of intravenous aminophylline is not likely to result in any additional bronchodilation compared to standard care with inhaled bronchodilators and steroid tablets. Ipratropium Bromide Combining nebulised ipratropium bromide with a nebulised β2-agonist has been shown to produce significantly greater bronchodilation that a β2-agonist alone. but should be continued (or started as soon as possible) to form the start of the chronic asthma management plan.7 mg/kg/h). Referral to Intensive Care Indications for admission to intensive care facilities or a high dependency unit include patients requiring ventilatory support and those with severe acute or life threatening asthma who are failing to respond to therapy. Future studies might usefully examine its role in the gradually training patient. Heliox The use of heliox (Helium/oxygen mixture in a ratio of 80:20 or 70:30) in acute adult asthma cannot be recommended on the basis of present evidence. . The role of bacterial infection has been overestimated. Routine prescription of antibiotics is not indicated for acute asthma. feeble respiration • Drowsiness. It is unlikely the NIV would ever replace intubation in these very unstable patients but it has been suggested that this treatment can be used safely and effectively. as evidenced by: • Deteriorating PEF • Persisting or worsening hypoxia • Hypercapnea • Arterial blood gas analysis showing fail in pH or rising H+ concentration • Exhaustion. Some patients with acute asthma require rehydration and correction of electrolyte imbalance. Hypercapneic respiratory failure developing during the evolution of an acute asthmatic episode is regarded as an indication for urgent admission to the ICU. All patients transferred to intensive care units should be accompanied by a doctor suitably equipped and skilled to intubate if necessary. but those with worsening hypoxia or hypercapnea. Intravenous Fluids There are no controlled trials or even observational or cohort studies of differing fluid regimes in acute asthma. Intubation in such patients is very difficult and should ideally be performed by an anaesthetist or ICU consultant. Hypokalaemia can be caused or exacerbated by β2-agonist and/or steroid treatment must be corrected. confusion • Coma or respiratory arrest Not all patients admitted to the Intensive Care Unit (ICU) need ventilation. it is likely to be viral in type. but at present this treatment cannot be recommended outside randomised controlled trials. drowsiness or unconsciousness and those who have had a respiratory arrest require intermittent positive pressure ventilation.New Guidelines for Asthma Management (Acute Asthma) 283 Antibiotics When an infection precipitates an exacerbation of asthma. Non-invasive Ventilation Non-invasive ventilation (NIV) is now well established in the management of ventilatory failure caused by extrapulmonary restrictive conditions and exacerbations of COPD. a proportion of patients reattend emergency departments. Recording of oxygen saturation by oximetry and maintaining arterial SaO2 >92% is very helpful. be on medical therapy they can continue safely at home. with a written PEF and symptom based action plan being provided allowing the patient to adjust their therapy within recommendations. but many delay seeking help. • Measure serum potassium and blood concentrations. There is some experience of a discrete population of patients who inappropriately use emergency departments rather than the primary care services for their asthma care. Prior to discharge. Some repeat attendees need emergency care. This should include education on inhaler technique and PEF record keeping . Asthma Management Protocols and Proformas The use of structured proformas has been shown to facilitate improvements in the process of case in emergency departments and hospital wards and to improve patient outcomes. Patients should have clinical signs compatible with home management. For these groups there is a role for a trained asthma liaison nurse based in. Patient Education Following discharge from hospital or emergency departments. Measurement and recording of PEF before and after nebulised or inhaled β2-agonist bronchodilator (at least four times daily) throughout the hospital stay and until controlled after discharge is quite helpful. or associated with the emergency department. . The use of this type of documentation can assist data collection aimed at determining quality of care and outcomes. • Measure and record the heart rate. trained staff should give asthma education. and thereafter according to the response is necessary. Although diurnal variability of PEF is not always present during an exacerbation. evidence suggests that patients discharged with PEF<75% best or predicted and with diurnal variability >25% are at greater risk of early relapse and readmission. or • The patient’s condition deteriorates One should ensure them again if the patient’s condition has not improved by 4-6 hours. These measures have been shown to reduce morbidity after the exacerbation and reduce relapse rates. • Measure the serum theophylline concentration if aminophylline is continued for more than 24 hours (aim at a concentration of 55-110 μmol/l. Hospital Discharge and Follow-Up Timing of Dsicharge There is no single physiological parameter that defines absolutely the timing of discharge form an admission with acute asthma. or • The initial PaCO2 is normal or raised.284 Bronchial Asthma Further Investigation and Monitoring Measurement and recording of PEF 15-30 minutes after starting treatment. and are under-treated and/or under-monitored. with more than 15% re-attending within two weeks. Repeat measurements of blood gas tensions within two hours of starting treatment is indicated if: • The initial PaO2 is < 8 kPa unless SaO2 is >92%. New Guidelines for Asthma Management (Acute Asthma) 285 Follow-Up A careful history should elicit the reasons for the exacerbation and explore possible actions. • Respiratory rate and degree of breathlessness (i. Low oxygen saturations after initial bronchodilator treatment selects a more severe group of patients. Objective measurements of PEF and SpO2 are essential. too breathless to complete sentences in one breath or to feed). optimising treatment and preventing delay in seeking assistance in the future. The following clinical signs should be recorded: • Pulse rate (increasing tachycardia generally denotes worsening asthma. and the patient provided with an asthma action plan aimed at preventing relapse. and with a hospital specialist asthma nurse or respiratory physician at about one month after admission. the patient should take to prevent future emergency presentations. Clinical signs correlate poorly with the severity of airways obstruction. it is essential to assess accurately the severity of their symptoms. Some children with acute severe asthma do not appear distressed. Ideally this communication should be directly with a named individual responsible for asthma care within the practice. Medication should be altered depending upon the assessment. ACUTE ASTHMA IN CHILDREN AGED OVER 2 YEARS Initial Assessment The details of criteria for assessment of severity of acute asthma attacks in children are: Acute severe Can’t complete sentences in one breath Or too breathless to talk or feed Life threatening Silent Chest Cyanosis Poor respiratory effort Hypotension Respiration >30 breaths/min aged>5 yrs Exhaustion >50 breaths/min aged 2-5 yrs Confusion Coma Before children can receive appropriate treatment for acute asthma in any setting. • Degree of agitation and conscious level (always give calm reassurance). Pulse >120 in children aged > 5 years >130 in children aged 2-5 years . a fall in heart rate in life threatening asthma is a pre-terminal event). Suitable equipment should be available for use by all health professionals assessing acute asthma in both primary and secondary care settings. Follow-up should be arranged prior to discharge with the patient’s general practitioner or asthma nurse within two working days. It is essential that the patient’s primary care practice is informed within 24 hours of discharge from emergency or hospital following an asthma exacerbation treated in hospital.e. • Use of accessory muscles of respiration (best noted by palpation of neck muscles) • Amount of wheesing (which might become biphasic or less apparent with increasing airways obstruction). Intensive inpatient treatment for children with SpO2 <92% on air after initial bronchodilator treatment should be considered. by means or fax or e-mail. A measurement of <50% predicted PEF or FEV1 with poor improvement after initial bronchodilator treatment is predictive of more prolonged asthma attack. An assessment driven algorithm has been shown to reduce treatment costs and hospital stay. Children with severe or life threatening asthma should be transferred urgently to hospital to receive frequent doses of nebulised β2-agonist (2.5-5 mg albuterol or 5-10 mg terbutaline).286 Bronchial Asthma Decisions about admission should be made by trained physicians after repeated assessment of the response to further bronchodilator treatment. The use of proformas can increase the accuracy of severity assessment. whilst awaiting transfer. Frequent doses of β2-agonist are safe for the treatment of acute asthma. Chest X-rays and ABG measurements rarely provide additional useful information and are not routinely indicated. TREATMENT OF ACUTE ASTHMA IN CHILDREN AGED OVER 2 YEARS Emergency units attending to children with acute asthma should have a registered sick children’s nurse available on duty at all times and staff familiar with the specific needs of children. The use of structured care protocols detailing bronchodilator usage. pMDI+ spacer are the preferred option in mild to moderate asthma. pMDI + spacer is an effective alternative to nebulisers for bronchodilator inhalation to treat mild to moderate asthma. Children receiving β2-agonist via pMDI+ spacer are less likely to have tachycardia and hypoxia than when the same drug is given via a nebuliser. Further doses of bronchodilator should be given as necessary. Oxygen Children with life threatening asthma or SpO2 < 92% should receive high flow oxygen via a tight fitting face mask or nasal cannula at sufficient flow rates to achieve normal saturations. Inhalers should be actuated into the spacer in individuals puffs and inhaled immediately by tidal breathing. Drug dosing is to be individualised according to severity and adjust according to the patient’s response. ideally expressed as percentage of personal best for PEF (as detailed in a written action plan) or alternatively as percentage of predicted for PEF or FEV1. omits. Continuous nebulised β2-agonist are of no greater benefit than the use of frequent intermittent doses in the same total hourly dosage. although children with mild symptoms benefit from lower doses. taking the best of three measurements. β2-Agonist Bronchodilators Inhaled β2-agonist are the first line treatment for acute asthma. clinical assessment. An attempt has to be made to measure PEF or FEV1 in all children aged >5 years. Doses can be repeated every 20-30. Children aged < 3 years are likely to require a face mask connected to the mouthpiece of a spacer for successful drug delivery. Children with acute asthma in primary care show have not improved after receiving up to 10 puffs of β2-agonist should be referred to hospital. . Two to four puffs repeated every 20-30 minutes according to clinical response might be sufficient for mild attacks although up to 10 puffs might be needed for more severe asthma. Treatment of children should be given before they are transported to hospital by ambulance with oxygen and nebulised β2-agonist during the journey. and specific criteria for safe discharge is recommended. Information about implementing evidence-based guidelines using such devices has been published. Those already receiving maintenance steroid tablets should receive 2 mg/kg prednisolone up to a maximum dose of 60 mg. Larger doses do not appear to offer a therapeutic advantage for the majority of children. Benefits are more apparent in the most severe patients. Continuous intravenous infusion should be considered when there is uncertainty about reliable inhalation or for severe refractory asthma. There is no evidence that increasing the dose of inhaled steroids is effective in treating acute symptoms. Children with chronic asthma not receiving regular preventive treatment will benefit from initiating inhaled steroids as part of their long-term management. Steroid Therapy Steroid Tablets The early use of steroids for acute asthma can reduce the need for hospital admission and prevent a relapse in symptoms after initial presentation. The early addition of a bolus dose of intravenous salbutamol (15 μg/kg) can be an effective adjunct to treatment in severe cases.New Guidelines for Asthma Management (Acute Asthma) 287 IV Salbutamol The role of intravenous β2-agonist in addition to nebulised treatment remains unclear. add ipratropium bromide (250 mg/dose mixed with the nebulised β2-agonist . One need not initiate inhaled steroids in preference to steroid tablets to treat acute childhood asthma. Intravenous hydrocortisone (4 mg/kg repeated four hourly) should be reserved for severely affected children who are unable to retain oral medication. but it is good practice for children already receiving inhaled steroids to continue with their usual maintenance doses. Ipratropium Bromide There is good evidence for the safety and efficacy of frequent doses of ipratropium bromide used in addition to β2-agonist for the first two hours of a severe asthma attack. ingested medication should be considered. The dose is 20 mg for children 2-5 years old and 30-40 mg for children > 5 years. Inhaled Steroids There is insufficient evidence to support the use of inhaled steroids as alternative or additional treatment to steroid tablets for acute asthma. Benefits can be apparent within three to four hours. A soluble preparation dissolved in a spoonful of water is preferable in those unable to swallow tablets. A dose of 20 mg prednisolone for children aged 2-5 years and a dose of 30-40 mg for children > 5 years is appropriate. Prednisolone is to be given early in the treatment of acute asthma attacks. One study has shown that an IV bolus of salbutamol given in addition to near maximal doses of nebulised salbutamol results in clinically significant benefits. The dose of prednisolone in children who vomit may be repeated and intravenous steroids in those who are unable to retain orally. Oral and intravenous steroids are of similar efficacy. If symptoms are refractory to initial β2-agonist treatment. There is no need to taper the dose of steroid tablets at the end of treatment. Doses above 1-2 μg/kg/min (200 μg/ml solution) should be given in a Paediatric intensive Care Unit (PICU) setting (up to 5 μg/kg/min) with regular monitoring of electrolytes. Treatment for up to three days is usually sufficient but the length of course should be tailored to the number of days necessary to bring about recovery. but the majority of acute asthma attacks are triggered by viral infection. Estimation of serum theophylline levels in patients already receiving oral treatment and in those receiving prolonged treatment will be necessary. Children with continuing severe asthma despite frequent nebulised β2-agonist and ipratropium bromide and those with life-threatening features need urgent review by a specialist with a view to transfer to a High Dependency Unit or PICU. However. IV Magnesium Sulphate Intravenous magnesium sulphate is a safe treatment for acute asthma although its place in management is not yet established. Repeated doses of ipratropium bromide should be given early to treat children poorly responsive to β2-agonist. Intravenous Fluids Children with prolonged severe asthma not tolerating. However. Frequent doses up to every 20-30 minutes (250 μg/dose mixed with the β2-agonist solution in the same nebuliser) should be used early.288 Bronchial Asthma solution). PEF and/or FEV1 should be >75% of best or predicted and SpO2>94%. The dose frequency should be reduced as clinical improvement occurs. Two-third of the child’s maintenance requirement should be given because of the possibility of inappropriate antidiuretic hormone secretion. Other Therapies There is no evidence to support the use of heliox or leukotriene receptor antagonists for the treatment of acute asthma in childhood. A 5 mg/kg loading dose should be given over 20 minutes with ECG monitoring (omit in those receiving maintenance oral theophyllines) followed by a continuous infusion at 1 mg/kg/hour. one may consider aminophylline in a High Dependency Unit or PICU setting for children with severe or life-threatening bronchospasm unresponsive to maximal doses of bronchodilators and steroid tablets. one well conducted study has shown evidence for benefit in severe acute asthma unresponsive to multiple doses of β2-agonist and steroids. oral fluids will require intravenous hydration. There is insufficient evidence to support or refute the role of antibiotics in acute asthma. Serum electrolytes should be measured and hypokalamia corrected. if detected. Aminophylline is not recommended in children with mild to moderate acute asthma. ECG monitoring is mandatory for all intravenous treatments. Further Investigation and Monitoring Children can be discharged when stable on 3-4 hourly inhaled bronchodilators that can be continued at home. IV Amniophylline There is no evidence that aminophylline is of benefit for mild to moderate asthma and side effects are common and troublesome. Doses of up to 40 mg/kg/day (maximum 2g) by slow infusion has been used. Antibiotics are not to be given routinely in the management of acute childhood asthma. . Studies of efficacy for severe childhood asthma unresponsive to more conventional therapies have been inconsistent in providing evidence of benefit. Discharge plans should address the following: • Check inhaler technique • Consider the need for regular inhaled steroids • Provide a written asthma action plan for subsequent asthma with clear instructions about the use of bronchodilators. pneumonia. Intermittent wheesing attacks are usually due to viral infection and the response to asthma medication is inconsistent.New Guidelines for Asthma Management (Acute Asthma) 289 Adult studies show that “optimal care” comprising self-monitoring. Steroid tablets are to be considered in infants early in the management of moderate to severe episodes of acute asthma in the hospital setting. These guidelines are intended for those who are thought to have asthma causing acute wheeze. Prematurity and low birth weight are risk factors for recurrent wheesing. The differential diagnosis of symptoms includes aspiration pneumonitis. if not better than. TREATMENT OF ACUTE ASTHMA IN CHILDREN AGED < 2 YEARS β2-Agonist Bronchodilators A trial of bronchodilator therapy should be considered when symptoms are of concern. Close fitting face masks are essential for optimal drug delivery. review the diagnosis and consider the use of other treatment options. ASSESSMENT OF ACUTE ASTHMA IN CHILDREN AGED LESS THAN 2 YEARS The assessment of acute asthma in early childhood can be difficult. tracheomalacia. a pMDI+ spacer is the optimal drug delivery device. For mild to moderate acute asthma. One . there is little evidence for an impact on the need for hospital admission or length of hospital stay. They should not be used as a guide for treating acute bronchiolitis. if appropriate. There is good evidence that pMD+ spacer is as effective as. Steroid Therapy Steroid tablets in conjunction with β2-agonists have been shown to reduce hospital admission rates when used in the emergency department. regular review and a written asthma action plan can improve outcomes. Oral β2-agonists are not recommended for acute asthma in infants. starting a course of oral steroids • Arrange follow-up by a General Practitioner within one week • Arrange follow-up in a paediatric asthma clinic within one to two months. Whilst β2-agonists offer marginal benefits to children aged < 2 years with acute wheeze. Inhaled β2-agonists are the treatment of choice for the initial treatment of acute asthma. Oral β2-agonists have not been shown to affect symptom score or length of hospital stay for acute asthma in infancy when compared to placebo. If inhalers have been successfully administered but there is no response. and complications of underlying conditions such as congenital anomalies and cystic fibrosis. bronchiolitis. Steroid tablets have also been shown to reduce the length of hospital stay. The dose received is increased if the child is breathing appropriately and not taking large gasps because of distress and screaming. Acute asthma attacks should be considered a failure of preventive therapy and thought should be given about how to help families avoid further severe episodes. seeking urgent medical attention in the event of worsening symptoms and. nebulisers for treating mild to moderate asthma in children aged <2 years. if available Patients with severe or life threatening attacks may not be distressed and may not have all the abnormalities listed below.. The majority do not require treatment with regular inhaled steroids. Management of acute severe asthma in adults and children is shown in the following diagrams. cyanosis. but delay can be fatal. Further Investigation and Monitoring Many children with recurrent episodes of viral-induced wheesing in infancy do not go on to have chronic atopic asthma. or feeble respiratory effort • Bradycardia. Referral to suitable agencies should be offered to those who wish to give up smoking. .. Parents should be advised about the relationship between cigarette smoke exposure and wheezy illnesses. Inhaled ipratropium bromide in combination with an inhaled β2-agonist may be considered for more severe symptoms. Assess and record: • Peak expiratory flow (PEF) • Symptoms and response to self treatment • Heart and respiratory rates • Oxygen saturation by pulse oxymetry. The presence of any should alert the doctor. confusion or coma ↓ Contd. Steroid tablet therapy (10 mg of soluble prednisolone for up to three days) is the preferred steroid preparation for use in this age group. Moderate asthma ↓ Acute Severe Asthma ↓ PEF > 50% best or predicted PEF 33-50% best or predicted Life Threatening Asthma ↓ Initial Assessment PEF < 33% best or predicted Further Assessment • Speech normal • Respiration . Parents of wheezy infants should receive appropriate discharge plans along similar lines to those given for older children. Management of acute severe asthma in adults in general practice Many deaths from asthma are preventable. Ipratropium Bromide The addition of ipratropium bromide to β2-agonists for acute severe asthma may lead to some improvement in clinical symptoms and reduce the need for more intensive treatment. dysrrhythmia. or hypotension • Exhaustion.290 Bronchial Asthma study has shown similar benefits when comparing oral and nebulised steroids for acute asthma. Factors leading to poor outcome include: • Doctors failing to assess severity by objective measurement • Patients or relatives failing to appreciate severity • Under use of corticosteroids Regard each emergency asthma consultation as for acute severe asthma until it is shown to be otherwise. It does not reduce the length of hospital stay either in combination with β2-agonists or in comparison with placebo. 25/min • Pulse < 110/min ↓ • Can’t complete sentences • Respiration > 25/min • Pulse > 110/min ↓ • SpO2 < 92% • Silent chest. respiration and pulse setting. Management Treat at home Assess response to treatment ↓ Consider admission Arrange immediate ADMISSION ↓ ↓ Treatment • High-dose β2-bronchodilator: • ideally via oxygen-driven nebulizer (salbutamol 5 mg or terbutaline 10mg) • Or via spacer or air-driven nebulizer (1 puff 10-20 times) If PEF > 50-70% predicted: • Give prednisolone 40-50 mg • Continue or step up usual treatment If good response to first nebulised treatment (symptoms improved. and PEF > 50%) continue or step up usual treatment and continue prednisolone • Oxygen 40-60% if available • High-dose β2-bronchodilator: • ideally via oxygen-driven nebulizer (salbutamol 5 mg or terbutaline 10mg) • Or via spacer (1 puff β2-agonist via a large volume spacer and repeat 10-20 times) or airdriven nebulizer • Prednisolone 40-50 mg or IV hydrocortisone 100 mg • If no response in acute severe asthma...New Guidelines for Asthma Management (Acute Asthma) 291 Contd.5 mg) • Or via spacer (1 puff β2-agonist via a large volume spacer and repeat 10-20 times) or air-driven nebulizer ↓ Follow up after treatment or discharge from hospital: • General Practitioner review within 48 hr • Monitor symptoms and PEF • Check inhaler technique • Written asthma action plan • Modify treatment according to guidelines for chronic persistent asthma • Address potentially preventable contributors to admission . Admit ↓ ↓ Admit to hospital if any: If admitted patient to hospital: • Life threatening features • Stay with patient till ambulance • Features of acute severe arrives asthma present after initial • Send written assessment and treatment referral details to hospital • Previous near-fatal asthma • Give high dose β2-bronchoLower threshold for admission if: dilator via oxygen-driven • Afternoon or evening attack. nebulizer in ambulance • Recent nocturnal symptoms or hospital admission • Previous severe attacks • Patient unable to assess own condition • Concern over social circumstances • Oxygen 40-60% • Prednisolone 40-50 mg or IV hydrocortisone 100 mg immediately • High-dose β2-bronchodilator and ipratropium: • Ideally via oxygendriven nebulizer (salbutamol 5 mg or terbutaline 10 mg and ipratropium 0. 292 Bronchial Asthma Management of Acute Severe Asthma in Adults in Emergency Room Time Measure PEFR and arterial saturation PEFR 33-75% best or predicted Moderate-Severe Features of severe asthma • PEF<50% best or predicted • RR > 25/min • Pulse > 110/min • Can not complete sentence in one breath PEFR > 75% predicted Mild 5 min 15-30 min Give usual bronchodilator Clinically stable. Markers of severity: • Normal or ↑ PaCO2 (35 mmHg) • Severe hypoxia (PaO2 < 60 mHg) • Low pH Observe Monitor SpO2. referral in appropriate cases • Give/repeat as above after 15 minutes • Continuous salbutamol nebulizer 5-10 mg/hr • Consider IV magnesium sulphate 1-2 gm/ 20 min. Prednisolone 40-50 mg for 5 days. ensure inhaled drugs and technique. arrange GP follow-up with detailed instructions. hypotension Exhustion. 100 mg Monitor ABG. poor respiratory effort Bradycardia. arrhythmia. confusion. PEF > 75% No life threatening feature PEF 5075% • • • • Obtain senior ICU help now Life threatening features OR PEF < 50% No sign of severe asthma and PEF 50-75% Sign of severe asthma or PEF < 50% 120 min Immediate Management • High concentration O2 (60%) • Salbutamol 5 mg +ipratropium 0. RR and HR Patient stable and PEF > 50% PEFR < 33% best or predicted or any lifethreatening feature SpO2 < 92% Silent chest. Cyanosis. • Fluid/electrolyte balance monitoring (specifically K+) • Chest X-ray ADMIT Patient should be accompanied by a nurse or doctor at all times . PEF > 75% Patient recovering and PEF > 75% 60 min Give 5 mg salbutamol by oxygen-driven nebulizer if any life threatening feature Clinically stable. coma Signs of severe asthma or PEF < 50% Potential Discharge: Extended observation if β-agonist before presentation.5 mg by oxygen-driven nebulizer • Prednisolone 40-50 mg orally or IV hydrocortisone. Alternate agents those have been evaluated in prospective randomized trials or have novel mechanisms of action are shown in Table 19.Alternate Treatments in Asthma 293 19 Alternate Treatments in Asthma Standard asthma therapy. The long-term use of oral and high-dose inhaled corticosteroids is often associated with significant side effects. cromolyn. frequent exacerbations. leukotriene antagonists. and nedocromil.1-4 Table 19. it is widely used in a variety of autoimmune and inflammatory diseases. It has anti-inflammatory properties at low doses. Although these agents are generally successful in controlling asthma symptoms. theophyllines. the mechanism of action of methotrexate in asthma remains unclear.6 It affects function of many cytokines. as defined by various management guidelines includes oral and inhaled corticosteroids.1: Alternate agents for bronchial asthma Methotrexate Azathioprine Gold Hydroxychloroquine Troleandomycin Cyclosporine IVIG Inhaled heparin Inhaled furosemide Dapsone Anti-IgE and soluble interleukin (IL)-4 receptor therapy Methotrexate Mechanism of Action Methotrexate is a folate antagonist. including severe steroid-dependent asthma. a small but significant number of patients will continue with persistent symptoms. and no improvement in objective pulmonary function parameters despite maximum standard therapy. A number of potential reasons for its effectiveness have been proposed. Therefore. Thus there is need for alternate agents that are effective in the treatment of asthma.1. The drug inhibits leukotriene B4-mediated and leukotriene C5a-mediated neutrophil chemotaxis in vitro5 although inflammatory cell numbers in vivo appear to be unaltered during treatment. short-acting and long-acting β-agonists. a . The drug inhibits the expression of Ia. No bone marrow toxicity was observed at the dosages used. and diarrhea). Others reported a statistically significant reduction in corticosteroid dose using methotrexate. A three-arm study compared methotrexate. with over half were weaned off all steroid therapy. disseminated varicella zoster.25. increased incidence of bacterial pneumonia. No significant interference with steroid metabolism has been noted. 26 Common side effects of methotrexate include liver function test abnormalities. Most studies reported significant reductions in oral steroid use in their placebo groups. Methotrexate competes with the hepatic metabolism of theophylline. Many trials had significant dropout rates. constitutional symptoms (including fatigue and decreased concentration). 15 mg weekly orally. and histamine release. 5 months to 28 years).9 Methotrexate may enhance the sensitivity of peripheral blood monocytes to glucocorticoids in cases of steroid-refractory asthma. Some studies reported statistically significant reductions in the baseline prednisone dose. GI symptoms (including abdominal pain. The majority received oral methotrexate. with a single dose of triamcinolone. with an average decrease in theophylline clearance of 19% in one case series. IL-6. and many used a variety of run-in periods to maximize asthma therapy prior to starting treatment. No statistically significant changes in peak flow.6-8 The inhibition of purine metabolism by methotrexate diminishes lymphocyte proliferation and antibody formation6 and increases in CD8+ T-suppressor cells and suppression of B-cell differentiation have been observed. bronchiolitis . IL-8. which was attributed to the close-interval followup and the education that patients received during enrolment. 360 mg IM. treatment for 12 weeks may be insufficient to demonstrate an adequate therapeutic response in patients with asthma. headache. 15 mg weekly.22-24 Of the 11 prospective randomized trials.20 Most trials required that patients had received a minimum of 12 months of long-term corticosteroid therapy to be eligible for enrolment (range. spirometry. and less common ones like opportunistic infections (Pneumocystis carinii pneumonia).294 Bronchial Asthma marker of macrophage activation and monocyte IL-1 production. could not demonstrate a significant difference in corticosteroid reduction between the methotrexate and placebo groups.10 A number of randomized trials11-21 have been made using methotrexate in bronchial asthma and three meta-analyses have been performed since then with mixed results. However. chronic pneumonitis and fibrosis.12 Other trials. including drug-induced hypersensitivity reaction. and follow-up was too short to address issues of potential hepatic fibrosis. and platelet-activating factor-induced eosinophil chemotaxis. Small patient numbers further limits the interpretation. nausea. or mean values for the dose of methacholine provoking a 20% fall in FEV1 were observed in patients taking methotrexate neither reduction in steroid-related side effects were reported. The duration of methotrexate therapy ranged from 12 to 24 weeks. oral ulcers and stomatitis.12-21 Although responses to methotrexate have been reported after 3 months in patients with immunologic diseases such as rheumatoid arthritis. with no further reported long-term follow-up. 10 evaluated the use of oral or IM low-dose methotrexate vs placebo in steroid-dependent asthma patients using either parallel or crossover design. or placebo. rash. however. Methotrexate is well-known to cause a variety of pulmonary manifestations. some demonstrating reduction of mean oral corticosteroid use up to 50%. side effects were transient and reversible and only minimal from the administration of low-dose methotrexate. and bronchospasm. noncardiogenic pulmonary edema.32 Clinical efficacy data on troleandomycin showed improvement in clinical symptoms and/or a reduction in corticosteroid dosage in when used as 14 mg/kg/d TAO (maximum dose. The Auranofin Multicenter Drug Trial49 has been the largest clinical trial to examine the efficacy of oral gold.30-32 Subjective patient improvement has not been correlated with evidence of infection using sputum culture.005). suggesting that a direct antimicrobial effect is less likely. at a concentration of 5 µg/mL demonstrated a 44% reduction in the concentration of methylprednisolone that was required to inhibit human lymphocyte blast transformation by 50% (p < 0. 1 g. Steroid-related side effects are common with the use of TAO.27 Troleandomycin Troleandomycin (TAO) is a macrolide antibiotic and was first described as a treatment for steroid-dependent asthma in 197428 The drug is believed to have a synergistic effect when administered with oral corticosteroids. Improvements have been reported in bronchial reactivity and oral corticosteroid requirements have been decreased46-48 oral or parenteral gold treatment was used for 12 to 22 weeks. decreases prostaglandin and leukotriene production in vitro.40 It also inhibits antibody production and lysosomal enzyme release from phagocytic leukocytes.34 Cushingoid features.36 The results were limited by significant patient The authors concluded that patients who had been randomized to TAO experienced no advantage and appeared to develop greater steroid-related side effects than did placebo subjects. Gold Gold is an immunomodulatory agent that has been used commonly for the treatment of a variety of inflammatory and autoimmune conditions. gold has been demonstrated to decrease neutrophil and macrophage phagocytosis. were less convincingly demonstrated in another trial of TAO efficacy.40-44 The enhancement of eosinophil survival with IL-5 is inhibited by the presence of gold.41 Gold inactivates C1 (complement). After a 4-week observation period 275 patients with daily oral prednisone requirements of ≥ 10 mg mg were randomized . There have been three prospective randomized studies examining the efficacy of gold. weight-gain. GI distress and hepatotoxicity. especially in earlier trials when patients were given doses of 1 g daily. The doses of theophylline and other medications with hepatic metabolism must be adjusted to avoid toxicity. Other studies have reported benefit. however. oleandomycin. predominantly at higher doses. Although the complete mechanism of anti-inflammatory activity is unknown.28.45 The beneficial effects of gold in the treatment of asthma were reported as early as 1932. ranging from transient liver enzyme abnormalities37 to prolonged cholestasis38 and jaundice39 have been reported. In vitro data using its parent compound. fluid retention. and glucose intolerance were the most common findings. Decreased IgG levels and one case of varicella zoster has been reported with its use.33.29 It is believed that Troleandomycin alters corticosteroid bioavailability by decreasing hepatic metabolism and excretion.33-35 These benefits.Alternate Treatments in Asthma 295 obliterans with organizing pneumonia. and inhibits IgE-mediated release of histamine from isolated basophils and lung mast cells. and lymphocyte reactivity to antigenic stimulation. respectively. The results were limited by a significant patient dropout rate (auranofin group. tumor necrosis factor.6% increase in FEV1 (p < 0. and hydrogen peroxide. placebo group.02) compared to those receiving placebo.59 However. a 17. and it decreases B-cell IgE synthesis and release. p = 0. protocol violations. Cyclosporine binds to cyclophilin. including GI upset and diarrhea. and voluntary withdrawals.001). another study with a longer follow-up period demonstrated no statistically significant effects of cyclosporine using the objective markers of pulmonary function and steroid-sparing effects. p = 0.40. gum hyperplasia. . 3 mg twice daily. hirsutism. respectively.003) were also observed in the auranofin group. and has been shown to decrease neutrophil chemotaxis and serum soluble IL-2 receptor concentrations.60 The side effects of cyclosporine are dose-dependent nephrotoxicity. and no intention-to-treat analysis was performed. which have shown a 12% increase in morning peak expiratory flow rates (PEFRs) (p < 0. and infectious complications. pruritic rash. Several patients experience hypertrichosis and a worsening of pre-existing hypertension that may result in the discontinuation of therapy. Three prospective randomized trials that have examined the effect of cyclosporine in asthma patients. although more patients treated with gold were able to reduce their daily oral corticosteroid dose by ≥ 50% compared to those receiving placebo (60% vs 32%. but no clear consensus exists on the issue. inhibiting eosinophil proliferation and survival activity. make it a preferable agent for the treatment of severe. and a 48% reduction in exacerbations requiring increased steroid dosing (p < 0.49-51 All side effects were self-limited with discontinuation or reduction of therapy. Some experts have argued that the relative lack of severe side effects with gold therapy. Nearly 40% of patients in the prospective randomized trials that were detailed earlier experienced. Cyclosporine Cyclosporine is an immunomodulatory and anti-inflammatory drug and is a fungal metabolite that is commonly used in organ transplantation.296 Bronchial Asthma to auranofin. oral ulcerations. 5 mg/kg/d) for 36 weeks in resulted in a statistically significant reduction in the median daily prednisolone dosage (62% vs 25%.57 Statistically significant improvement in airway hyperreactivity has been observed in steroid-dependent asthma patients after 12 weeks of therapy with cyclosporine. Statistically significant reductions in serum IgE level (reduction.52 The drug also reduces the synthesis and release of inflammatory mediators from mast cells and basophils. 46%) due to adverse effects. Treatment-limited neuropathy also has been observed. hypertension.004). superoxide. or placebo for a period of 6 months. 40%.53 Cyclosporine has been demonstrated to reduce the macrophage synthesis of IL-1.043) along with improvements in PEFR.55. inhibiting cytokine messenger RNA transcription and CD4+ T-cell activation. compared to methotrexate therapy. proteinuria.001).56 Cyclosporine has been shown to block the late asthmatic reaction and to inhibit the production of eosinophil-related cytokines after allergen challenge.54 The production of granulocyte macrophage colony-stimulating factor (GMCSF) and IL-5 from stimulated monocytes is also reduced with drug therapy.63 IU/mL. 44. tremor. No significant differences were found in symptoms or objective measurements of pulmonary function.52. and frank nephrotic syndrome. Gold has been associated with a variety of side effects. 58 In another study treatment with cyclosporine (initial dose. The majority of these side effects are not observed in the low doses that were used in the trial listed above. glucocorticoid-dependent asthma. p < 0. cytopenias. Alternate Treatments in Asthma 297 IVIG IVIG has been shown to reduce immediate skin test reactivity to allergens. and to suppress cytokine-dependent lymphocyte proliferation in vitro.4.83-85 Conflicting data exist .68 The minor adverse effects of therapy include headache and nausea.69 Subjective improvements in asthma symptoms have been reported with the use of IV heparin. Elevated levels of heparin-like anticoagulants have been demonstrated in atopic asthma patient and have been induced in some patients after antigen inhalational challenge leading to further interest in investigating the role of heparin in this disease.68 Heparin Heparin is an endogenous glycosaminoglycan and is extensively used as an anticoagulant. including eosinophilic cation protein and peroxidase. reducing their activity.77 It has been suggested78 that the sulfate groups on the heparin molecule may attenuate antigen-induced bronchoconstriction via the inhibition of inositol 1.000 U preserved specific airway conductance (sGaw) better than did 20 mg inhaled cromolyn or placebo following exercise82 but not following histamine challengen. as was mentioned above. or the number of clinical exacerbations among patients in the IVIG groups and the placebo group. there remains the remote possibility of IVIG transmission of a yet-undefined viral illness. Its flexible structure and high anionic charge allow heparin to interact with a variety of molecules in vivo and it is involved in airway inflammation.72 It also increases the association rate of secretory leukocyte protease inhibitor with human neutrophil elastase and cathepsin G. smooth muscle growth. to inhibit lymphocyte activation and the production of IL-2 and IL-4 in vivo.64 Monthly administration of high-dose IVIG resulted in a three-fold reduction in the oral glucocorticoid dose.4. to decrease total serum IgE levels. More serious reactions can be associated with patients who have IgA deficiency. and IVIG administration should be avoided in this population. and reducing airway hyperreactivity.79-81 Inhaled heparin therapy administered at a maximum dose of 80.66 Other investigators have observed after 3 months of therapy a reduction of oral corticosteroid doses67. even in patients with prior documented steroid resistance. which generally occur with the infusion and are self-limiting.61 These steroid-sparing effects are observed both in adult and pediatric asthma patients. Perhaps heparin is bound to cell surface proteins in the airway epithelium may modulate smooth muscle tone either by inhibiting inositol 1. Although current commercial preparations should have no risk of transmission of viral hepatitis.73 Heparin has been associated with the inhibition of lymphocyte activation74.5 triphosphate-mediated calcium release or by preventing C-fiber stimulation. IgE-mediated mast cell histamine release. a reduction in symptoms.5 triphosphate-dependent.65. neutrophil chemotaxis75.76 It also reduces complement activation. pulmonary function testing results.69-71 Heparin binds and inhibits a variety of cytotoxic and inflammatory mediators. and vascular tone. It also has been rarely associated with interstitial nephritis and aseptic meningitis. decreasing bronchial responsiveness. and in improved PEFRs with decreases in serum total IgE levels and skin test reactivity to allergens. others failed to identify a significant difference in steroid dose reductions.61-63 IVIG also has been shown to increase lymphocyte sensitivity to the suppressive effects of dexamethasone. with variable effects on the provocative concentration of methacholine causing a 20% fall in FEV1.86 Furosemide is a loop diuretic that acts in the kidney by inhibiting the Na+/K+/2 Cl.105. Heparin inhalation alone has not been demonstrated to affect baseline FEV1 despite the frequent use of isotonic saline solution as its carrier.298 Bronchial Asthma regarding the effects of heparin pretreatment on the early asthmatic response to inhaled allergen challenge (dust mite extract). aspirin105 and propranolol. with mild but statistically significant protective effects in FEV1 seen 7 to 8 h postchallenge (p < 0.87. including early and late responses to allergen101 and the effects of exercise86 distilled water102 adenosine 5'-monophosphate103 sodium metabisulfite104.91 Conflicting data exist regarding the effects of furosemide on airway prostaglandins.05).93 Further.106 . Despite early speculations about the effects of furosemide on airway water concentration.000 U inhaled heparin during asthma exacerbations have been reported.96 reinforcing the lack of clarity in this area. other data have shown that furosemide has little99 or no effect100 on mucociliary clearance.cotransporter in the ascending limb of the loop of Henle. No adverse effects associated with the use of inhaled heparin at the doses described above have been reported. but with no significant effects on FEV. Other postulated mechanisms of action based on animal data include the reduction of airway temperature variation through local airway vasodilation following dry air challenge97 and the enhancement of paracellular water movement in response to an osmotic stimulus. 20 to 40 mg) for significant antiasthma effects. airway resistance. Furosemide is well-known to enhance renal synthesis of prostaglandin E292 and the stimulation of inhibitory prostaglandins from the airway epithelium may be the cause of its protective role in some challenges.90 Furosemide acts by inhibiting the release of histamine and leukotrienes from passively sensitized human lung. respectively. it is suggested that the drug inhibits the production of bronchoconstricting prostaglandins. Furosemide and Other Diuretics Changes in water concentration and surface osmolarity of the airway epithelium are important contributing factors to exercise-induced bronchospasm that prompted the first use of inhaled frusemide (ie. and no significant changes in serum partial prothrombin time or anti-factor Xa activity have been observed with unfractionated and low-molecularweight heparin.94 Effects of cyclooxygenase inhibitors on the activity of furosemide have been mixed95. No bleeding complications have been reported.98 However. Furosemide is not effective against asthma when administered orally at the usual diuretic doses and must be inhaled at relatively high doses (i. Furosemide appears to attenuate the effects of indirect bronchoconstrictor mechanisms. furosemide) as a potential treatment for asthma. an indirect measure of the rate of recovery of periciliary fluid volume after isocapnic hyperventilation. Two cases of corticosteroid-resistant asthma patients who responded to 100. its mechanism of action does not appear to be related to the diuretic effects of the drug. nonadrenergic sensory nerves and cholinergic neural responses in animal models.e. Trials examining the effects of inhaled heparin on bronchoprovocation using methacholine also have yielded mixed results.86 Furosemide attenuates bronchoconstriction by reducing apical chloride channel activity and by decreasing the potential difference and short-circuit current in airway epithelial cells.88 The drug’s inhibition of chloride transport also appears to inhibit the release of eosinophil mediators89 and may be related to the modulatory effects observed on presynaptic neuropeptide release from noncholinergic. or sGaw postchallenge. but not in asthmatic patients. it is unclear whether methotrexate or gold .107 and prostaglandin F2α108 are not affected by furosemide.05) in acute asthma exacerbations. Two case series have suggested that long-term therapy with methotrexate may be required to demonstrate objective benefit. Furosemide can cause allergic reactions due to its incorporated sulfa moiety and has been reported to cause ototoxicity with high-dose rapid IV infusion.112 A significant steroid-sparing effect using a combination of lysine acetylsalicylate (LASA) and furosemide is observedin severe steroid-dependent asthma for 10 to 28 weeks. although no differences between the good responders and the poor responders could be identified. Methotrexate has been shown to reduce oral corticosteroid requirements modestly in steroiddependent asthma patients in some short-term.116 Others have reported similar results.117 Others reported statistically significant improvements in PEFRs (p < 0.115 Serial FEV1 measurements showed a mean increase of 14. however. Side effects with gold therapy are common but generally are minor and self-limited with dose reduction or the cessation of therapy.109 Inhaled furosemide has been shown to inhibit the cough response induced by the inhalation of low-chloride-content solutions110 in healthy volunteers. but this conclusion must be made with caution due to the confounding effects of the high dropout rate in the Auranofin Multicenter Drug Trial. randomized. The similarities between the protective spectrum of furosemide and cromolyn have led to speculation about a common mechanism of action.003) and no additive benefit with combination therapy.113-115 Effect of inhaled furosemide in acute asthma exacerbations showed mixed results.Alternate Treatments in Asthma 299 Bronchoconstrictors that work directly on airway smooth muscle like histamine 103 methacholine104.111 The presumed effect of the drug is due to changing the local concentration of chloride ions in the vicinity of myelinated afferent nerve fibers that are acting as cough receptors at the airway surface. Of all the agents that have been examined in prospective randomized trials. although cromolyn has been shown to have a statistically greater protective effect on airway reactivity when equal doses of the two inhaled drugs were compared. methotrexate and gold appear to be the most important in terms of steroid-sparing and side effect. CONCLUSION Standard anti-asthma therapy is highly successful in most patients.9 ± 15. Therefore. and no diuretic effect has been reported. the use of alternate agents for treating asthma should be reserved for the steroid-resistant asthma patient or for the steroid-dependent asthma patient in whom a thorough evaluation to exclude other diagnoses and exacerbating factors has been performed.5% in FEV1 with furosemide therapy alone (difference not significant) compared to an increase of 42.9 ± 10. although its mechanism of action remains unclear and the data examining this issue remain limited and conflicting.2% with metaproterenol therapy (p = 0. FEV1 had increased by > 2 SDs compared to those receiving placebo. None of the clinical trials using inhaled furosemide have reported significant side effects. clinical trials. Until further data from controlled clinical trials are available. Gold also has significant steroid-sparing effects in patients with high daily corticosteroid requirements.118 A follow-up case series119 reported clinical improvement in 9 of 11 patients with severe asthma exacerbations that were refractory to conventional medical therapy with the addition of inhaled furosemide. 20:625-42. BN Molecular mechanism of methotrexate action in inflammation. San Juan HS. At this time. Lynch JP. although their exact mechanism of action remains unknown. convenience. 2. Chest 2003. Niven AS. Oettgen HC. Cronstein. Mohapatra SS. and larger prospective placebo-controlled trials are needed to determine the efficacy.14:9-11. 3. 4. Asian Pac J Allergy Immunol 1994. Inflammation 1992. The current data and the lack of significant side effects make them potential steroid-sparing agents in the long-term treatment of mild persistentto-severe asthma. 5. McCune. 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O’Connor BJ. 89. 95. Prevention of exercise-induced bronchoconstriction by inhaled frusemide.76:409-15. Robuschi M. et al. Effect of furosemide on hyperpnea-induced airway obstruction. Alton EW. Gonda I. Eur Respir J 1994. Ahmed T. Elwood W. Dolowitz DA. Diuretics and asthma. Anderson SD. Munkonge FM. J Appl Physiol 1996. Chung KF. Barnes PJ. Thorax 1992. Gilbert IA. 100. Kingsleigh-Smith DJ. Thorax 1994.324:131. 96. 97. Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin. 86. et al. 78. 80. 79. Endou H. Pavia D. Barnes PJ.7:1497-1500. et al. J Appl Physiol 1994. Lotvall JO. Freed AN. Spiteri MA. Loop diuretics inhibit cholinergic and non-cholinergic erves in guinea pig airways. Lenner KA. et al. 93. et al. Lancet 1988. Temple DM. The use of heparin as an anti-inflammatory agent. Miyanoshita A.48:195-96. et al. Laryngoscope 1960. 87. Nannini LJ. Alton EW. Steroid sparing effect of inhaled lysine-aspirin and furosemide in steroid-dependent asthma. Stone RA. et al. Dworkin F. . Vaghi A. Effect of inhaled furosemide in acute asthma.321. 116.Alternate Treatments in Asthma 305 101. et al. 110. Teizeira LR. Myers JD. Yeo TC. 111. Stone RA. Ono Y. Am Rev Respir Dis 1991. Effect of frusemide on cough response to low-chloride solution in subjects with mild asthma. G O’Byrne. Chung KF Furosemide and other diuretics in asthma. Barnes PJ. Effect of inhaled furosemide on metabisulfite. Croce M. Nix A. Barnes PJ. Robuschi M. Rapid response to inhaled frusemide in severe acute asthma with hypercapnia. Moscato G.261-69 Elsevier.143:1329-33. Chung KF. Chest 1994. J Allergy Clin Immunol 1995. Nichol GM. Furosemide given by inhalation ameliorates acute exacerbations of asthma. et al. Kondo T. Effect of frusemide on cough responses to chloride-deficient solution in normal and mild asthmatic subjects. Steroid-sparing effect of inhaled lysine acetylsalicylate and furosemide in high-dose beclomethasone-dependent asthma. et al. Am Rev Respir Dis 1991. 108.64:108-10. Kondo T. Vaghi A. 117. Effect of inhaled furosemide and cromolyn on bronchoconstriction induced by ultrasonically nebulized distilled water in asthmatic subjects. Eur Respir J 1993. Higham MA. 107.52:861-65.31:85-92.78:238-43. Ventresca PG. Respiratory Allergy 1993.142:576-80. the Netherlands. 109.1069-73.and sodium metabisulfate-induced bronchoconstriction in asthmatic subjects. Chest 1992.95. Chen-Worsdell. Mastropasqua B. Chilaris M. et al. Refini RM. J Asthma 1997. 112. 102.143-46.and methacholine-induced bronchoconstriction and nasal potential difference in asthmatic subjects.142. 113. Hager D. et al. Amsterdam. Ann Allergy Asthma Immunol 1997. Bianco S. 105. et al. 104. 115.102:408-11. Nichol GM. YM. Robuschi M. et al.1:85. Inhaled furosemide is not effective in acute asthma. Vargas FS.937-43. Pendino JC. Inhaled frusemide inhibits cough induced by lowchloride solutions but not by capsaicin. et al. Melillo. Effect of inhaled furosemide and bumetanide on adenosine 5'-monophosphate. O’Conner BJ. 106. Barnes PJ. Am Rev Respir Dis 1991. et al. et al. Siffredi M. Chung KF. Stone RA. Robuschi M. Barnes PJ. Shakur BH. G (Eds). Pelucchi A. Thorax 1997. 119. Tanigaki T. et al. 114. Thorax 1991. PH Marone. Am Rev Respir Dis 1990. Chung KF. Falagiani P. Attenuation of propranolol-induced bronchoconstriction by furosemide. et al.6:862-67. Frusemide inhibits cough but not bronchoconstriction to prostaglandin F2α in patients with asthma. Vaghi A. J Asthma 1994. Chapman KR. Effect of inhaled furosemide on the bronchial response to lysine-aspirin inhalation in asthmatic subjects. Protective effect of inhaled furosemide on allergeninduced early and late asthmatic reactions. Respiration 1997. Inhaled furosemide does not alter the bronchial response to methacholine in asthmatics. Karpel JP.46:752P.89-93.106:1396-1400. Bianco S. Eur Respir J 1988. Bianco S. Inhaled furosemide prevents both the bronchoconstriction and the increase in neutrophil chemotactic activity induced by ultrasonic “fog” of distilled water in asthmatics. Pieroni MG. et al.143:561-66.34:283-89. Tanigaki T.143:A548.35. 103. Hayashi Y. et al. N Engl J Med 1989. Am Rev Respir Dis 1990. 118. J Asthma 1998. Dellabianca A. These patients respond poorly to the usual treatment and are very difficult to manage. Patients also must have had compliance and exacerbating factors . However. Physiologically. these patients often have air-trapping and may have loss of elastic recoil. a second group develops severe disease in adulthood. and. It is not clear which genetic and environmental elements may be the most important in the development of severe disease. Accordingly the cost of treatment is very high with poor outcomes. structural changes. The introduction of high-potency inhaled corticosteroids (CS) had a marked impact on the numbers of patients who were dependent on therapy with oral CS. physiologically. and pathologically.306 Bronchial Asthma 20 Severe Asthma (Fatal Asthma. in at least one third of patients. Exacerbations. The entity is poorly understood clinically. beyond those medications.1 This definition includes the following: Major Criteria • Continuous high-dose inhaled corticosteroids or • Oral corticosteroids for > 50% of the previous year Minor Criteria • • • • Aspects of lung function. Disease stability. a different pathology. Definition Severe or “refractory” asthma was defined by the workshop sponsored by the American Thoracic Society. The pathology demonstrates a wide variety of findings. Although some patients with severe asthma have had severe disease for most of their lives. Refractory Asthma) INTRODUCTION Severe or fatal asthma or refractory asthma constitutes about <5% of all the asthmatics. those include continued eosinophilic inflammation. Treatment remains problematic. little further progress has been made in understanding the disease and improving its treatment. Amount of additional medications For a diagnosis of fatal asthma at least one major and additional two of the seven minor criteria are to be fulfilled. Severe forms of the disease often remain refractory to the best current medical care. distal disease. as well. 1. although there is little “progressive decline” of the mean data. Two studies3. rather than the “letter” of the definition. In the database of > 100 patients with severe asthma who were seen at National Jewish Medical and Research Center (Denver.1: Various risk factors for development of severe asthma Genetic Mutations in both the interleukin-4 gene or the interleukin-4 receptor Non-T helper (Th) type 2 factors Transforming growth factor (TGF)-β1 Monocyte chemotactic protein-1 Environmental factors Allergens (house dust mite.4 from Europe have suggested that late-onset asthma is associated with a more rapid decline in lung function. alternaria exposure) Smoking Pet allergy Infections Respiratory syncytial virus infections in childhood Mycoplasma and Chlamydia infections in adults Lung-externa factors Obesity (Increased body mass index) Gastroesophageal reflux disease Chronic sinusitis Compliance/adherence to medications Inadequate response to therapy . or whether they slowly but steadily decline over the years. Table 20. CO). cockroach. approximately two-thirds of patients had onset in childhood. but the list of criteria still may not be definitive and may have many pitfalls. It is not clear whether most patients with severe asthma have a life-altering event in childhood that irreversibly alters their lungs. or if at all they have a more rapid decline in function once the asthma begins. Aetiology Various risk factors for development of severe asthma are shown in Table 20. Australia followed for 35 years.2 Those data suggest that reduced lung function in childhood leads to reduced lung function in adulthood. Some suggest that expanding the minor criteria requirements to three would likely improve the capture of those who fulfill the “spirit” of the definition. Refractory Asthma) 307 should be fully addressed.5 Existence of any distinct phenotypic differences in adult-onset and childhood onset asthma or severe asthma is not known. These definitions are a guide. No satisfactory answer to these questions has been found although some information has come from the large cohort of asthma patients studied in Melbourne. and the remaining one third experienced onset after the age of 20 years. Epidemiology Very little is known about the development of severe asthma.Severe Asthma (Fatal Asthma. from which they will never recover. It is also not certain whether those patients with a history of adult-onset disease actually have some level of asthma as children those were ignored. are important.4 These changes are not completely irreversible.18 This instability may be an important aspect to the symptomatology of a subgroup of patients with severe asthma. both of which can promote fibrotic reactions.308 Bronchial Asthma As is the case for many diseases. Epidemiologic study of patients with severe/difficult-to-treat asthma suggested that body mass index increases with increasing severity of disease and that 76% of the cohort of patients with severe disease were either overweight or obese.16 Physiology Progressive increase in airflow limitation.8. and chronic sinusitis.17 This may be true in some patients.7 of relevant mutations in both the interleukin-4 gene or the interleukin-4 receptor. Unfortunately. Interestingly.4 Although not precisely “environmental. It is possible that other physiologic factors. Another external factor related to severity of disease is compliance/adherence to medications. It is suggested that the airways and the parenchyma are more collapsible than are the airways in healthy . many patients will continue to smoke or own a cat despite being aware of the negative effects. transforming growth factor (TGF)β1 and monocyte chemotactic protein-1. some of which have been linked to loss of lung function. and Alternaria exposures. Severe asthma is not likely to be different and is less well-studied. in whom continuous airflow limitation may play a role. two non-T helper (Th) type 2 factors also have been associated with severity of asthma. risk factors can be divided into genetic and environmental. instability of disease is related to adherence to therapy with corticosteroids. such as depomethylprednisolone or triamcinolone.21 Compliance is increased in patients with moderate persistent asthma. although there is poor correlation between FEV1 and disease symptoms . although the precise pathologic mechanism behind the change is not clear.” additional “lung-external” factors may include obesity. particularly adults. asthma itself is a disease involving multiple genes. There are reports6.20. The elastic recoil properties of the lung in asthma patients are not normal.19 FEV1 and airway reactivity changes do not adequately explain disease severity. and others to near-fatal events. while pathogens like Mycoplasma and Chlamydia may play a role in adults. Environmental factors include both allergen and tobacco exposure. If the patient is receiving therapy with oral corticosteroids. while others. Airway hyperreactivity also plays a role in the severity of asthma. with the strongest data for house dust mite. Studies15 have suggested that in children and adolescents. then treatment trials with injectable longacting steroids.13 Infection also may contribute to severe disease. Adherence to medication may be influenced by lack of responsiveness to medication. the early-morning measurement of cortisol level can be helpful in determining compliance. may develop a more rapid decline in lung function over a 10-year-period of time. The provocative concentration causing a 20% fall in FEV1 with disease severity is often present but is poor indicators. However. Others may have severe airflow limitation at presentation. gastroesophageal reflux disease.9 Whether mutations of the receptors for the primary treatments for asthma (β2 and glucocorticoid receptors [GRs]) decrease responsiveness to medications and influence outcomes is not yet clear. If this is not helpful.10-12 Additionally. similar to gastroesophageal reflux disease and chronic sinusitis. such as changes in elastic recoil and/or small airway physiology. There may be irreversibility to current aggressive medical management.14 However. which is often irreversible leads to a more rapid decline in the FEV1. with respiratory syncytial virus infections implicated in childhood. the relationship of effective treatment of obesity to severity of disease is not clear. can be informative. it does not necessarily mean the lungs are in a fixed fibrotic state. cockroach. which has lessened inhibitory capabilities. non-Th-2.23 These patients are at a higher risk of nearfatal events than those with a more normal (1:1) ratio. Patients dying of status asthmaticus have increased smooth muscle mass in the airways from the largest airways to nearly the smallest. or increased levels of an alternatively spliced GR (i. Pathology Up to two-thirds of patients with severe asthma have persistent tissue eosinophils. The amount (and perhaps phenotypes) of smooth muscle in the airways of patients with severe asthma is also increased. There are associated increases in T lymphocytes and markers for activation of a Th-2 pathway. Patients with severe asthma with persistent eosinophil levels had the thickest SBM when compared to those of healthy control subjects. This lack of effect is due to a number of factors those include high levels of proinflammatory mediators sequestering the glucocorticoid receptors (GR). epithelium.23 This pattern of inflammation represents steroid resistance. . despite continued therapy with high-dose systemic steroids. Although the SBM is thickened in asthma patients. diminished binding of the GR to the genome. There is an increase in the ratio of goblet cells to ciliated epithelial cells. or quantity of extracellular matrix elements in other regions of the airway or parenchyma. and blood vessels.24-26 Other. the absolute increase in thickness is small and cannot explain the increase in airflow limitation. nerves. smooth muscle. without associated hyperinflation. Numerous structures have been implicated. airtrapping.30 Relationship of increased airway smooth muscle to severity of disease is possible although relationship of any of these structural changes to functional changes is not very clear. Mucus plugging of the small and medium airways contributes further to airflow limitation and air trapping in patients with severe asthma. Residual volumes are routinely > 200% of predicted in severe asthma. hyperresponsiveness.23 Whether this increase in residual volume may be reflective of small airway disease. patients with milder cases of asthma. including the sub-basement membrane (SBM). whereas a Th-2 pattern of inflammation persists despite the presence of high-dose steroid therapy.e. It may be used as a marker for abnormalities in composition. proeosinophilic factors also play a role in the process. The apparent progressive loss of lung function in more severe forms of asthma is due to structural or remodeling changes in the airways and perhaps the parenchyma as well although tthe precise changes are unclear. but the cause of changes in elastic recoil is not clear. This thickened SBM was seen in association with high numbers of TGF-β-positive cells in the submucosa.27 However.Severe Asthma (Fatal Asthma. and loss of elastic recoil/collapsibility are important. which may contribute to inappropriate and inadequate repair process. GR-β). augmenting goblet cell metaplasia and mucus production. with only modestly increased thoracic gas volumes. The epithelium is abnormal in asthma patients. Alterations in the alveolar attachments to the airways and the airways themselves play a role in collapsibility. Refractory Asthma) 309 individuals.29 suggested alterations in epithelial growth factor receptor and TGF-β1 and/or TGF-β2 in asthma patients.22 The FVC1 slow vital capacity ratio is decreased in a group of patients with severe asthma who had persistent eosinophilia. Other studies28. There is no correlation of physiologic measures with inflammatory or structural changes.23. the relationship to disease severity is unclear. In addition to airflow limitation. There is air-trapping in patients with severe asthma. distribution. These changes lead to poor/modified drug response in patients with more unstable asthma. use of alternate agents in treating asthma patients. especially as a large percentage of patients with severe asthma may be aspirin-sensitive.36 of living asthma patients also have suggested that distal lung inflammation may be more important than proximal lung inflammation. patient education. and the clinical approach to the patient with poorly controlled asthma must be systematic and individualised. It is important to recognize that the reasons for lack of response to treatment are numerous.50 have demonstrated statistically significant improvements in lung function and reductions in bronchial reactivity to histamine after treatment with macrolides. contribute to the unique structural/functional relationships of patients with severe asthma. These observations have implications for current drug therapy. 39 The patients without eosinophils also do not appear to have the same degree of collapsibility and have less severe asthma attacks. Due to the significant side effects of many alternate asthma .43 However. Corticosteroids remain the drug of choice because of their broad and nonspecific effects. and there are few alternatives in existence. as most inhaled medications are unlikely to reach the lung periphery in high amounts.37 These structural and inflammatory changes in the small airway and parenchyma may interact to a greater degree in the small airways than the large airways due to the smaller general mass of the airway structure. Leukotriene modifiers may be helpful in some cases.32 It is possible that changes in elastin composition. Autopsy studies33. chest radiograph. It is of importance of maximising standard asthma therapy with close outpatient follow-up.e. less well-defined obstructive diseases like bronchiolitis obliterans also could masquerade as severe asthma.34 have suggested that both increased inflammation and wall thickness may exist in patients who have died of asthma. whose disease remains poorly controlled while receiving standard therapy. including antacids. also supporting a different presentation for this disease subtype.38.42 Other forms of therapy. as opposed to those with milder asthma and healthy control subjects. cholestyramine.47 The increased detection of Mycoplasma pneumoniae and Chlamydia pneumoniae by polymerase chain reaction in the airways of patients with chronic asthma has led to questions regarding their role in pathogenesis48 and several small case series49. Studies35. spirometry.310 Bronchial Asthma Elastin levels have been shown to be abnormal (i.40 Management The treatment of severe asthma remains difficult. may be considered. Physiologic and pathologic data suggest that inflammatory changes exist in the lung periphery. patients with severe asthma have neutrophil predominance or very little inflammation23. and numerous antiepileptic agents. and compliance monitoring. The objective confirmation of asthma and the exclusion of other pulmonary conditions with screening blood tests.46 and the removal of environmental triggers of asthma have been shown to improve asthma control. Classically bronchial asthma has continued eosinophilic inflammation but. The treatment of concomitant gastroesophageal reflux44 and chronic sinusitis45. bronchoprovocation challenge. decreased or disordered) in patients who have died of asthma. Glucocorticoid absorption and metabolism can be affected by thyroid disease and a variety of drugs. Recently CT scan findings confuse the issue whether other. such as cyclosporine and methotrexate have limited value.41 Anti-IgE also appears to be efficacious in patients with more severe forms of asthma and may be of benefit in some of these patients. rifampin.31. secondary to chronic inflammatory elements. The numbers of proteolytic enzymes that alter elastin composition are increased in several instances in asthma. and cardiopulmonary exercise testing is vital in any patient who does not respond to asthma therapy. et al. J Allergy Clin Immunol 2001. Weiss ST. Refractory Asthma) 311 therapies. a blunted eosinopenic response to cortisol-21-succinate. Silverman EK. et al. Speizer FE.156:1760-64. 6. Relationships of active smoking to asthma and asthma severity in the EGEA study: Epidemiological study on the genetics and environment of asthma. 4. et al. et al. 8. Zhu S. recommendations and unanswered questions. Ten Brinke A. Alternaria as a major allergen for asthma in children raised in a desert environment. 10.165. Rakes G. steroid dependent asthmatics studied at National Jewish. Initial demographic information from an extensive data base of severe. J Allergy Clin Immunol 2000.108:375-81. Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection. Kattan M. which was first described in 196851 is characterised by patients with larger than usual daily oral corticosteroid requirements and poor symptom control. and < 15% improvement in FEV1 following 7 to 14 days of treatment with high-dose (i. it is essential to thoroughly address these issues before going for a novel treatment strategy. et al. Miranda C. Oswald H. 9. Adcock IM.109:623-27. Eur Respir J 2000. Ulrik CS.Severe Asthma (Fatal Asthma. Polymorphisms in the IL4. Kozma GT. and FCERIB genes and asthma severity. Pin I. Chagani T. Oryszczyn MP. TGF-β-1 allele association with asthma severity.160:919-22. et al.e. Am J Respir Crit Care Med 1997. Decline of lung function in adults with bronchial asthma. N Engl J Med 1997. Am J Respir Crit Care Med 2002. Persistent wheeze: Its relation to respiratory illness.52 The recognition and early identification of these patients may isolate a subgroup of patients who could benefit from early intervention with alternate asthma therapies with better long-term asthma control and reduction in corticosteroid side effects.15:470-77. et al. Sterk PJ. Am J Respir Crit Care Med 1994. Halonen M. Lanigan A. van Dissel JT.336:1356-63. Proceedings of the ATS Workshop on Refractory Asthma: Current understanding. Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity. Am J Respir Crit Care Med 2000. Irvin CG. > 40 mg daily) oral glucocorticoids. J Allergy Clin Immunol 2001. Stern DA. Gibbs R. Wenzel S. Nagy A. and increased clearance of cortisol. Siroux V. et al. Other clinical characteristics that are associated with steroid resistance include African-American race.23:14-20. et al. Sensitisation to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia: Multiple regression analysis of a populationbased study. Hum Genet 2001. Szalai C. Newton R. Rosenwasser LJ. Rosenstreich DL. IL4RA. Phelan PD. Burchard EG. Tager IB. Sandford AJ. 2.150:629-34. 3. Wright AL. et al. Am J Respir Crit Care Med 1997. Fahy JV. 14. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. 12. Sporik RB. It is also important to distinguish the “difficult-to-manage” asthma patient from the patient who is steroid-resistant. symptoms requiring oral glucocorticoid agents at an early age. Association between a sequence variant in the IL-4 gene promoter and FEV1 in asthma. Pulleyn LJ. Eggleston P.162:2341-51. 11.155:1356-61. Squillace SP. 13.106:135-40. REFERENCES 1. cigarette . Pediatr Pulmonol 1997. 5. 7. Childhood asthma and lung function in mid-adult life. et al. Am J Respir Crit Care Med 1999.107:449-54. Lange P.A119. et al. This asthma subgroup. Wenzel SE. Howat WJ. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. Gelb AF. J Immunol 1993.186:1567-74. Holgate ST.147:405-10. 16. Gosset P. Cytokine mRNA expression in asthma is not restricted to the large airways. et al. 35. Pare PD. Zamel N. J Clin Invest 1998. Djukanovic R. Lackie PM. Kam JC. Am Rev Respir Dis 1980. Am J Physiol 2002. Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Unsuspected pseudophysiologic emphysema in chronic persistent asthma. Am J Respir Crit Care Med 1998. Sturm TM. Am J Respir Crit Care Med 1999. Takeyama K. Elliot J. Wenzel SE. Leung DY. Chan MT. 20. Aldrich TK. Wilson S. Am Rev Respir Dis 1968. et al. Hogg JC. Vignola AM. Distribution and degranulation of airway mast cells in normal and asthmatic subjects. Fahy JV. et al. J Allergy Clin Immunol 1998. Van Natta ML. Combination IL-2 and IL-4 reduces glucocorticoid receptorbinding affinity and T cell response to glucocorticoids. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. 18. 32. Vottero A.312 Bronchial Asthma 15.122:697-707. Rebuck AS. Lane SJ. Adcock IM. Alveolar tissue inflammation in asthma. 26.19:879-85.113:272-77.98:1051-57. Ackerson L. 28. Lamblin C. Hogg JC. Zeiger RS. 24. J Allergy Clin Immunol 1996. Teeter JG. Am J Respir Crit Care Med 2000. Schwartz LB. Lung volume changes in asthma measured concurrently by two methods. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Eur Respir J 2002. Surs W.163:511-16.282:L115-L23. Ogirala RG. 23. Morton AR. Minshall EM. et al. James AL. Woolcock AJ. James AL. Leung DY. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. Woolcock AJ. 25. 21. high-dose intramuscular triamcinolone acetonide versus weekly oral methotrexate in life-threatening asthma: A double-blind study. 19. Am Rev Respir Dis 1993. 33. The static elastic properties in the lungs in asthma. The mechanics of airway narrowing in asthma. et al.151:3460-66. Read J.160:1001-08. et al. Am J Respir Crit Care Med 1995.102: 2156-64.98:788-94. 29. Langmack EL.101:594-601. Riccobono L. Szefler SJ.101:386-90. Szefler SJ. Difficult-to-control asthma: Clinical characteristics of steroid-insensitive asthma. Am J Respir Crit Care Med 1999.139:242-46. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Hamid Q. Kraft M. 34. Carroll NG. Am J Respir Crit Care Med 2001. 30. Milgrom H. J Exp Med 1997. Bender B. Am J Respir Crit Care Med 2000. Noncompliance and treatment failure in children with asthma. Lemjabbar H. 22. Hamid QA. Nadel JA.152:1461-66. 27. J Allergy Clin Immunol 1998. 31. Am J Respir Crit Care Med 1996. et al.154:1505-10.158:1945-50. The structure of large and small airways in nonfatal and fatal asthma.162:1778-82. et al. Richards D. Weiss ST. Bleecker ER Relationship between airway obstruction and respiratory symptoms in adult asthmatics. Am Rev Respir Dis 1971.159:12981307. Am Rev Respir Dis 1989. et al. Chest 1998. smoking and level of pulmonary function in a population sample of children. et al.162:50-56. Mirabella A. et al. Relationship between increased airway responsiveness and asthma severity in the childhood asthma management program. TGF-β isoform release and activation during in vitro bronchial epithelial wound repair.104:703-09. et al. Mutavdzic S. . Cade JF. Single. 17. Carroll NG. Curr Med Res Opin 2001. Jr. Steroid resistance in bronchial asthma.103:1662-69. Am J Respir Crit Care Med 2000. High-resolution CT features of severe asthma and bronchiolitis obliterans. Balzar S. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: Effect of clarithromycin. Brown KK. Holgate S. 50.162:578-85. Radiology 2000. 38. Ekici M. Wenzel S. Curley FJ. et al. Bousquet J.20:254-59.17:233-40. Virchow JC. Lowell FC. Cassell GH.39:181-85. Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma. Irwin RS. Szefler SJ. Sinus disease in children with respiratory disease. Ann Intern Med 1968. Severe/Fatal Asthma.158:998-1001. Bronchoscopic evaluation of severe asthma: Persistent inflammation associated with high dose glucocorticoids. Goldberg M. . Kraft M. Chest 1993. French CL. Siegel SC Chronic sinus disease with associated reactive airway disease in children. 46. Bron AO. Wenzel SE. Difficult-to-control asthma: Contributing factors and outcome of a systematic management protocol. Leung DYM. Difficult-to-control asthma: Clinical characteristics of steroid insensitive asthma.61:310-14. Prasse A. 39. Davidson PJ.156: 737-43. et al. Efficacy of omalizumab. Katz RM. Covar R. Leung DYM. 42. Eur Respir J 2002. Am J Respir Crit Care Med 2000. Transbronchial biopsy as a tool to evaluate small airways in asthma. Am J Respir Crit Care Med 1997. Effect of azithromycin on the severity of bronchial hyperresponsiveness in patients with mild asthma. Szefler SJ. et al. Louis R.Severe Asthma (Fatal Asthma. The relationship between airways inflammation and asthma severity. Refractory Asthma) 313 36. 52. et al. Eur Respir J 1998. Spahn JD. Pediatrics 1984. 40. Chan MTS. Jensen SP. 37. Improved airway targeting with the CFC-free HFAbeclomethasone metered-dose inhaler compared with CFC-beclomethasone. Lau LCK. Erdemoglu AK.21:569-87. Katz RM. Am J Respir Crit Care Med 1998. an anti-immunoglobulin E antibody. Kraft M. Rachelefsky GS. Pak J.101:594-601. Lynch DA. 41. Boudreau RJ. et al. Steroid-resistant asthma. Ekici A. Immunol Allergy Clin North Am 2001. Melby JC. J Asthma 2002. 48. 49.121:1782-88. Naya I. 51.161:9-16. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Chu HW.12:1346-53. 47. in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality. et al.123:405S-10S. J Clin Immunol 1998. 45. Cassell GH. J Allergy Clin Immunol 1978. Chest 2003. Leach CL. et al.69:493-99. 44. Henson JE. Wenzel S. Rachelefsky GS.73:526-29. et al. Chest 2002. 43.217(suppl):595. et al. Wenzel SE. Schwartz HJ. both in cases of adult as well as childhood asthma.1 shows the prevalence of current asthma. to different allergen loads. However. It is possible that the differences may be as a consequence of responses to different allergens. PREVALENCE International Scene A worldwide rise in the prevalence of asthma is being reported with increase in wheeze at an alarming rate of 5% per year. More authentic data was available from the International Study of Asthma and Allergies in Childhood (ISAAC) designed in late 90’s. which is applicable. There are large differences in the prevalence among the rich. and atopy in children. This protection of parasitic infections against asthma may be a cause of less prevalence of the later in many developing countries.2 Table 21. these mites are mainly found in bedding and it is possible that steeping on a bed rather than on a floor. which many poor children do. There was considerable concern that the prevalence of asthma and allergic diseases is increasing in Western and developing countries. airway hyperresponsiveness. From 1983 onwards an increase in asthma mortality and morbidity has been noticed worldwide.3 The study allowed comparisons between populations in different countries. diagnosed asthma. Little is known about such worldwide variations in the prevalence of asthma and allergic diseases.314 Bronchial Asthma 21 Asthma in Children The previous chapters have dealt with bronchial asthma in general. although there is no convincing experimental confirmation. the etiology of these conditions remains poorly understood. the house dust mite has been found everywhere it has been looked for. There are some suggestions that patients with high levels of parasitic infections are less atopic. However. Diet may also be a factor. ISAAC Phase One used standardized simple surveys conducted among representative samples of school children from centres in most regions of the world. partly rich. this chapter will highlight certain important points about childhood asthma. and poor populations. with the highest prevalence found in Australia. wheeze ever. However. increases exposure to them. Exposure to allergens may be important although the most common allergen.1 Data on prevalence of bronchial asthma on children are few from most countries but many from countries like Australia and UK. despite a large volume of clinical and epidemiological research within populations that has been directed at explaining why some individuals and not others develop asthma and allergies. Two age groups (13-14 years and . or to other factors in the environment in the affluent and not-so-affluent populations. 5 • Current asthma: Airway hyperresponsiveness (AHR) + wheeze in the last 12 months.768 9 to 11 4.1) 16.2 (H) 11 to 17 1.2 26.9 37.1 27.1-32.4 1. A video questionnaire completed in the older age group in 99 centres (42 countries) showed a similar pattern.3 30.3 Self completed wheezing questionnaire data in 13-14 years and 6-7 years old age group from different regions of the world are shown in Tables 21.4 6.9 11. The results provide a framework for studies between populations in contrasting environments that are likely to yield new clues about the aetiology of asthma. The major differences between populations found in the International Study of Asthma and Allergies in Childhood Phase One are likely to be due to environmental factors.800) were studied in 91 centres (38 countries).217 1.3 11.1(H) 10.0 (E) ? 527 7 to 16 5.8 21.1 9.0 (H) ? 257 6 to 20 0 0 Kenya Australia Indigenous 402 9 to 12 3.1 8.4 6. The ISAAC study has demonstrated.1 (H) ?30 1.5 2.8 22.3 14.9 New Zealand 813 1.1-32.9(E) 10.4 Aborigines 215 7 to 12 0.7 9. There were marked variations in the prevalence of asthma symptoms with up to 15-fold differences between countries.10 17.084 873 9 6 to 11 12 11.2 and 21. The prevalence of wheeze in the last 12 months ranged from 2.487 1.1% in the younger age group and was particularly high in English-speaking countries and Latin America.9 5.0 14.0 (M) 20. that there are large variations in the prevalence of asthma symptoms throughout the world.7 1.000 children in each group were studied in each centre. • All figures are a percentage of the population tested. E: exercise. The self-reported 12 months prevalence of wheezing among 13-14 years-old between countries .801) were studied in 155 centres (56 countries) and the 6-7 year-old (n=257.2 16.2 14.2 2.7 26.0 (H) 12.7 10.3 ?(H) 8.8(H) 20.7 (E) 1.3 1.1 0 31 6.0 (H) 29.2 7.9 2. by means of simple standardized questionnaires.216 9 to 14 ? 406 7 to 15 1.5 40. 6-7 years) with approximately 3.067 16.3 31.3.613 8.8 27. Diagnosed asthma: asthma ever diagnosed.0 (E) 45. H:histamine.Asthma in Children 315 Table 21.2% in the older age group and 4.3 2.0 (1.6 England Wales Germany Denmark Spain Indonesia China Papua New Guinea 1.0 965 5.575 8 to 10 8 to 11 8 to 11 5.0 (H) 17 3. The 13-14 years-old (n = 463.3 4. M:methacholine.8* 22.1: Prevalence of asthma in children in different countries Country Number Age Current asthma Diagnosed Wheeze asthma ever Airway Hyperresponsiveness Atopy (SPT) Australia 1. 7 1. Chile.7 39.3 12.460 Northern and Eastern Europe Oceania 9.7 36.301 South East Asia Western Europe 6.755 Northern and Eastern Europe Oceania 8.9 1.6 4.460 11.8 22.1 1.2 9.7 12.2 1.7 2.6 11.0 13.57.2 31.6 3.8 16 16.1 10.8 12.1 39.4 23.264 5.549 12.476 Eastern Mediterranean Latin America North America 6.8 29.3 23.6 4.8 2.3 11. Georgia.475 Asia Pacific Eastern Mediterranean 8 10.5 5.2: Twelve months prevalence of bronchial asthma (%) in school going children 13-14 years old age group Region Wheeze ≥4Attacks Severe wheeze Exercise wheeze Night cough Ever had asthma Number studied Africa 11.2 3.819 29.6 4.468 Latin America North America 16. to >30% in the UK. Greece.8 3.0 16.3 16.801 Table 21.5 12.2 19.5 4.827 24. and Russia.8 3.2 2.1 9.1% in Costa Rica.853 19.3 4.6 6.63.0 17.1 4.6 10. and Mexico to >25% in centre in Brazil and Peru.1 3.6 17.9 1. The highest values for 12-moth prevalence of wheeze were found in developed English-speaking countries (e.4 14. Italy.7 4.35.4 60. Romania. and within Latin America from <10% in centres in Argentina. Peru and Costa Rica).1 2.1 12.4 7.5 3.0 14.6 8.7 1.5 13.4 6.5 1.1 30.7 13.4 5.2 1. Parental reported 12 months prevalence of wheezing in 6-7 years-old ranged from 4.4 3.559 Grand Total (All World) 13. the 12 months prevalence in the 13-14 years-old age group varied within Europe from <5% in Centres in Albania.171 1. e.5 20.316 Bronchial Asthma Table 21.2% in the UK.5 3.2 4.9 31.5 9.1% in Indonesia to 32.3 25.0 5.7 7.826 28.9 17.800 Grand Total (All World) ranged from 2.7 83.g.2 9.4 26.6 8.6 2.4 16.7 3.9 28.9 24.0 9.7 3.5 52.6 25.9 1.3 10.8 1.2 2.9 9.2 20.9 29.1% in Indonesia to 32. .6 30.0 37.2 19.g.9 1.8 20.5 3.2 23.4 10. There were considerable variations within regions.6 33.9 4.3: Twelve months prevalence of bronchial asthma (%) in school going children 6-7 years old age group Region Wheeze ≥4Attacks Severe wheeze Exercise wheeze Night cough Ever had asthma Number studied Asia Pacific 9.0 29.9 8.8 3.0 1.6 3.468 South East Asia Western Europe 5.697 68.1 27.8 18.0 4.6 15. 550 children in the age group of 6 to 15 years was undertaken for prevalence of asthma and children were categorized into three group-depending upon the geographical situation of the school in relation to vehicular traffic and the socioeconomic group of children.5 which studied males and females aged 20-44 years. Multiple logistic regression analysis showed that male sex.Asthma in Children 317 The analysis shows that there is consistently more variation between countries than within countries.6% whereas the highest figures was reported from Kottayam (17.4).000 children under the age of 18 years from 1979.15 Another study from Delhi in 1999 revealed the prevalence of current asthma was 11. the ranking of prevalence of wheeze in the last 12 months was similar.5%. In Akola the prevalence was 1. The increased prevalence correlated well with demographic changes of the city.4 to 6. 24.5% respectively. group II—children from heavy traffic region and low socioeconomic population had 31. and group III—children from low traffic area school had 11. it must be remembered that the countries. The prevalence was also the highest 24. 1994 and 1999 in the city of Bangalore showed a prevalence of 9%. and the UK) having the highest and Italy and Greece the lowest rates. A continuation of study in rural areas showed 5. a positive family history of atopic disorders.5 Another hospital based study from South India.1% while that associated with colds by 2. Republic of Ireland. 18. Further to the hospital study.7%.4% of children.6% from Kottayam in the 6-7 years-old age group (Table 21. and the . and centres within countries were self-selected. and type of domestic kitchen fuel were not.5).6-14 Indian Scene The ISAAC data from 12 different parts of the country shows wide variability in the history of wheeze over a 12 months period in children between 13-14 years-old age group ( Table 21..9% in the 6-7 years-old age group. Group I—children from schools of heavy traffic area showed prevalence of 19. India with 14 centres representing the low prevalence group.4%. air pollution (total suspended particulates). Bangalore on 20.4. The only other comparable international survey of asthma is the European Community Respiratory Health Survey (ECRHS). Boys had significantly higher prevalence of current asthma as compared with girls (12. Among the 13 centres 10 countries that were reported in both studies. a school survey in 12 schools on 6.4% of children. New Zealand. Subsequent other studies from different parts of the world also show similar trends. respectively). There is a difference in the prevalence of asthma in children from Northern and Southern part of the country. and it is possible that countries with larger within-country variation did not participate. From the Northern part of the country the figure varied between 5. mainly from European centres.5% between 1994-99. The children from this town also had history of “Ever had asthma” of 12. The figures from the Western part were less compared to those from the Northern and Southern regions.9%.5%. with the English-speaking countries (Australia.7% in children of 6-15 areas. Exclusive exercise-induced asthma was reported by 2.5% and 29. Three countries with a very large number of centres were represented across the range of prevalence. 10. and the presence of smokers in the family were significant factors influencing the development of asthma while economic class.15% respectively. 1989. Significant risk factors for its development are male sex. 1984.14%.34%. a positive family history of atopic disorders. The prevalence of current asthma in children in Delhi is 11.8% and 10. Italy with 14 centres representing the middle prevalence group and the UK with 15 centres representing the high prevalence group.5% and persistent severe asthma 4% to 6.8%) in the South. However. The persistent asthma also showed an increase from 20% to 27.9% while past asthma was reported by 3. 7 2.0 1.8 0.2 1.0 2.9 1.1 1.5 18.8 1.1 3.4 3.4 32.2 2.2 8.3 2.4 6.0 1.6 1.5 24.3 31.8 1.7 17.8 1.2 0.8 1.4 2.318 Bronchial Asthma Table 21.9 13.0 1.1 3.9 3.3 3.030 Bombay (Area 2) Bombay (Area 3) 3.7 1. There were 4.5 1.3 3.9 0.8 4. Using a previously standardized questionnaire.8 12.7 4.090 students in the 9 to 20 years age range were analyzed.3 1.7 7.139 10.2 25.8 4.4 15.3 4.1 2.7 3.6 27.4 1.938 1.0 2.520 3.0 1.3 3.4 1.4 23.367 (48%) boys.5 2.6 1.2 8.4 12.8 2.6 3.5 9.7 3.9 4.2 6.3 3. Among 4.8 3.4 1.9 18.672 2.5 3.225 Bombay (Area 2) Bombay (Area 3) 10.5 1. North India examined the prevalence of asthma and its association with environmental tobacco smoke exposure among adolescent school children.4 2.891 3.6 0.7 1. asthma .4 2.5 0.1 1.026 3.5 5.8 6.723 (52%) girls.226 3.903 3.0 10.3 3.6 1.9 3. data from 9.5 15.0 4.8 2.4 2.16 A more recent study from Chandigarh.3 8.9 1.4 2.8 1.4 14.9 5.3 3.8 16.6 8.702 Borivali Chandigarh Jodhpur Kottayam Madras (Area 1) Madras (Area 2) New Delhi Neyveli Orissa Pune Table 21.8 2.3 13.4 1.6 2.5: Twelve months prevalence of bronchial asthma (%) in school going children 6-7 years old age group in different parts of India Region Wheeze ≥4Attacks Severe wheeze Exercise wheeze Night cough Ever had asthma Number studied Akola Bombay (Area 1) 5.1 14.6 1.178 3.5 1.104 2.5 2.0 12.6 11.8 4.3 4.8 3.9 0.4 22.2 1.9 6.4 4.0 2.9 17.6 1.6 1.8 2.0 1.6 3.248 2.3 10.5 1.6 0.491 New Delhi Neyveli 6.6 8.4 7.5 2.0 13.697 2.8 0.4 11.7 9.0 3.4 1.7 1.7 1.2 5.4 0.2 1.156 Madras (Area 1) Madras (Area 2) 7.6 3.2 1.8 1.6%.0 3.878 3.6 2.3 2.8 1.8 13.248 Jodhpur Kottayam presence of smokers in the family.1 2.9 1.9 3.406 2.1 1.498 Orissa Pune 4.2 1.8 16.568 Borivali Chandigarh 5.1 7.8 1.967 3.6 3.138 4.6 7.4 14.3 6.4 14.0 6. in whom the observed prevalence of asthma was 2.7 5.5 2.7 2.094 2.8 12.5 8.5 3.3 0.5 2.086 13.0 5.047 8.4: Twelve months prevalence of bronchial asthma (%) in school going children 13-14 years old age group in different parts of India Region Wheeze ≥4Attacks Severe wheeze Exercise wheeze Night cough Ever had asthma Number studied Akola Bombay (Area 1) 1.6 0.281 3. It has been suggested that after 26 weeks gestation.16 urbanization.0001).17 and other socio environmental factors. with increased IFN-γ production. environmental tobacco smoke. Several studies have reported an increased prevalence of respiratory symptoms like cough.20 . Such a mechanism might also be invoked as a factor in sudden infant death syndrome in which mast cell tryptase and eosinophils are encountered in the lung and circulation. to prevent maternal rejection and that. IL-4 is produced by the human amnion epithelium throughout pregnancy. If. and the presence of smokers in the family. how minute amounts of allergen taken in by the mother can cross the placenta to sensitive offspring. such as birch pollen. wheeze and reduction in lung function in children or adolescents who were born as premature infants or who had a low birth weight. ETS was also positively associated with prevalence of all the respiratory symptoms. not paternal. however.6 and 2. a cytokine that inhibitors have been found in human placenta.9%) students. However. and IL-10. on account of factors.33-2.19. allergy in the development of allergy and asthma. with odds ratios varying between 1. such an occurrence is excessively uncommon and the intrauterine environment is a more likely cause. the fetus adopts a T’hl immunephenotype.25.Asthma in Children 319 was present in 90 (1.31). in the last trimester. during the last trimester of pregnancy are more likely to have children who develop allergy and asthma. A positive relationship has been found between greater head circumference at birth and the later development of allergy and high serum IgE levels. but placental and nutritional factors that increase brain growth in the last trimester of pregnancy may well influence the maturation of the thymus gland. that children who subsequently develop allergy or asthma.17 Risk Factors A number of risk factors have been identified for the causation of bronchial asthma in children. 31% students reported presence of one or more respiratory symptoms. p<0.78 (95% confidence interval 1.15. this phenotype converts to a more T’hl picture. The odds ratio for being asthmatic for patients exposed to ETS compared to those not exposed to ETS was 1. This impaired response suggests an impaired inhibitory mechanism for shutting down a Th2 response rather than one that primarily enhances it.18 Intrauterine Exposure Some studies have suggested a link to maternal. It is also possible that allergens crossing the placenta may be involved in subsequent development of allergy and asthma since mothers exposed to high concentrations of allergens. More students with asthma had either parents or other family members smoking at home as compared to nonasthmatics (41% vs. it has been shown. They include male sex a positive family history of atopic disorders. have impaired cord blood T-lymphocyte production of IFN-γ at birth in response to exposure to specific allergens. It is not known. an allergic diathesis might be expected to occur. such an association may sound strange. the Th2 mode is maintained rather than converting to a T’hl mode. While it has been suggested that preferential acquisition of the mother’s genes (genomic imprinting) may account for this phenomenon. At first. 28%. the origin of the immune system. Other environmental factors that may direct the placental-fetal relationship towards a Th2 response include young maternal age and smoking during pregnancy. air-pollution. 320 Bronchial Asthma Viral Infection It has long been recognized that viral infections, especially the common cold viruses, can lead to deterioration of asthma lasting several weeks. In infants, respiratory syncytial virus (RSV) is responsible for most wheezing illnesses. These observations have suggested that viral infections may be intimately involved in the development of asthma and allergy. It has been shown that over 80% of acute asthma exacerbations in school children and about 60% in adults result from viral infections (mostly common cold viruses). One explanation of the susceptibility of the asthmatic airway to viral inflammation is that persistent allergic mast cell and eosinophil-driven inflammation stimulates the release of cytokines such as tumour necrosis factor-alpha, which cause an increase in the expression of receptors for human respiratory viruses on the airway lining epithelium. In the case of most rhinoviruses, the receptor is an adhesion molecule, intracellular adhesion molecule-1. Once the virus enters the epithelial cells, it replicates and is able to generate wide variety of proinflammatory cytokines, which further enhance eosinophil and mast cell inflammation. Protective Infections Curiously, an important additional socioeconomic factor may be a reduction in early childhood infections (viral, bacterial, or parasitic) associated with improved living conditions. While viral infections can undoubtedly cause deterioration of established asthma, there is evidence that viral or bacterial infection during the first 3 years of life may serve a protective function against the development of allergic diseases. One of the most consistent risk factors for allergy relates to family size. The prevalence of mucosal allergy and positive skin tests in children declines markedly in the last-born child with increasing numbers of siblings. A working hypothesis is that over the past 30 years, opportunities for acquiring infections from siblings or playmates in early childhood have declined with reduction in average family size, vaccination programs, and higher standards of personal hygiene. Most viruses and some bacteria are able to evoke a Thl like protective response with the generation of IFN-α and IL-12. Thus, if multiple infections occur during the first few years of life, high concentrations of these Th1, cytokines could inhibit the release of Th2 cytokines, thereby biasing the mucosal immune response away ‘for this hypothesis is seen in an African study of, from allergen sensitization. Support adolescents infected with measles during the first year of life compared to those vaccinated later. Those infected early had a 63% lesser chance of developing positive skin tests to common aeroallergens. Repeated Bacille Calmette-Guerin (BCG) vaccination in young Japanese children also exerts a protective effect against the development of allergy. Both measles and BCG are potent stimulators—of the Th1 cytokine response’. It has also been suggested that the increase in asthma and allergy with movements to urban centres may be related to the decrease in early exposure to parasitic infections common in some rural areas. One study tested the effect of anti-helminthic treatment on the allergic reactivity of children in a slum area of Caracas, Venezuela. One group was treated for 22 months while a second group who declined treatment was used as a control. Active treatment eliminated worms in children (from 68 to 5%) and resulted in a decrease in total serum IgE levels (from 2,543 to 1,124 IU/ml) but was accompanied by an increase in skin test reactivity to house dust mite (from 17 to 68%). In contrast, in the untreated group, parasite colonization continued to increase (43 to 70%), IgE levels increased (1,649 to 3,697 IU/ml), but dust mite Asthma in Children 321 sensitization fell (26 to 16%). Further testing showed that polyclonal stimulation of IgE synthesis by the parasites resulted in mast cell receptor saturation and suppression of specific IgE antibody synthesis. From a public health stand point; high levels of nonspecific IgE may protect rural dwellers exposed to parasites from allergy and asthma. It follows that eradication of parasites or reduced opportunities for infection could, in part, explain the rural to urban differences in the prevalence of allergic diseases. Some investigators believe that early childhood respiratory symptoms are a risk factor for asthma.21 This inference however, is weakened by the possibility of recall bias. Perhaps, respiratory symptoms reported by parents very early in life are not significantly associated with future asthma, but those symptoms that begin at or persist through age 3 to 4 years are likely to be associated with asthma.22 Diet As societies become affluent, the dietary habits change and such changes are linked with increased prevalence of asthma observed in recent years.23-25 Prospective studies have shown that breastfeeding has a transient beneficial effect on the incidence of eczema, food allergy, atopic sensitization, and wheezing illness in the first three years of life.26,27 However, there is little evidence for a persistent protective effect of breastfeeding on the ‘incidence of childhood asthma.28-30 In the UK, the amount of salt eaten with food seems to be correlated with bronchial hyperreactivity and asthma mortality.31 The severity of asthma—not its inception—has been linked to increased salt intake, but only in males.32 Recent studies have shown lower prevalence of asthma and bronchial hyperresponsiveness in children with a high intake of fresh oily fish,33 a source of’ polyunsaturated oils. Other studies also have shown an association of a, high fish consumption and improved baseline FEV1.34 Children who eat fish regularly consume more omega-3 fatty acids, which may protect them from bronchial hyperresponsiveness. Air-Pollution Air-pollution has been cited as—a causal factor in the development of asthma. The US Environmental Protection Agency concludes that35 passive exposure to tobacco smoke is causally related to: i. An increased risk of lower respiratory tract infections, such as bronchitis and pneumonia in infants and young children, ii. A small but significant dose-dependent reduction in pulmonary function, and iii. Additional episodes and increased severity of asthma symptoms in asthmatic children. Exposure to tobacco smoke is also considered to be a risk factor for the development of new cases of asthma in children.36 Trucson Children’s Respiratory Study has shown that maternal smoking is related to both transient early wheezing and persistent wheezing.37 The role of sulphur dioxide and particulate matters in the causation of asthma is not well established.38-41 Traffic pollutions42 and effects of ozone may also be of consequence for childhood asthma.43 Evolution of Asthma Asthma may develop during the first few months of life, but it is often difficult to make a definite diagnosis until the child is older. In infants, the most common cause of wheezing is 322 Bronchial Asthma respiratory viral infections. However, there is a correlation of early wheeze with reduced lung function before the onset of symptoms, which suggests that small lungs may be responsible for some infant wheeze that resolves with the child’s growth. Those children with asthma continue to wheeze in later childhood. Recurring exacerbations of asthma may be associated with exposure to allergens. In the susceptible infant, atopy may predispose the airways to sensitization by environmental allergens or irritants and the child experiences recurrent episodes of wheezing. In particular, early exposure to Alternaria, housedust mite, and animal allergens in high quantities appears to be important as discussed above. During early childhood, wheezing and cough may occur at infrequent intervals. In some infants wheezing becomes more frequent and asthma is well established at an early age. It is reported that the majority of 7-years-old children with airway hyperresponsiveness suffered from atopy during their infancy.44 Asthma also affects development of the lung. Asthma in infancy can result in a decrease ‘in lung function by approximately 20% in adulthood,45 although subsequent studies did not confirm the same.46 The predominant feature associated with asthma in children is allergy, and house dust mite represent major allergens worldwide in, both affluent and partly affluent countries.47 The role of viral infection in the causation of asthma in older children is less clear, although in atopic children viral infection is clearly important triggers of asthma exacerbations. By the age of 8 years, a proportion of children develop airway hyperresponsiveness and the associated symptoms of moderate to severe persistent asthma, while others continue to have mild intermittent asthma.48 Lung growth is unaffected in most children with asthma, but it can be reduced throughout childhood and adolescence in those with severe and persistent symptoms. A longitudinal study in New Zealand concluded that improved spirometric function was impaired in children with airway hyperresponsiveness and/or allergy to house dust mite or cat allergen.49 Although childhood asthma has long been considered as a single, easily recognizable disease characterized by reversible airflow limitations,50 recent findings have challenged this concept. Martinez et al21 studied the natural history of children (0-6 years) and found that approximately half of them experienced wheezing at some time during the study period. They recognized three patterns of wheezing: 1. Transient early wheezing. Wheezing occurred in life but resolves by the age of three years 2. Late onset wheezing. Some experience wheezing between the ages of three and six years 3. Persistent wheezing. Wheezing illness throughout the entire study period. The outcomes of these patterns are associated with different risk factors. Children with transient early wheezing had reduced pulmonary function as measured by functional residual capacity shortly after—birth and before any lower respiratory tract illness had occurred. The risk also increases in children—of mothers who smoked during pregnancy, had lower lung function values compared to those whose mothers did not smoke. Thus, the authors concluded that congenitally smaller airways might predispose children to wheeze illness later in life. Persistent and late onset wheezing is more likely associated with atopy with their mothers being asthmatics. Lung function in persistent wheezers is also less. The long-term prognosis of childhood asthma is a matter of controversy and of major concern. It has often been believed that the child grows out of its asthma when he or she reaches adulthood (asthma disappears). However, epidemiological studies are less convincing.46,51,52 Although there are methodological difficulties it is estimated that asthma disappears in 30 to 50% of children at puberty, but often reappears in adult life. Up to Asthma in Children 323 two-third of children with asthma continue to suffer from the disorder through puberty and adulthood. Even when asthma symptoms disappear, the lung function frequently remains altered or airway hyperresponsiveness or cough persists. The prognosis of asthma becomes worse when the child has eczema or there is a family history of eczema. Wheezing in the first year of life is not a prognostic indicator for asthma or for more severe asthma or for more severe asthma later in childhood. About 5 to10 % of children with asthma that is considered trivial will have severe-asthma in later life. Therefore, childhood asthma should never be neglected with the hope that the child will grow out of it. Children with mild asthma are likely to have a good prognosis, but those with a moderate to severe asthma probably continue to have some degree of airway hyperresponsiveness and will be at risk of the long-term effects of asthma throughout life.53 Some, clinical studies have reported that up to 80% of asthmatics become asymptomatic during puberty.54,55 In a cohort study of Australian school children56 tested initially at the age of 8 to 10 years and then again at 12-14 years of age, the persistence if bronchial hyperresponsiveness at 12 to 14 years of age was found to be related to the severity of disease at 8 to 10 years of age, the atopic status of the child, and the presence of asthma in the parents. Most of the children who had a slight or mild degree of bronchial hyperresponsiveness at 8 to 10 years of age lost their increased response by the age of 12-14 years. However, only 15.4% of children with severe or moderate bronchial hyperresponsiveness at initial assessment had normal levels of bronchial responsiveness at the later assessment. There are several factors why asthma often goes unrecognized and tends to be under treated in teenagers because usually this is a period of turmoil, awkwardness, rebelliousness, and intolerability.53-59 Notwithstanding the factors described above as the factors responsible for the induction of asthma in childhood, occurrence of asthma within families is the strongest risk factor for the development of asthma in children.60-63 DIAGNOSIS Various symptoms and signs of bronchial asthma are not different than those in adults as discussed earlier. However, in children there is more chance of under diagnosis in this age group. This is a frequent problem and occurs most often when young children who wheeze only when they have respiratory infections and are dismissed as having wheezy bronchitis, asthmatic bronchitis, bronchitis, bronchiolitis, or pneumonia, despite evidence that the signs and symptoms are most compatible with a diagnosis of bronchial asthma. Although, recurrent episodes of cough and wheezing are almost always due to asthma in both children and adults, it is to be remembered that all that wheezes is not asthma always. There are other causes of airways obstruction leading to wheezing. The differential diagnosis will be as follows. Infants and Children Obstruction in the Large Airways 1. Foreign body in trachea, bronchus 2. Vascular rings 3. Laryngotracheomalacia 324 Bronchial Asthma 4. 5. 6. 7. Enlarged lymph nodes or tumors Laryngeal webs Tracheal stenosis Bronchial stenosis Obstruction Involving both Large and Small Airways 1. 2. 3. 4. 5. 6. 7. 8. 9. Bronchial asthma Viral bronchiolitis Cystic fibrosis Chlamydia trachomatis infection Obliterative bronchiolitis Bronchopulmonary dysplasia Aspiration Vascular engorgements Pulmonary oedema Miscellaneous 1. 2. 3. 4. Primary ciliary dyskinesia syndrome Primary immune deficiency Congenital heart disease Congenital malformations causing narrowing of intrathoracic airways. Asthma in childhood can present a particularly difficult problem largely because episodic wheezing and cough are among the most common symptoms encountered in childhood illnesses, particularly in the under-3-years-old. Although health care professionals are increasingly encouraged to make a positive diagnosis of asthma whenever recurrent wheezing, breathlessness, and cough occur (particularly if associated with nocturnal and early morning symptoms), the underlying nature of the disorder’s process may differ in infants from that in older children and adults. The use of the label “asthma” to describe such children has important clinical consequences. It implies a syndrome in which there is airway inflammation and for which there is a specific protocol of management. The younger the child, particularly below ages 5, the greater the possibility of an alternative diagnosis for recurrent wheeze as described above. Chest radiography is important as a diagnostic test to exclude alternative causes. Features such as a neonatal onset of symptoms, associated failure to thrive, vomitingassociated symptoms, and localized lung or cardiovascular signs all suggest an alternative diagnosis and indicate the need for investigations, such as a sweat test to exclude cystic fibrosis, measurements of immune function, and reflux studies. Among those with no alternative diagnosis, there is the possibility that the problem does not have a uniform underlying pathogenesis. Nonetheless, there are two general patterns of wheezing in infancy. Some infants who have recurrent episodes of wheeze associated with acute viral respiratory infections, often with a first episode in association with respiratory syncytial virus (RSV) bronchiolitis, come from nonatopic families and have no evidence of atopy themselves. These infants usually outgrow their symptoms in the preschool years and have no evidence of subsequent asthma, though they may have minor defects of lung function Asthma in Children 325 and airway hyperresponsiveness. This syndrome may have more to do with airway geometry than airway inflammation, and thus may differ mechanistically from the more established chronic inflammatory condition that underlies asthma in older children and adults. Other infants with asthma have an atopic background often associated with eczema and develop symptoms later in infancy that persists through childhood and into adult life. In these children, characteristic features of airway inflammation can be found even in infancy. However, there are no practical clinical tests that can be done to establish the presence of airway inflammation. Only associated atopic problems can be used as a guide to prognosis. Early age (less than 2 years) of onset of wheeze is a poor predictor of continuing problem in later childhood. It is likely that the issue of asthma associated with recurrent virus-related episodes and the later development of persistent asthma requires further study. Apart from the confusion over aetiological mechanisms of asthma in childhood, there is also considerable reluctance in establishing a diagnosis and, as a consequence, initiating appropriate therapy. Because lower respiratory tract symptoms similar to symptoms of asthma are so common in childhood (and frequently occur in association with upper respiratory tract symptoms), either a correct diagnosis is not made or an inappropriate diagnosis is given, thereby, depriving the child of antiasthma medication. Although in these young children there is the possibility of over treatment, the episodes of wheezing may be foreshortened and reduced in intensity by the effective use of antiinflammatory drugs and bronchodilators rather than antibiotics, and it is for this reason that health care professionals are encouraged to use the word “asthma” rather than other terminology to describe this syndrome. Asthma in all age groups may present only as repeated coughing especially at night, with exercise, and with viral illness, but these are particularly common forms of presentation of asthma in childhood. The presence of recurrent nocturnal cough in an otherwise healthy child should raise awareness of asthma as a probable diagnosis. Although repeated infections of the sinuses, tonsils, and adenoids may explain nocturnal coughing, the occurrence of this symptom awaking the child in the early hours of the morning is almost always diagnostic of asthma. Under the age of 5 years, the diagnosis of asthma has to rely largely on clinical judgment based on a combination of symptoms and physical findings. Because the measurement of airflow limitation and airway hyperresponsiveness infants and small children requires complex equipment and is difficult, it can therefore only be recommended as a research tool. A trial of treatment is probably the most confident-way in which a diagnosis of asthma can be secured in children (and in many adults as well). Prognostic features include a family history of asthma or eczema and presence of eczema in a young child with respiratory symptoms. Children aged 4 to 5 can be taught to use a peak expiratory flow (PEF) meter and obtain reliable readings. However, unless there is careful parental supervision over when and how the measurements are made, PEF recording in childhood can be unreliable. Some children with asthma only present with exercise-induced symptoms. In this group, or when there is doubt over the existence of low-grade asthma in childhood, exercise testing is helpful. A 6-minute running protocol is easily performed in clinical practice, and when used in-conjunction with measurements of airflow limitation (FEV, or PEF), it can be most 326 Bronchial Asthma helpful in establishing a firm diagnosis, especially if the cough produced by the exercise is similar to that occurring spontaneously at night. MANAGEMENT OF ASTHMA IN CHILDREN Several guidelines have been published since 1990 with the aim of improving management of asthma both in children and adults. However, a systematic analysis of guidelines till 1995 had brought out several controversial-issues as well as gaps in knowledge. In May 1997, an expert committee of the National Heart Lung and Blood Institutes of USA published guidelines about management of asthma where they have tried to overcome many of the previous lapses. These guidelines along with the recent British thoracic society guideline have been discussed in previous chapters. The need for similar guidelines has always been felt amongst the physicians managing children in India, but no uniform guidelines are available for the disease as seen in India. It. was felt that the guidelines originating in India would have much more relevance to the ground situation and the status of health services. To setup the process of achieving consensus, towards suitable guidelines, a Consensus Conference was held on April 17 and 18, 1998 at the Advanced Paediatric Centre of the Post Graduate Institute of Medical Education and Research, Chandigarh in which, 15 experts who manage asthma patients and have published papers in this field, participated. Recent evidence was accessed using searches on Medline, Embase, Index Medicus, and Excerpta Medica. Some of the contentious issues were resolved with the help of the Cochrane Library.64 Since the consumer of health care in India is not sufficiently literate, physicians have been assigned a lot of responsibility in decision making for the patients. The guidelines are required to be updated periodically and provide flexibility to individualize patients. Since in a large area in our country, all the recommended modalities may not be available then suitable improvisations must be made. The objectives of the conference were: i. To reach at a uniform treatment approach towards children with asthma keeping in mind the limitations of resources in the Indian context and to develop guidelines based on available evidence for the pediatricians, and ii. To prepare a consensus document for management of children with asthma which would provide guidelines to a general pediatricians managing asthma in India. Various components discussed included pathogenesis, definition, classification of severity, measure of assessment and monitoring, referral, control of factors contributing to asthma in seventy, pharmacological therapy and education of patient, family and health professionals regarding asthma care. The Expert Group I recommended that for the diagnosis of asthma in children a detailed medical history, careful physical examination and peak-expiratory flow rate (PEFR) measurement to demonstrate obstruction with reversibility of variable airflow obstruction are needed. To establish the diagnosis of asthma the clinician must determine that: i. Episodic symptoms of airflow obstruction, more than 3 episodes are present ii. Airflow-obstruction is at least partially reversible iii. Alternative diagnoses are excluded. Asthma in Children 327 Physicians who care for children with asthma should be well versed in PEFR monitoring. They should perform spirometery wherever possible. Measures of Assessment and Monitoring A child with asthma is to be monitored for clinical signs and symptoms of asthma with the help of asthma diary given to the patients/parents and record of PEFR with a standardized peak flow meter. PEFR must be monitored at the physician’s office, asthma clinics (where spirometry should be available) and in the emergency room, and patients must be encouraged and trained to monitor their PEFR at home once a day routinely and twice a day if the morning reading is abnormal to determine their PEFR variability. Patient’s personal best should be assessed and used subsequently. Spirometry has been kept optional, and emphasis must be given to patient’s quality of life. Emphasis must be on self-management but physician’s supervision must still be the prima mode. Patients must be given a written crisis management plan where literate. Otherwise verbal communication at each contact must continue. Classification of Asthma Severity Asthma severity classification was accepted as changed to be mild intermittent, mild persistent, moderate persistent and severe persistent asthma (Table 21.6). Since spirometry is not routinely available to pediatricians in this country it was felt that more emphasis be placed on PEFR measurement, especially at the physician’s office. Patient’s personal best be used as the standard but in its absence expected PEFR according to norms published on children in India must be used.65 It was also mentioned that a severe form of asthma requiring daily oral steroids or stronger treatments like immunosuppressants is extremely uncommon in Indian children, and most of the children get controlled with inhaled medications. Goals of Asthma Therapy The goals of asthma therapy are: • Prevent chronic and troublesome symptoms • Maintain near normal (PEFR) • Maintain normal activity levels (including exercise and physical activity) • Prevent recurrent exacerbations of asthma and minimize the need for emergency room visits and hospitalization • Provide optimal pharmacotherapy with minimal side effects • Meet patient’s and family’s expectations of satisfaction with asthma care. Pharmacological Therapy Pharmacological therapy is the cornerstone of management. It must be instituted with proper environmental control measures. Medications are classified into two broad categories: i. Long-term control medications or the preventatives, and ii. Medications or rescue medications. Long-term control medications, are, inflammatory compounds. Early intervention with inhaled steroids can improve control and normalize lung function, and preliminary studies show that it might prevent irreversible airway injury. These are to be administered with the help of a metered dose inhaler (MDI) and A child should be assigned to the most severe category in which any feature occurs.7).8 gives details of assessment of severity of asthma in children and Figures 21.1 and 21.2 outline management of asthma exacerbation. Table 21. . steroid pesistent (BDP 1200 μg or BUD>600 or FP* step 4 200-400 μg + Long acting beta sympathomimetic or SR Theophylline or oral steroids. Another cheaper alternative is a dry powder inhaler (transparent rotahaler).Step 1 + selfdilator Infants as monitoring in step I education/ counselling Short-acting broncho. For infants inhaled medication with spacer and mask Mild Daily medication NSAIDs like Cromolyn persistent (1-5 mg/dose Oh) or low-dose inhaled step 2 steroid (BDP 200-600 or BUD 100-400 or Quick relief Education Short-acting broncho. Asymptomatic between exacerbations The presence of one of the features is sufficient to place a patient in that category. lasting days Symptoms > 2/week But <1 /day Exacerbation may affect activity Symptoms ≤ 2/week Exacerbation brief.328 Bronchial Asthma a spacer (in patients who cannot afford the spacers a home-made spacer can be used). Infants as monitoring in step 1 Group education Short-acting broncho. An individual classification may change over a period of time Table 21.. For infants ≤ 2 years inhaled medication with spacer and/or mask Moderate Daily therapy.7: Stepwise approach in long-term management of children with asthma Grade Long-term Severe Daily therapy high dose inhaled.6: Classification of asthma severity Guide Symptoms Night-time symptoms Lung Function Severe persistent Step 4 Continual symptoms Frequent PEFR < 60 % predicted > 1 time/week PEF>60 to <80% predicted >2 time/month PEF ≥80 % predicted ≤ 2 time/month PEF ≥80 % Moderate persistent step 3 Mild persistent step 2 Mild intermittent step 1 Limited physical activity Frequent exacerbations Daily symptoms Daily use of beta-agonist Exacerbation affecting activity.Step 1 + selfdilator. Table 21. ≥ 2/weeks. Infants as in monitoring step 1 Group education Contd. A step care approach management of asthma starting at a higher level and then stepping-down as control is established (Table 21.. Medium-dose inhaled pesistent steroid (BDP 600-1200 μg or BUD step 3 400-600 or FP 100-200 μg) or Low-medium dose inhaled steroid + SR Theophylline or long acting beta sympathomimetic.Step 1 + selfdilator. shorter cry. intermittent step 1 Long-term Quick relief Education FP50-100 μg) and Theophylline 5-15 mg/kg spacer and mask for infants ≤ 2 years No daily medications needed Short acting bronchodilator. environmental control Abbreviation: BDP-beclomethasone dipropionate.. discuss role of medication. SR-sustained release. selfmanagement and action plans.. Use facemask with holding chamber or nebuliser or oral β2agonist Basic facts about inhaler technique. difficult feeding) Prefers sitting Phrases Words Symptoms Breathlessness While walking Talks in sentences Alertness May be agitated Usually agitated Signs Respiratory rate Increased Increased ReiTiratory Arrest Imminent Sits upright Usually agitated Drowsy/confused Often >30/ m (Guide to breathing rates in awake children): Age Normal rate < 2months < 60/niin < 2-12 months < 50/n-dn 1-5 years < 40/n-dn 6-8 years < 30/min Use of accessory muscles: Suprasternal retractions Usually not Commonly Usually Paradoxical thoracoabdominal movement Contd. .. BUD-budesonide.. FP is recommended for children older than 4 years Table 21.Asthma in Children 329 Contd. inhaled β2 agonists sos use of β2-agonist > 2 times/ week indicates need for preventative drugs.8: Classifying severity of asthma exacerbations Mild Moderate Severe While at rest (infant—stops feeding) Can lie down While talking (infant—softer. Grade Mild asduna. FP-fluticasone propionate. For infants (< 2 years) bronchodilator as needed for symptoms. At the end of hour repeat assessment with more emphasis on symptoms and signs.3 to 0.. exercise. stress. Contd. breath sounds intensity. Respiratory rate. pulses paradoxus <10 mm Hg. PEFR< 50 to < 70%. 3. drugs. Mild Moderate Severe ReiTiratory Arrest Imminent Wheeze Moderate often only end expiratory Loud. Incomplete response/poor response Mild to moderately severe symptoms and signs (see Table No. 1. . heart rate. respiratory rate. throughout exhalation Usually loud. Start β2 sympathomimetic nebulisation 0. Sensorium 2. PEFR done if possible. throughout inhalation and Absence of wheeze Pulse/min < 100 100-120 > 120 Bradycardia (Guide to heart rate in normal children): Age Normal rate 2-12 months < 160 min 1-2 years < 120 min 2-8 years < 110 min Ask and record Examine for 1. use of accessory muscles. Severity of previous episodes of treatment required Treatment Phase I—Ist one hour 1.. seasonal.15 mg/kg/dose (minimum dose 2. B.8) for mild. 3. Prednisolone 2 mg/kg/dose or methylprednisolone 1-2 mg/kg/dose or hydrocortisone 10 mg/kg/dose. From the assessment 2 groups are identified: A. In interpreting PEFR value is compared with predicted value of Indian children or personal best of the child if available. Oxygen by mask to achieve saturation >90% (minimum 5 L/min through simple facemask) 2. For delivery dilute aerosols to minimum of 4 ml of saline at (flow of 6-8 1/minutes) or β2 sympathomimetic through MDI and spacer with/without facemask 4 to 8 puffs every 20 minutes (10-20 puffs in one hour).330 Bronchial Asthma Contd.5 mg every 20 minutes for 3 doses in the first hour subcutaneously..01mg/kg up to 0. etc. 5. In case of nonavailability of nebuliser or MDI and spacer or where the patient cannot move the needle of the peak flowmeter—parenteral beta-agonists (adrenaline/terbutaline) should be given in the dose of 0. wheeze 3. colour. 2. Peak expiratory flow rate Duration of present episode Medications already being used Time of last aminophylline dose (if taking) Precipitating factors—infections. no usage of accessory muscles.5 mg) every 20 min for 3 doses. Saturation-SaO2 if pulse oxymeter is available 4. moderate and severe classification of symptoms signs. All children presenting with acute exacerbation should receive systemic steroids. PEFR>70%. 21. 4.. alert sensorium) O2 saturation >90 per cent. Good response Physical examination normal (decrease in heart rate from the previous value. breathlessness. . Fig. shallow respiration. β2-sympathomimetic inhalation every 20 mts Continuous nebulization can also be used under strict monitoring for heart rate and blood potassium levels.1: Management protocol for acute exacerbation of childhood asthma emergency room Assess Severity Measure PEF: Value <50% personal best or predicted suggest severe exacerbation Note signs and symptoms: Degrees of cough. recommend close medical follow-up. .Continue systemic steroids. Good response Incomplete response Poor response Mild episode PEF>80% predicted or personal best Moderate episode PEF 50-80% predicted or personal best Severe episode PEF<50% predicted or personal best Contd. If deterioration. B.Discharge home. confusion or drowsiness ii. Continue systemic steroids 1-2 mg/kg/day in 2 divided doses for 3-10 days.Add ipratropium bromide nebulization 250 micrograms every 20 mts for three doses. wheeze and chest tightness correlate imperfectly with severity of exacerbation.. (0. aminophylline infusion. Stop parenteral aminophylline. Initial Treatment Inhaled short-acting beta-agonist: Up to three treatments of 2-4 puffs by MDI at 20-minute intervals or single nebuliser treatment.Patient education.continue treatment with β2-agonist and course of oral systemic corticosteroid 1-2 mg/kg/day maximum 60 mg/day in a single or 2 divided doses for 3-10 days. Incomplete/Poor responders .IV Magnesium sulphate 50% 50 mg/kg/dose IV infusion in 30 ml normal saline/30 mt can be given before transfer to ICU. . Phase II—Management A. Exhaustion.25 mg/kg/hr) can be tried. continue same treatment for 4 hours. 21. . Improvement at end of 6 hours since initiation of treatment decrease the frequency of β2sympathomimetic inhalations every 1 to 4 hr as needed. Accessory muscle use and suprasternal retraction suggests severe exacerbation. Coma/respiratory arrest iii. Continue to assess every one—hour. Worsening or persisting hypoxia. . If no deterioration continue same treatment.Continue O2.. . follow intensive care of the child with asthma in pediatric ICU for possible intubation and mechanical ventilation in presence of: i. Good response group . review medicine use.. May mix in same nebulizer with β2-sympathomimetic.If no response. initiate action plan..Asthma in Children 331 Contd. 21. animals (pets) are the main sources. Keep rooms well ventilated and allow sunlight in. fungal spores. pulmonary function tests endoscopy. humid climate. Proper mapping of the country needs I to be done to see where dust mite is an important allergen-expected in warm. Pets Pets like dogs. Reports on pets are very few in this country. House dust mite Sun the bedding weekly. Moulds or indoor fungal spores Prevent see page of water through rooms or walls during the rainy season. Skin testing can be used. .332 Bronchial Asthma Contd. If pets are already in the house contact with the patients should be minimized or they should be kept out of the premises. cats or birds should not be kept. call your doctor and proceed to emergency department. • Severe symptoms such as step 4 care • Nonadherence to therapy • Need for good asthma education • Significant psychosocial or psychiatric problems Environmental Control and Prevention of Asthma Allergen Avoidance Indoor allergens Cockroach.. consider calling ambulance • Contact clinician for follow-up instructions • Contact clinician urgently (this day) for instructions • Proceed to emergency department Fig. Cockroaches Leave no food uncovered. for the diagnosis.2: Home treatment of asthma exacerbation in children Referral Patients must be referred to a special clinic of asthma if any of the following problems arise: • Failure to meet the goals of therapy • Atypical signs or symptoms or uncertain diagnosis • Presence of complications • Need for additional diagnostic testing like skin tests.. incremental growth assessment etc. house dust mite. Traps are better than the anticockroach chemicals. No carpets or stuffed. the house. No wheezing or shortness of breath Response to β2-agonist sustained for 4 hours • May continue β2-agonist every 3-4 hours for 24-48 hours • For patients on inhaled corticosteroids. Following control measures are suggested. double dose for 7-10 days Persistent wheezing or shortness of breath • Add oral corticosteroid • Continue β2-agonist Marked wheezing or shortness of breath • Add oral corticosteroid • Repeat β2-agonist immediately • If distress is severe and nonresponsive. and parents of the patients . Mental health workers can provide important services to asthmatic children. Irritants or Chemicals Avoid tobacco smoke. Future Directions for Research The data presented indicates gross inadequacy of information regarding basic facts of asthma to patients and their parents. using kerosene. Hence. It is important that psychologists be part of the multidisciplinary treating team in order to provide comprehensive services to children with asthma. radio and other communication media. for immunotherapy. he or she should be referred to a specialist for skin testing and if required. In high risk families (atopy on both sides or even one side). family therapy is considered an adjunct to the conventional treatment in asthma in children with severe disease. cowdung. who have obvious psychological or behavioural problems. experience school difficulties and are noncompliant with treatments. All the participants felt that there was a local social stigma attached to the disease. More studies need to be done to assess the knowledge. In case an allergen is found to contribute significantly to patient problem. The attitudes and practices concerning this disease demonstrate a high degree of ignorance and misinformation. wood. fumes from various kinds of stoves/chullah. strong odours. Written material containing information regarding basic facts of asthma should be made available to the patient and the parent at the time of transmission of information regarding the diagnosis. It was decided at the meeting that the primary physician to the patient be able to deliver the necessary preventive services like explaining the basic facts about the disease and try to improve the quality of life by optimum care. Health Education The experts stressed the need for health education not only in asthma clinic or hospital but also on TV. Psychosocial Aspects of Asthma Management in Children Children with chronic illnesses are at an increased risk for developing psychological disturbances. exclusive breastfeed to continue for 4 to 6 months and mother to avoid well-known allergenic food in diet while baby is exclusively breastfeed. Intervention in the form of written material significantly improves the knowledge of these individuals. Children with severe asthma have been found to be three times more likely to develop emotional/behavioural problems as compared to healthy children.Asthma in Children 333 Seasonal exposure to pollens and fungi can be reduced by keeping the doors and windows closed from every morning till evening. air-conditioning can be used. Special measures were recommended to be taken to educate the people about the harms of passive smoking. Wherever affordable. attitudes and practices of these patients and specific materials developed to improve the baseline information and change attitudes towards inhalational therapy. Family therapy aimed at modifying family interaction problems and parent-child relationships can help in improved management of asthma and also improve the overall quality of life. In children less than 5 to 6 years of age immunotherapy is avoided. Why incidence of asthma is relatively less in India and the disese is less severe as compared to some of the Western countries. 2. 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WAHom JD. 62. 194. 243 Genes 32 Genetics 31 Gold salts 163. 143 Bradykinin 52 Brittle asthma 96 Bronchial asthma aetiology 14 complication 117 diagnosis 98 epidemiology 1 management 127 pathology 86 pathophysiology 40 pharmacologic management 134 prognosis 114 Bronchial asthma. 139.Index 337 Index A B D Acupuncture 261 Acute severe asthma 208. 188 Allergic bronchopulmonary aspergillosis 117. 272 Allergy 14. 296 Cytokines 49. 272 Assessment of asthma control 202 Asthma definition 1 sign 99 symptoms 98 Asthma remission 89 Atopy 14 β2-agonists 281 Basophils 48 Beta-adrenergic receptors 62. 295 Gut hormones 59 reflux H Heparin 297 Histamine 52 Hospital discharge 284 House-dust mite 18. 189. 250 E Early asthmatic reaction 40 Endocrinal factors 30 Environmental factors 32. 235 acute severe asthma 208 diet modification 258 nonpharmacologic 128. 61 Bronchoprovocation test 103 Dietary manipulation 263 Diuretics 298 Drug-induced asthma 243 Drugs 22 Dry powder inhalers (DPI) 178 C Childhood asthma 7 Chronic bronchial asthma 183 Chronic eosinophilic bronchitis 44 Complementary and alternative medicine 261 Corticosteroids 151 Cough variant asthma 92 Cromones 157 Cyclosporin 163. 53.226 in children 285 clinical features 210 complications 211 definition 208 differential diagnosis 212 indices 213 management 215. 272 assessment 212. 20. 67. 129 management 129 Alternative and complementary therapies 201 Alternative treatment oral steroid dependence 161 Animal allergens 19 Anticholinergics 148 comparison 155 side effects 156 Antihistamines 159 Arachidonic acid 43 Aspirin 22. 260 Environmental tobacco smoke 30 Eosinophils 44 Epithelial-mesenchymal trophic unit 89 Exercise-induced asthma 23. 290 pathophysiology 209 therapeutic approach 227 Add-on therapy 268 Adhesion molecules 48 Adrenergic bronchodilators 142 Allergens 16. 259 Hygiene hypothesis 258 . 69. 55. management 127. 196 Bronchial hyperreactivity 40. 129. 257 pharmacologic 134. 256. 271 Extrinsic asthma 93 F Fatal asthma 306 Food allergen 20 G Gastro-oesophageal (GER) 27. 191 step-care 192. 235. 276 anti-immunoglobulin E 248. 276 Newer drugs 247 Nitric oxide 58. 260 Pregnancy 236 Prostaglandins 52 Provocateurs 21 S Secondary prophylaxis 259 Severe asthma 306 Sherwood-Jones index 213 Sinusitis 27 Smoking 260 Spacer devices 181 Status asthmatics 208 drugs 221 Step-care management 273. 64. 185. 65 Inflammatory mediators 49 Inhalation therapy 176 Interleukin 249 Intrinsic asthma 93 Natural history 6 Nebulisers 179 Nedocromil sodium 158 Neural control 59 Neurogenic inflammation 60 Neuropeptides 59 Neutrophils 48 Neutrophins 58 New guidelines for asthma management 256. 272 K Ketotifen 158 L Laboratory findings 100 Late asthmatic reaction 40 Late onset asthma 93 Leukotriene 43. 70. 94.6. 241 Oxygen radicals 57 M Macrophages 47 Mast cells 42 Mechanical ventilation 224 Mediators 58 Metered dose inhalers 177 Methotrexate 162. 293 Methylxanthines 134 Monocytes 47 Morning dippers 96 Mortality 4. 275 Sulphite sensitivity 26 Surgery 239 Sympathomimetic agents 145 T Tartrazine 26 Theophylline 140 Tiotropium 272 Tokyo-Yokohama asthma 29 Troleandomycin 295 V Ventilator 222 noninvasive 283 Virus-induced asthma 69 Y Yin-Yang hypothesis 60 . 251 Platelet 52 Pollen 16 Pollution 29.338 Bronchial Asthma I N R Immunotherapy 131. 88 Rhinitis 27. 274. 106. 49 antagonists 159 Lymphocytes 45 O Objective tests 102 Occupational asthma 24.190 Infection 20. 284 Phosphodiesterase inhibition 134. 265. 64 Nocturnal asthma 72.114 Mould 16 P Patient education 128.21 Inflammation 55. 109. 95 Refractory asthma 306 Remodelling 57.