Chapter 9.Bronchial Asthma Khaled O Hadeli MD, FCCP The Oea a Review of o Medicin ne 19 98 he defi inition of bronchial b a asthma has s been revi ised since i t was first described by Sir Wi lliam Osler r in ing the last t century, the t definiti on focused d on 1892. Duri clinical and d physiolog gical featur es of rever sible bronc chospasm and bronchial hyper resp onsiveness . This resul lted in confusio on because the two fe eatures may y be shared d by other chro onic airway y disorders such as chronic c airw way pulmonary y disease (C COPD). The lat est definiti ion was rep ported by t he Global Initiative for Asthma (G GINA) prog gram in 20 004; a chro onic inflammato ory disorde er of the airways in n which many m cells and cellular el lements pl lay a role. . The chro onic inflammati ion causes an associ iated incre ase in airw way hyper-resp ponsiveness s that leads s to recurre ent episode s of wheezing, breathlessn b ness, chest tightness, and coughi ing, particularly y at night t or in th e early m orning. Th hese episodes are a usually y associate ed with wi idespread but variable airflow a obs struction that t is oft ten revers ible either spon ntaneously or with tre atment. T Air way Inflamation Air way y hyper‐ responsivness Reversable Air way obstructio on Asthma A Figure 1. Definition of Asthma 199 Asthma Epidemiology According to WHO statistics, bronchial asthma affects 300 million people; and 255,000 people died of asthma in 2005. Asthma prevalence increases globally by 50% every decade. The most striking increase in asthma prevalence is seen among children. 80% of asthma deaths occurred in low and lower-income countries, and asthma deaths are projected to increase by 20% if appropriate actions are not taken. The prevalence of asthma in the developed countries ranges from 10.9% in the United States, to more than 15% in the United Kingdom. In developing countries the prevalence of asthma is less. The highest prevalence in Africa (8%) is seen in South Africa, but is increasing at a higher rate in developing countries as they urbanize and westernize. Worldwide, the burden of asthma on the economy exceeds that of tuberculosis and HIV combined. In the United States, asthma-related treatment cost, cost related to loss of work, loss of productivity, and early retirement was estimated to be $12 billion in 2004. These costs are directly related to the severity of the disease. Even though patients with severe asthma constitute only 20% of the total asthma population, they are responsible for 50% of the cost of the disease. • • • • Industrialized countries have a higher prevalence of asthma Developing countries have a higher incidence of asthma Asthma mortality is higher in poor countries The cost of asthma treatment is high The Oea Review of Medicine 200 Pathophysiology of Asthma Asthma is a chronic disease with a complex interaction of cells, mediators, and cytokines that result in inflammation. This interaction causes smooth muscle contraction, smooth muscle hypertrophy, micro vascular leakage, bronchial wall oedema, activation of airway neurons, increase in airway responsiveness, stimulation of mucus-secreting cells, mucus plugging of the airways, disruption of the airway epithelium, and ultimately causes widespread airflow limitation. The inflammatory cells involved in the path physiology of asthma include mast cells, macrophages, eosinophils, lymphocytes, neutrophils, basophils, and platelets. These cells are capable of generating mediators that can induce bronchospasm “early phase response”, or guide the activation and migration of the eosinophils and neutrophils, and cause a “late phase response” that results in epithelial damage, capillary leak, and mucus hyper secretion. These mediators include histamine, platelet activating factors, leukotrienes LTC4, LTD4, LTE4, prostaglandin D2 and other derivatives of the arachidonic acid cascade. • • • Complex interaction of cells, mediators, and cytokines. Early or Late phase response Widespread airflow limitation is the ultimate result 201 Asthma Risk Factors for Asthma The Environment : This is the most important risk factor for asthma attacks. Correlation between the prevalence of asthma and exposure to allergens is documented in several epidemiological studies. Indoor allergens include mites, cat & dog allergens, fungi, cockroach allergens, insect parts and feces, molds, and dander. Outdoor air quality is a major contributor to asthma expression as well. Outdoor allergens (pollens, weeds, and grass) and outdoor pollution (industrial smog, ozone, and nitric oxide) are included in the list of culprits. Another interesting point is that environmental factors in early life influence the development of asthma. Children who grow up in large families, go to day care, or live on farms will have a smaller chance of developing asthma in later life, despite the fact that these same environmental factors may have a negative effect on asthma activity, as described above. Genetics of asthma : Somewhat complex due mainly to the heterogeneity of the asthma phenotype, but is well documented. Gender, Age, & Race : Females are more prone to asthma, but in childhood, boys are more affected than girls. Racial variation in the incidence and mortality of asthma is proven, but geographic location is more important as immigrants acquire the risk of the local population. Extreme weights : Both over weight and under weight people are at a higher risk of developing asthma. In asthmatics, improvement in peak expiratory flow rate (PEFR) variability is seen in patients who correct their weight. The Oea Review of Medicine 202 Triggers of asthma attacks • • • • • • Allergens Infections Environmental endotoxines and irritants Stress Pain Medications • • • • • Non-selective B-blockers (oral or ophthalmic) NSAID Steroid or other asthma controller withdrawal Food additives Gastro-esophageal reflux disease Clinical Features of Asthma The most common symptoms of asthma are wheezing, shortness of breath, and cough. Chest tightness, chest pain, and nocturnal awakening are less common, but well described in the literature. Asthmatics may have multiple symptoms, or may present with cough or wheeze only. Most attacks of asthma are preceded by allergen exposure; usually aeroallergens are responsible. As described above in the Pathophysiology of Asthma a reaction could be immediate and symptomatic, or delayed where the patient may not appreciate any symptoms even with a similar degree of spirometric decline in FEV1. The reason for this is thought to be the rapidity of the decline of FEV1. If the decline is rapid the patient will be symptomatic, but if the reaction is slow the attack may pass unnoticed. Patients with a slow decline in their FEV1 and who have a poor perception of their symptoms are likely to be under medicated and are more likely to develop fatal or near-fatal attacks. Cough variant asthma is a common manifestation of asthma where objective measurements of airflow limitation may be difficult. In 203 Asthma such patients bronchoprovocation testing may be needed to diagnose the disease. A constellation of signs can be seen with bronchial asthma. Most common are tachypnea, prolonged exhalation phase, wheeze, use of accessory muscles, and pulsus paradoxus. The degree of wheezing does not predict the severity of the disease; a quiet chest may actually be a late sign of an acute severe attack. Early in the attack, hyperventilation leads to decrease in CO2. Later on, in advanced and severe cases when FEV1 is less than 15%, VQ mismatch leads to “dead space ventilation”, combined with increased work of breathing and increased production of CO2 and O2 consumption. Blood levels of CO2 may “normalize” or even rise to high levels, O2 levels continue to drop. • Wheeze, breathlessness, and cough are the most common asthma symptoms Perception of asthma symptom is variable, depending on the person and the speed of FEV1 declin. Tachypnea and prolonged exhalation phase are the most common physical signs in asthma Hypercarbia, dead space ventilation, and quiet chest in physical examination are advanced findings suggesting a severe attack • • • The Oea Review of Medicine 204 Classification of Asthma Class Frequency of Attacks Mild Intermittent < 2 attacks weekly Night time attacks < Two times per month FEV1 or PERF>80%predicted, but PERF variability <20% Mild Persistent > 2 attacks per week, but < 1 attack daily Moderate Persistent Daily attacks > One time per week Severe Persistent Continuous attacks Frequent/ Daily FEV1 or PERF >60%<80%, >30% PERF variability FEV1 or PERF <60%, >30% PERF variability > Two times per month FEV1 or PERF >80% predicted, but PERF variability 20-30% Lung Function Diagnosis and Monitoring of Asthma Signs and symptoms of asthma are nonspecific, patients often poorly perceive symptoms, and there is a poor correlation between signs and severity, making the diagnosis and management of asthma challenging. Several tests are developed to help with the diagnosis and management of asthma: Spirometry : FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) are very important variables that help to quantify the degree of airway obstruction. In acute attacks, the FEV1 usually drops by 30% of the baseline. The finding of 15% reversibility or greater (of FEV1) after the use of short acting bronchodilators is suggestive of asthma. Peak expiratory flow rate: This is a good tool to assess the variability in airflow limitation seen in asth- 205 Asthma matics. After establishing an individual’s normal range, the peak flow rates can then be followed to monitor the progression of the disease. The National Institute of Health (NIH) has developed guidelines to help patients monitor disease severity and control (zones of airflow limitation). • Green zone (80% and 100% of person’s best) indicates good control Yellow (50%-80% of person’s best) indicates poor control and warrants patient attention, and possibly a need to increase treatment Red (less than 50%) indicates very poor control and warrants physician involvement • • Arterial Blood Gas (ABG): The most common finding in an asthma attack is hypoxemia due to ventilation perfusion (VQ) mismatch. In mild to moderate attacks, hyperventilation leads to hypocarbia and respiratory alkalosis. As previously described, severe asthma exacerbations may lead to normalization or hypercarbia and worsening hypoxemia, heralding respiratory failure. Bronchoprovocation testing: In patients with typical features of asthma, but without spirometric or peak flow confirmation, an inhalation challenge test may be helpful. After giving the patient a dose of short-acting bronchodilators to ensure normal airway at the start of the test, standardized escalating doses of inhaled methacholine or histamine are given. A 20% decline in FEV1 is diagnostic of asthma. Radiological Features: Most commonly, the chest x-ray of an asthmatic will be normal . The main findings The Oea a Review of o Medicin ne 20 06 with severe e airway ob bstruction are hyperin nflation of the chest (figur re 2) and a flat diaphr ragm. Figure 2. Hyperinflation in 56 year old female with severe asthma Other Clinica C l Forms s of As sthma Occupa ational a sthma: A particular r occupatio onal environme nt precipit tates attack ks in certa ain suscept ible s. Animal handlers, grain han dlers, pou ultry individuals workers, a nd spray p ainters are e some occu upations as ssociated with imh this form m of asthm ma. Often, symptoms s prove in a few days away a from the occup ation. Seek king occupation nal history in patients s with asth ma may pr rove to be the most impo ortant step p in the management m t of ma. their asthm Noctur rnal asthm ma: Attack ks occur m ore frequen ntly at night, perhaps p as a differen nt expressi ion of gen eric asthma. Th he nocturn al attacks are a though ht to be due e to circadian rhythm r vari iability in bronchial b in nflammatio n. Exerci se induce ed asthma a: The exa act mechan ism m of asthm ma is not clear. c Evapo orative loss s of of this form water and heat by inh halation of large volu mes of unc conditioned ai ir during ex xercise may y provoke b ronchospas sm. 207 Asthma Coug gh varian nt asthma : Cough is the main symps tom, and d diagnosis s can be made m with bronchopro b ovocation tes sting. The cough usually u res sponds we ell to treatmen nt with bron nchodilator rs and stero oids. Drug g induced d asthma: Main culpr rit drugs in nclude aspirin and a beta-blo ockers. ABPA A (allergic c bronchop pulmonary aspergillos sis or allergic bronchopu ulmonary mycosis): m A form of as sthma t hypersen nsitivity to o fungi u sually thought to reflect Aspergill lus fumigat tus. This fo orm is char racterized by b the formatio on of thick respiratory r secretions and mucus s plug (figure 3), 3 presenc ce of eosi nophilia, high h IgE levels, l antibodie es to asper rgillus, and d recurrent lung infilt trates. If untrea ated this may m lead to bronchiec tasis. Treat tment includes the use of o steroids s. The role e of anti-f fungal medicati ions is less defined. Figure 3. Mucus plug pulled of 45 year old female with ABPA The Oea Review of Medicine 208 Churg-Strauss syndrome: Is a multisystem disease characterized by allergic rhinitis, asthma, and blood eosinophilia. Involvement of other systems could be seen. The gold standard diagnostic procedure is open lung biopsy with findings including eosinophilic infiltrates, giant cell vasculitis, interstitial granulomas, and eosinophilic lymphadenopathy. Leukotriene modifying agents were implicated in the development of the disease, however, it is believed that the tapering off of the steroids in these patients unmasked the disease rather than the other way around. Treatment is usually with high dose steroids. Fatal or near-fatal asthma: is an important variant of asthma presentation. Despite better understanding of the pathophysiology of asthma and the availability of effective medications, acute attacks with significant mortality rates still occur. According to the British Thoracic Society, risks of developing near fatal attacks are: • Previous history of near fatal asthma • Previous history of hospitalization due to asthma • Previous history of mechanical ventilation due to respiratory failure from asthma • Patient on 3 or more classes of asthma medication • Heavy use of B-agonist • Behavioral problems (non-compliance, alcohol abuse, drug abuse…etc.) • Social problems (poverty, social isolation, child abuse…etc.) • Other risk factors include: • • • Marked fluctuations of PERF am/pm readings People with blunt response to hypoxemia Lack of prophylactic anti-inflammatory treatment Death is usually due to hypercarbic respiratory failure. Despite severe hypercarbia and very low pH, severe attacks can be reversed with appropriate management. 209 Asthma When an asthma attack is sudden and respiratory failure occurs fast, the recovery can be quick and complete, compared to attacks that are slow to progress. Patients who require mechanical ventilation pose a significant challenge to the physician. Severe bronchospasm and limitation of airflow make ventilation very difficult; and old strategies aimed at quick correction of blood gas derangement may lead to increased mortality from barotrauma and decreased cardiac output due to increased intrathoracic pressure and decreased venus return. The use of mechanical ventilation strategies leading to permissive hypercarbia has improved the outcomes. Proper asthma control can significantly reduce near fatal attacks and asthma mortality. Measures like the regular use of peak flow meters, written action plans, better patient-physician communication, better patient compliance, and the use of corticosteroids can help in this regard. Management of Asthma Environmental control of asthma Once a patient is diagnosed with asthma, a detailed environmental and occupational history is essential. General or specific advice about environmental changes is the cornerstone of asthma management and control. Patients need to appreciate that asthma is a clinical syndrome, where the clinical manifestation can be controlled but the condition is likely to be lifelong. Environmental education is important for the patient for the rest of his/her life. Occupational exposures and type of home furnishings, that may influence the disease, may be difficult to change at the time of diagnosis, but may be necessary to improve control of the disease. The Oea Review of Medicine 210 Pharmacological Treatment of Asthma Short- term objectives : The use of short acting bronchodilators to control an acute attack and to manage a fall in the PERF or FEV1. Long-term objectives: The use of anti- inflammatory medications and long-acting bronchodilators for daily maintenance and diminished acute exacerbations. Asthma Treatment By Severity:* Asthma Severity/ treatment Short acting “Rescue medication” Long acting “maintainer” Mild Intermittent Mild Persistent SABA as needed SABA NON ICS or LMA or Cs Moderate persistent SABA LABA or and ICS vs. Higher dose ICS with without LMA/Theo Severe Persistent SABA All the above and oral steroids Short acting beta-agonist (SABA), Long Acting beta-agonist (LABA), Inhaled corticosteroids (ICS), Leukotrienemodifying agent (LMAs), Cromolyn sodium (Cs), Theophylline (Theo) *If uncontrolled at any severity level, consider pulse treatment with oral steroids. 211 Asthma Medications Anti-inflammatory Agents Corticosteroid • Mode of action: Prevent migration and activation of inflammatory cells, interfere with the production of prostaglandins and leukotrienes, and reduce capillary leak. Use: All forms of asthma with severity higher than mild intermittent. Preparations: Oral and inhaled. Side effects: Long-term use of inhaled corticosteroids is associated with a good safety profile; nonetheless local effects such as hoarseness of voice, dysphonia, cough, and oral candidiasis can be expected. Hypophyseal-pituitary-adrenal suppression, osteoporosis, cataract, hypertension, diabetes mellitus, and immune suppression can be seen, especially with long-term use of oral preparations. Mode of action: Mast cell stabilization Use: Allergen-induced asthma Preparation: Inhalation. Very good safety profile Mode of action: Inhibit the cysteinyl leukotrienes and Leukotriene C4, D4, and E4. Use: particularly useful in allergen-induced asthma, exercise- induced asthma, and aspirin- induced asthma. Preparation: Oral Side effects: Generally very safe with reports of rare cases of Churge-strauss vasculitis in patients with • • • Cromolyn Sodium • • • • • • Leukotriene Modifying Agent • • The Oea Review of Medicine 212 severe steroid-dependent asthma during steroid taper while being on LPMs. Bronchodilators Short Acting Beta Agonist (SABA) • Mode of action: Airway dilation by producing cAMP, also reduce the release of inflammatory mediators and improve mucocilliary transport. Used as rescue medication and prophylactic in exerciseinduced asthma. Use: All levels of severity, preferably on “as needed” basis. Preparation: Oral and inhaled. Side effects: Despite selectivity, may have systemic adrenergic effects like tremors, arrhythmias, palpitation, and paradoxical bronchospasm. Regular use of Beta 2 agonists is thought to be associated with increased mortality. So, these medications are better used as an “as needed” rescue medication. Mode of action: Similar to that of short acting bronchodilators, but due to lipophilicity the duration of action is much longer. Use: Moderate persistent severity or higher. Preparation: Inhaler. Side effects: the safety profile of long acting beta agonists is controversial. The weight of evidence favors their use in moderate persistent severity or higher in combination with corticosteroids. Mode of action: Not defined. Methylxanthines are effective bronchodilators with anti-inflammatory properties. Use: Moderate persistent asthma or higher. • • • Long Acting Beta Agonist (LABA) • • • • Methylxanthines • • 213 Asthma • • Preparation: Oral. Side effects: Narrow therapeutic margin, requires monitoring of therapeutic levels especially in the elderly. Side effects include GI upset in mild toxicity and serious cardiac arrhythmias seen in high blood levels. Mode of action: Inhibits calcium channel smooth muscle and reduce acetylcholine release. Use: Acute severe attack. Preparation: Intravenous. Side effects: circulatory collapse. Mode of action: Reduce vagal tone, synergistically when used with Beta agonists. Use: mainly used in COPD, or as a substitute to beta agonists and methylxanthines in patients with cardiac arrhythmias. Preparation: inhaler. Side effect: slow-acting. Caution in patients with glaucoma or urinary retention. Magnesium Sulfate • • • • • • An t icho lin erg i cs • • The Patient–physician Relationship and its Effect on Asthma Control The outcome of asthma management and the degree of asthma control are influenced by the patient-physician relationship. Best compliance and outcomes are seen with patient-focused approach, where the physician interacts with the patient in a friendly and open-minded way. The physician listens to the patient’s concerns and develops a trusting two-way communication. This approach will enable the physician to understand the patient, not only his illness. Disease-focused approaches The Oea Review of Medicine 214 may lead to loss of effective communication with the patient, and ultimately poor adherence and outcome. Summary of Asthma Management • Use of objective measures of lung function to assess the severity of asthma and to monitor the efficacy of treatment. Identification and elimination of factors that worsen symptoms, precipitate attacks, or promote ongoing airway inflammation (environmental control). Comprehensive pharmacological therapy to reverse bronchoconstriction and prevent airway inflammation. Creating a patient-focused relationship between the patient and health provider. • • • Further Reading 1. Bethesda MD. Expert panel 2: guidelines for the diagnosis and management of asthma. NIH publication 1997; No. 97-4051. Braman SS. Decreasing the global burden of asthma. Chest 2006; 130(suppl):S4-S12. Masoli M, Fabian D, Holt S, Beasley R, von Hertzen L. GINA program: The global burden of asthma. Allergy 2004;59:469-478. Canonica GW. Treating asthma as inflammory disease. Chest 2006;130(suppl):S21-S28. Hall IP. Genetics and Thorax 1999;54:65-69. pulmonary medicine: asthma. 2. 3. 4. 5. 6. 7. 8. Kay AB. Pathology of mild, severe, and fatal asthma. Am J Respir Crit Care Med 1996;154(suppl):S66-S69. Graham LM. Classifying 130(suppl):S13-S20. asthma. Chest 2006; Palma-Carlos AG. Correlation between clinical classification, PEF and FEV1: guidelines and reality. Allergy Immunol (Paris) 2003;35:130-132. 215 Asthma 9. Corbridge TC, Hall JB. The assessment and management of patient with status asthmaticus. Am J respire Crit Care Med 1995;151:1296-1316. 10. Cockrill BA. ABPA. Annual Rev Med 1999;50:303-316. 11. Jimenez-Friedman G, Beckett W, Szeinuk J, Petsonk E. Clinical evaluation, management, and prevention of workrelated asthma. Am J Ind Med 2000;37:121-141. 12. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus high-dose corticosteroids in asthma patients. Lancet 1994;344:219-224. 13. Salvi SS, Krishna MT, Sampson AP, Holgate ST. The antiinflammatory effects of Leukotriene-modifying drugs and their use in asthma. Chest 2001; 119:1533-1546. 14. Irwin R. Patient-Focused 130(suppl):S73-S82. Care. Chest 2006; 15. The Smart study. Chest. 2006;129:15-26. Websites 1. 2. http://www.ginasthma.com/ Global Initiative for asthma (GINA). www.who.int/respiratory/gard/en/ Global Alliance against Chronic Respiratory Diseases (GARD). 3. www.who.int/topics/asthma/en/ World Health Organization: Asthma, Fact Sheet.