Asthma – Pathophysiology and treatment
Asthma is a chronic disorder of the airways characterized by variable airway obstruction, airway hyperresponsiveness, and airway inflammation. No single histopathologic feature is pathognomonic but common findings include airway inflammatory cell infiltration with eosinophils, neutrophils, and lymphocytes (especially T cells); goblet cell hyperplasia, sometimes plugging of small airways with mucus; collagen deposition beneath the basement membrane; hypertrophy of bronchial smooth muscle; airway edema; mast cell activation; and denudation of airway epithelium.
There is a variable degree of airflow obstruction (related to bronchospasm, edema, and hypersecretion), bronchial hyperresponsiveness (BHR), and airway inflammation.
In acute inflammation, inhaled allergens in allergic patients causes early-phase allergic reaction with activation of cells bearing allergen-specific immunoglobulin E (IgE) antibodies. After rapid activation, airway mast cells and macrophages release proinflammatory mediators such as histamine and eicosanoids that induce contraction of airway smooth muscle, mucus secretion, vasodilation, and exudation of plasma in the airways. Plasma protein leakage induces a thickened, engorged, edematous airway wall and narrowing of lumen with reduced mucus clearance.
Late-phase inflammatory reaction occurs 6 to 9 hours after allergen provocation and involves recruitment and activation of eosinophils, T lymphocytes, basophils, neutrophils, and macrophages. Eosinophils migrate to airways and release inflammatory mediators. T-lymphocyte activation leads to release of cytokines from type 2 T-helper (TH2) cells that mediate allergic inflammation (interleukin [IL]-4, IL-5, and IL-13). Conversely, type 1 T-helper
(TH1) cells produce IL-2 and interferon-γ that are essential for cellular defense mechanisms. Allergic asthmatic inflammation may result from imbalance between TH1 and TH2 cells.
Mast cell degranulation results in release of mediators such as histamine; eosinophil and neutrophil chemotactic factors; leukotrienes C4, D4, and E4; prostaglandins; and platelet-activating factor (PAF). Histamine can induce smooth muscle constriction and bronchospasm and may contribute to mucosal edema and mucus secretion.
Alveolar macrophages release inflammatory mediators, including PAF and leukotrienes B4,C4, and D4. Production of neutrophil chemotactic factor and eosinophil chemotactic factor furthers the inflammatory process. Neutrophils also release mediators (PAFs, prostaglandins, thromboxanes, and leukotrienes) that contribute to BHR and airway inflammation. Leukotrienes C4, D4, and E4 are released during inflammatory processes in the lung and produce
bronchospasm, mucus secretion, microvascular permeability, and airway edema.
Bronchial epithelial cells participate in inflammation by releasing eicosanoids, peptidases, matrix proteins, cytokines, and nitric oxide. Epithelial shedding results in heightened airway responsiveness, altered permeability of airway mucosa, depletion of epithelial-derived relaxant
factors, and loss of enzymes responsible for degrading inflammatory neuropeptides.
The exudative inflammatory process and sloughing of epithelial cells into the airway lumen impair mucociliary transport. Bronchial glands increase in size, and goblet cells increase in size and number. The airway is innervated by parasympathetic, sympathetic, and nonadrenergic inhibitory nerves. Normal resting tone of airway smooth muscle is maintained by vagal efferent activity, and bronchoconstriction can be mediated by vagal stimulation in small bronchi.
Airway smooth muscle contains noninnervated β2-adrenergic receptors that produce bronchodilation. The non-adrenergic, noncholinergic nervous system in the trachea and bronchi may amplify inflammation by releasing nitric oxide.
Causes and risk factors
The strongest identifiable predisposing factor for the development of asthma is atopy, but obesity is increasingly recognized as a risk factor.
Exposure of sensitive patients to inhaled allergens increases airway inflammation, airway hyper-responsiveness, and symptoms.
Symptoms may develop immediately (immediate asthmatic response) or 4–6 hours after allergen exposure (late asthmatic response).
Common allergens include house dust mites (often found in pillows, mattresses, upholstered furniture, carpets, and drapes), cockroaches, cat dander, and seasonal pollens. Substantially reducing exposure reduces pathologic findings and clinical symptoms.
Nonspecific precipitants of asthma include exercise, upper respiratory tract infections, rhinosinusitis, postnasal drip, aspiration, gastroesophageal reflux, changes in the weather, and stress. Exposure to products of combustion (eg, from tobacco, crack cocaine, methamphetamines, and other agents) increases asthma symptoms and the need for medications and reduces lung function.
Air pollution (increased air levels of respirable particles, ozone, SO2 , and NO2 ) precipitate asthma symptoms and increase emergency department visits and hospitalizations.
Selected individuals may experience asthma symptoms after exposure to aspirin (aspirin exacerbated respiratory disease), nonsteroidal anti-inflammatory drugs, or tartrazine dyes. Other medications may precipitate asthma symptoms.
Occupational asthma is triggered by various agents in the workplace and may occur weeks to years after initial exposure and sensitization.
Women may experience catamenial asthma at predictable times during the menstrual cycle.
Exercise-induced bronchoconstriction begins during exercise or within 3 minutes after its end, peaks within 10–15 minutes, and then resolves by 60 minutes. This phenomenon is thought to be a consequence of the airways’ attempt to warm and humidify an increased volume of expired air during exercise. “Cardiac asthma” is wheezing precipitated by decompensated heart failure.
Cough-variant asthma has cough instead of wheezing as the predominant symptom of bronchial hyperreactivity.
Goals for chronic asthma management include:
✓ Reducing impairment: (1) prevent chronic and troublesome symptoms (eg, coughing or breathlessness in the daytime, at night, or after exertion), (2) require infrequent use (2 days/wk or less of inhaled short-acting β2-agonist for quick relief of symptoms (not including prevention of exercise-induced bronchospasm [EIB]), (3) maintain (near-) normal pulmonary function, (4) maintain normal activity levels (including exercise and attendance at work or school), and (5) meet patients’ and families’ expectations and satisfaction with care.
✓ Reducing risk: (1) prevent recurrent exacerbations and minimize need for emergency department visits or hospitalizations; (2) prevent loss of lung function; for children, prevent reduced lung growth; and (3) minimal or no adverse effects of therapy
• For acute severe asthma, treatment goals are to (1) correct significant hypoxemia, (2) rapidly reverse airway obstruction (within minutes), (3) reduce likelihood of recurrence of severe airflow obstruction, and (4) develop a written action plan in case of future exacerbation.
Patient education is mandatory to improve medication adherence, self-management skills, and use of healthcare services. Objective measurements of airflow obstruction with a home peak flow meter may not improve patient outcomes. NAEPP advocates PEF monitoring only for patients with severe persistent asthma who have difficulty perceiving airway obstruction.
Avoidance of known allergenic triggers can improve symptoms, reduce medication use, and decrease BHR. Environmental triggers (eg, animals) should be avoided in sensitive patients, and smokers should be encouraged to quit.
Patients with acute severe asthma should receive oxygen to maintain PaO2 greater than 90% (95% in pregnancy and heart disease). Dehydration should be corrected; urine specific gravity may help guide therapy in children when assessment of hydration status is difficult.
Short-acting β2-agonists are the most effective bronchodilators. Aerosol administration enhances bronchoselectivity and provides more rapid response and greater protection against provocations (eg, exercise, allergen challenges) than systemic administration.
Albuterol and other inhaled short-acting selective β2-agonists are indicated for intermittent episodes of bronchospasm and are the treatment of choice for acute severe asthma and EIB. Regular treatment (four times daily) does not improve symptom control over as-needed use.
Formoterol and salmeterol are inhaled long-acting β2-agonists for adjunctive longterm control for patients with symptoms who are already on low to medium doses of inhaled corticosteroids prior to advancing to medium- or high-dose inhaled corticosteroids.
Short-acting β2-agonists should be continued for acute exacerbations. Long-acting agents are ineffective for acute severe asthma because it can take up to 20 minutes for onset and 1 to 4 hours for maximum bronchodilation.
In acute severe asthma, continuous nebulization of short-acting β2-agonists (eg, albuterol) is recommended for patients having unsatisfactory response after three doses (every 20 min) of aerosolized β2-agonists and potentially for patients presenting initially with PEF or FEV1 values less than 30% of predicted normal.
Inhaled β2-agonists agents are the treatment of choice for EIB. Short-acting agents provide complete protection for at least 2 hours; long-acting agents provide significant protection for 8 to 12 hours initially, but duration decreases with chronic regular use.
In nocturnal asthma, long-acting inhaled β2-agonists are preferred over oral sustained-release β2-agonists or sustained-release theophylline. However, nocturnal asthma may be an indicator of inadequate antiinflammatory treatment.
Inhaled corticosteroids are the preferred long-term control therapy for persistent asthma because of potency and consistent effectiveness; they are the only therapy shown to reduce risk of dying from asthma. Most patients with moderate disease can be controlled with twice-daily dosing; some products have once-daily dosing indications. Patients with more severe disease require multiple daily dosing. Because inflammation inhibits steroid receptor binding, patients should be started on higher and more frequent doses and then tapered down once control has been achieved.
Response to inhaled corticosteroids is delayed; symptoms improve in most patients within the first 1 to 2 weeks and reach maximum improvement in 4 to 8 weeks. Maximum improvement in FEV1 and PEF rates may require 3 to 6 weeks.
Systemic toxicity of inhaled corticosteroids is minimal with low to moderate doses, but risk of systemic effects increases with high doses. Local adverse effects include dose-dependent oropharyngeal candidiasis and dysphonia, which can be reduced by using a spacer device.
Systemic corticosteroids are indicated in all patients with acute severe asthma not responding completely to initial inhaled β2-agonist administration (every 20 min for 3 or 4 doses).
Prednisone, 1 to 2 mg/kg/day (up to 40–60 mg/ day), is administered orally in two divided doses for 3 to 10 days. Because short-term (1–2 week), high-dose systemic steroids do not produce serious toxicities, the ideal method is to use a short burst and then maintain appropriate long term control therapy with inhaled corticosteroids.
In patients who require chronic systemic corticosteroids for asthma control, the lowest possible dose should be used. Toxicities may be decreased by alternate-day therapy or high-dose inhaled corticosteroids.
Theophylline appears to produce bronchodilation through nonselective phosphodiesterase inhibition. Methylxanthines are ineffective by aerosol and must be taken systemically (orally or IV).
Sustained-release theophylline is the preferred oral preparation, whereas its complex with ethylenediamine (aminophylline) is the preferred parenteral product due to increased solubility. IV theophylline is also available.
Theophylline is eliminated primarily by metabolism via hepatic CYP P450 enzymes (primarily CYP1A2 and CYP3A4) with less than or equal to10% excreted unchanged in urine. CYP P450 enzymes are susceptible to induction and inhibition by environmental factors and drugs.
Significant reductions in clearance can result from cotherapy with cimetidine, erythromycin, clarithromycin, allopurinol, propranolol, ciprofloxacin, interferon, ticlopidine, zileuton, and other drugs. Some substances that enhance clearance are rifampin, carbamazepine, phenobarbital, phenytoin, charcoalbroiled meat, and cigarette smoking.
Because of large interpatient variability in theophylline clearance, routine monitoring of serum theophylline concentrations is essential for safe and effective use. A steady-state range of 5 to 15 mcg/mL (27.75–83.25 μmol/L) is effective and safe for most patients.
Sustained-release oral preparations are preferred for outpatients, but each product has different release characteristics. Preparations unaffected by food that can be administered every 12 or 24 hours are preferable.
Adverse effects include nausea, vomiting, tachycardia, jitteriness, and difficulty sleeping; more severe toxicities include cardiac tachyarrhythmias and seizures.
Sustained-release theophylline is less effective than inhaled corticosteroids and no more effective than oral sustained-release β2-agonists, cromolyn, or leukotriene antagonists.
Addition of theophylline to optimal inhaled corticosteroids is similar to doubling the dose of the inhaled corticosteroid and is less effective overall than long-acting β2-agonists as adjunctive therapy.
Ipratropium bromide and tiotropium bromide produce bronchodilation only in cholinergic-mediated bronchoconstriction. Anticholinergics are effective bronchodilators but are not as effective as β2-agonists. They attenuate but do not block allergenor exercise-induced asthma in a dose-dependent fashion.
Time to reach maximum bronchodilation from aerosolized ipratropium is longer than from aerosolized short-acting β2-agonists (30–60 min vs 5–10 min). However, some bronchodilation is seen within 30 seconds, and 50% of maximum response occurs within 3 minutes. Ipratropium bromide has a duration of action of 4 to 8 hours; tiotropium bromide has a duration of 24 hours.
Inhaled ipratropium bromide is only indicated as adjunctive therapy in severe acute asthma not completely responsive to β2-agonists alone because it does not improve outcomes in chronic asthma. Studies of tiotropium bromide in asthma are ongoing
Mast Cell Stabilizers
Cromolyn sodium has beneficial effects that are believed to result from stabilization of mast cell membranes. It inhibits the response to allergen challenge as well as EIB but does not cause bronchodilation.Cromolyn is effective only by inhalation and is available as a nebulizer solution. Cough and wheezing have been reported after inhalation.
Cromolyn is indicated for prophylaxis of mild persistent asthma in children and adults. Effectiveness is comparable to theophylline or leukotriene antagonists. It is not as effective as inhaled β2-agonists for preventing EIB, but it can be used in conjunction for patients not responding completely to inhaled β2-agonists.
Most patients experience improvement in 1 to 2 weeks, but it may take longer to achieve maximum benefit. Patients should initially receive cromolyn four times daily; after stabilization of symptoms, the frequency may be reduced to three times daily.
Zafirlukast (Accolate) and montelukast (Singulair) are oral leukotriene receptor antagonists that reduce the proinflammatory (increased microvascular permeability and airway edema) and bronchoconstriction effects of leukotriene D4.
In persistent asthma, they improve pulmonary function tests, decrease nocturnal awakenings and β2-agonist use, and improve symptoms. However, they are less effective than low-dose inhaled corticosteroids. They are not used to treat acute exacerbations and must be taken on a regular basis, even during symptom-free periods.
Adult zafirlukast dose is 20 mg twice daily, taken at least 1 hour before or 2 hours after meals; dose for children ages 5 through 11 years is 10 mg twice daily. Montelukast adult dose is 10 mgonce daily, taken in the evening without regard to food; dose for children ages 6 to 14 years is one 5-mg chewable tablet daily in the evening.
Rare elevations in serum aminotransferase concentrations and clinical hepatitis have been reported. An idiosyncratic syndrome similar to the Churg–Strauss syndrome, with marked circulating eosinophilia, heart failure, and associated eosinophilic vasculitis, has been reported rarely; a direct causal association has not been established.
Zileuton (Zyflo) is a 5-lipoxygenase inhibitor; use is limited due to potential for elevated hepatic enzymes, especially in first 3 months of therapy, and inhibition of metabolism of some drugs metabolized by CYP3A4 (eg, theophylline and warfarin).
Dose of zileuton tablets is 600 mg four times daily with meals and at bedtime. Dose of zileuton extended-release tablets is two 600-mg tablets twice daily, within 1 hour after morning and evening meals (total daily dose 2400 mg).