Asthma

Timothy D. Bigby and Patricia W. Finn

Asthma is characterized clinically by reversible airway obstruction in association with symptoms of dyspnea, cough, and sputum production. Asthma is defined in pathophysiological terms by emphasizing the physiologic finding of airway hyperresponsiveness and the pathologic finding of airway inflammation.

Asthma is a common disorder worldwide. The World Health Organization recently stated that approximately 300 million people have asthma. Asthma is not distributed equally throughout the world: industrialized, Western countries have a higher incidence. In the United States, asthma afflicts 25 million people, including more than 7 million children. Asthma is the most common chronic disease of childhood. In the United States, asthma is more common in urban than in rural populations, and the incidence is higher among minority populations. Epidemiologic studies indicate that most asthma begins in early childhood, although it can develop at any age. At least one half of children who develop asthma will have remission as adults, but adult-onset asthma rarely abates. The prevalence, severity, and mortality rates associated with asthma have increased over the last 40 years. The explanation is unclear, but urban living conditions, exposure to oxidant pollutants, diet, nutrition, passive smoking, obesity, and even current therapies have been implicated. More recent concerns have been raised about relationships to the modernization of Western culture, including a decreased incidence of common childhood infectious diseases, widespread antibiotic use, declining physical fitness in children, and rising incidence of obesity beginning in childhood. Although many of these issues have been related to affluence, the greatest rise in asthma in the United States has occurred in inner-city, African-American children (prevalence of 17% in 2009, a 50% rise over the decade).

The hallmark of airway pathology in asthma is mixed inflammatory cell infiltration; eosinophils are the most striking feature, but the infiltrates also include large numbers of less easily recognized mast cells, neutrophils, lymphocytes, and macrophages. The inflammatory changes are also associated with denudation of airway epithelium and mucous gland hypertrophy. Longstanding asthma can be associated with subepithelial fibrosis and smooth muscle hypertrophy. Severe asthma is often associated with inflammation having a neutrophil predominance.

The etiology of asthma remains enigmatic. It does not appear to be a single disease, but a syndrome. An older hypothesis suggested that so-called intrinsic asthma (i.e., asthma in individuals without identifiable triggers) might be neurally mediated. However, a distinct abnormality of the sympathetic, parasympathetic, or peptidergic nervous systems has not been found in asthmatics. Mutations of the β₂-adrenergic receptor have now been described, but these mutations may be more important in dictating response to treatment than in the etiology of the disease itself. Substantial data support an allergic pathogenesis mediated predominantly by both inhaled and systemic antigens. Allergy appears to play a central role in sustained wheezing in early childhood that can be characterized clinically as asthma. Cytokines released by T-helper (T_H)2 lymphocytes are increasingly recognized as important in allergic and, possibly, all asthma. Pivotal cytokines include interleukins 13, 4, 5, and 9. Adaptive, allergic dependent immunity has been shown to play pivotal roles in asthma pathogens. Recent studies suggest that the interface between adaptive and innate new antigen-dependant immunity is also crucial. This interface has been suggested to play a role in the increase in asthma prevalence. An attempt to link the increase in asthma in the industrialized world to improved healthcare and decreased childhood infections has been termed the hygiene hypothesis. If hygiene does play a role in the development of asthma; it may do so through the interface between innate and adaptive immunity.

Multiple studies have demonstrated that airway inflammation precedes the development of hyperresponsiveness. In some models, hyperresponsiveness does not develop if this inflammatory cell influx is blocked. Most investigators now believe that, despite multiple triggers for the inflammatory cell influx, airway inflammation is the common pathway by which airway hyperresponsiveness is induced. Inflammatory cells also appear to be the source of mediators that induce acute bronchoconstriction, mucus hypersecretion, airway edema, and further inflammatory cell influx. The inflammatory milieu is complex, and a single inflammatory cell or inflammatory mediator is unlikely to explain all the clinical features of asthma. Although a genetic component of asthma clearly exists, it is not explained by a single gene, but instead is a complex genetic disorder. Thus, asthma appears to be polygenic, and the phenotypic expression of involved genes is significantly influenced by environmental factors. A variety of candidate genes in asthma are currently under investigation. Some very large genome-wide association studies have shown strong associations between asthma and eosinophilia with single nucleotide polymorphisms in genes encoding for IL-1RL1, the receptor for IL-33, and IL-33 gene. These studies suggest an important and perhaps central role for this cytokine and its receptor. However, the true significance of these associations is unknown.

Intermittent reversible airway obstruction is a clinical hallmark of asthma. However, symptoms improve or can fully remit between episodes. During episodes, symptoms can vary from mild to severe, with profound limitation of activity and symptoms at rest. Patients may not notice symptoms of obstruction until their acute exacerbation is of moderate to severe intensity. A detailed history of factors that precipitate acute symptoms is critical in subsequent management.

The 2007 National Asthma Education and Prevention Program (NAEPP), Expert Panel Report III, and the 2010 Global Initiative for Asthma (GINA) stratify severity of disease into levels that can be used to determine the appropriate step of therapy (a step-care approach). These guidelines have been well received by pulmonary and allergy clinicians. The current NAEPP and GINA guidelines differ from prior reports in that they have included 6 and 5 steps, respectively. The stratification includes mild intermittent (step 1), mild persistent (step 2), moderate persistent (steps 3 and 4), and severe persistent disease (step 5). Patients with mild intermittent asthma have only occasional symptoms (two or fewer times per week), normal pulmonary function, use intermittent inhaled β₂-agonists no more than twice per week, and modest variability in peak expiratory flow (PEF), a measure of airflow obstruction that can be obtained by patients themselves. Patients with mild persistent asthma have symptoms more than twice per week but less than once per day, normal pulmonary function between exacerbations, and more significant variability in PEF with exacerbations. Patients with moderate persistent asthma have daily symptoms that interfere with activity, require daily use of a β₂-agonist for quick relief, and have abnormal baseline pulmonary function with more severe variability of PEF. Patients with severe, persistent asthma have continuous symptoms that significantly impair their lives, limit physical activity, and are associated with frequent exacerbations. Baseline pulmonary function is abnormal, and there is more dramatic variability of PEF.

Historical details, such as age of onset, frequency and severity of episodes, requirements for medications, hospitalizations, and prior need for mechanical ventilation, are important to document. Daily fluctuations in symptoms also are important. Some patients have predominantly nocturnal symptoms, which can be associated with uncontrolled reflux esophagitis, sinusitis, or pharyngeal dysfunction. Daily fluctuations also can be precipitated by exertion or exposure to a variety of environmental agents, including cold, dry air, oxidant pollutants, tobacco smoke, perfumes, dust, or provocative agents in the workplace. Symptoms that increase throughout the workday or work week and tend to improve with days off from work suggest the possibility of occupational asthma. A history of allergy, atopy, eczema, allergic rhinitis, or nasal polyps may be elicited. Medication allergies or symptoms associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) also can be associated with asthma. The syndrome of sensitivity to NSAIDs, nasal polyps, and asthma has been termed triad asthma or Samter syndrome. Patients with asthma should be instructed to avoid these drugs, and those with sensitivity to them should be advised to strictly avoid them.

Occasionally, cough is the only symptom of asthma, thus underscoring the importance of considering asthma in the differential diagnosis of this symptom. Cough associated with asthma may be dry, but it is often productive of thick, tenacious sputum that may contain mucous plugs. The sputum may become purulent as symptoms worsen. This may represent secondary bacterial infection but more often is caused by inflammatory cell infiltration without viral or bacterial superinfection. This purulent sputum most often contains numerous eosinophils, but severe exacerbations may be associated with neutrophils in sputum.

Physical findings in asthma correlate poorly with more objective measures of airway obstruction, such as pulmonary function tests, that are obtained in a laboratory setting. Nevertheless, the findings are clinically useful. In an asymptomatic asthmatic patient, physical findings may be absent; however, wheezing may be elicited by forced expiration. Mild bronchospasm, in general, is associated with wheezing only during expiration. With greater degrees of obstruction, wheezing is heard in both the inspiratory and expiratory phases, with prolongation of the expiratory phase. With profound obstruction, wheezes may be heard only during the inspiratory phase or even may be absent with profoundly diminished air movement. When wheezing is correlated with other physical examination findings, a more reliable assessment can be made of the severity of obstruction. Normally, the inspiratory-to-expiratory ratio is less than 1:2, but this ratio increases in a graded fashion to 1:3 or more with increasing degrees of airway obstruction. Patients also begin to use accessory muscles of respiration with moderate to severe acute bronchospasm and may have active rather than passive expiration. With significant obstruction, evidence also may be seen of hyperinflation with low diaphragms and an increased anteroposterior diameter. Pulsus paradoxus is a term used to describe an indirect measure of fluctuations in transpulmonary pressure that occur with severe obstruction. Rather than truly paradoxical, pulsus paradoxus is an exaggerated decline in blood pressure with inspiration. The degree of obstruction correlates crudely with pulsus paradoxus. A pulsus greater than 10 mmHg is abnormal, and greater than 20 mmHg suggests profound obstruction. However, this measure has been supplanted and should not substitute for direct measures of the degree of obstruction by bedside or home PEF measurements. Measurement of forced expiratory volume in 1 second (FEV₁) is the gold standard, but is obtainable in a pulmonary function laboratory and is thus less readily available. With severely labored respirations, the patient can become diaphoretic, anxious, and unable to speak in full sentences. A respiratory rate greater than 30 breaths per minute and a heart rate of 120 beats per minute or more suggest severe bronchospasm. Agitation, confusion, somnolence, and cyanosis are foreboding findings and suggest impending respiratory failure. Unilateral loss of breath sounds can be consistent with mucous plugging and secondary atelectasis, but these findings also must raise the possibility of pneumothorax.

The clinical laboratory examination of asthmatics is often of limited value. Peripheral blood eosinophilia is frequently present but rarely exceeds 25%. Serum immunoglobulin E (IgE) is often elevated in asthmatics, and in allergic asthmatics specific antibodies can be detected. Very high serum IgE should raise the question of allergic bronchopulmonary aspergillosis. Likewise, examination of sputum or nasal mucus can often reveal the presence of increased numbers of eosinophils.

During bronchospasm, pulmonary function tests, including spirometry, reveal obstruction with a decrease in FEV₁ and decreased mid-expiratory flows. The ratio of FEV₁ to forced vital capacity (FVC) also is reduced. With more severe obstruction, hyperinflation is evident, with an increased residual volume and functional residual capacity more than total lung capacity. The flow-volume loop reveals evidence of obstruction with diminished flows and coving inward of the expiratory limb. One of the hallmarks of asthma is partial or complete reversal of airway obstruction after the administration of a bronchodilator. This response also can be used to gauge the adequacy of treatment. However, the lack of response to a one-time dose of a bronchodilator does not preclude a reversible component to the patient’s obstruction. Moreover, it is now recognized that asthma is often associated with a progressive decline in lung function over years; presumably, this decline is caused by fixed airway obstruction associated with airway remodeling. The diffusing capacity of the lung for carbon monoxide is often increased in asthmatics who do not smoke. The exact mechanism of this increase is unknown, but it is thought to represent an increase in pulmonary capillary blood volume associated with obstruction. PEF measurements, which are inexpensive, simple measurements that patients can assess and interpret, are also reduced during bronchospasm.

Bronchial challenge testing can establish the presence of airway hyperresponsiveness. Nonspecific bronchial hyperresponsiveness is demonstrated by exaggerated bronchoconstriction to inhaled histamine or methacholine. Nonspecific bronchial challenge is most useful in the evaluation of cough or to establish the diagnosis of asthma when the history is compatible, but physical examination and pulmonary function evidence of obstruction are lacking. However, bronchial challenge can be hazardous and should not be performed when significant airway obstruction is present. Bronchial challenge with specific provocative agents has utility in selected cases. The most commonly used specific bronchial challenges are exercise or cold air. Specific airway challenges with other agents (e.g., antigen) should only be performed in specialized centers having experience with these procedures.

Assessment of arterial blood gases usually is not necessary in the management of mild to moderate asthma. However, pulse oximetry may be of value during moderately severe exacerbations, and arterial blood gas assessment may be indicated during severe exacerbations. Hypoxemia is a frequent finding in this setting, and the arterial Pco₂ is usually decreased. During prolonged and severe episodes of airway obstruction, the patient can develop respiratory muscle fatigue, and the Pco₂ may normalize or become elevated. A normal or elevated Pco₂ during a severe exacerbation is an ominous sign, suggesting impending respiratory failure.

In the setting of chronic asthma and in the absence of another underlying condition, chest radiographic findings are usually normal. During an exacerbation, chest radiographs are not required unless fever, sputum production, chest pain, leukocytosis, or physical evidence of barotrauma are present. Hyperinflation of the lung can be present during severe exacerbations.

The diagnosis of asthma is made principally on clinical grounds; laboratory data are used in a supplementary or confirmatory fashion. A history of episodic wheezing in a nonsmoking patient, with findings of wheezing on physical examination, is strongly suggestive of asthma. Other causes of wheezing should be excluded. The diagnosis is confirmed with spirometry, which demonstrates obstruction (a FEV₁/FVC ratio of less than 70% with or without a significant reduction of FEV₁) that normalizes or significantly improves with use of a bronchodilator. If spirometry is normal, it should be repeated after a forced expiratory maneuver, which usually induces a fall in FEV₁ in asthmatics. If spirometry still remains normal, bronchial challenge testing should be considered. Alternatively, the patient can be followed over time with serial spirograms (or PEF monitoring) to demonstrate variable obstruction.

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