Being an inflammatory condition with both allergic and nonallergic precipitants, asthma engages a wide variety of inflammatory pathways and mediators.

Airway hyperresponsiveness, a characteristic feature of asthma, is manifested by an exaggerated bronchoconstrictor response to multiple stimuli. Purported mechanisms include inflammation, dysfunctional neuroregulation, and structural changes.

Asthmatic reactions have early and late phases. The acute bronchoconstrictive phase involves the rapid development of reversible airway obstruction; it represents the hyperresponsiveness to environmental stimuli characteristic of the asthmatic airway. It is most pronounced in persons with adult-onset disease. Stimuli include allergens (e.g., molds, sulfites, animal dander, pollens), aspirin, exercise, emotional stress, viral respiratory infections, and respiratory irritants such as perfumes, tobacco smoke, and dusts.

In addition to the initial hyperreactivity, asthmatic patients experience a second or late-phase reaction 6 to 12 hours later. This late-phase reaction is believed to be a manifestation of the inflammatory response that is more refractory to bronchodilator treatment than is the initial one. Neutrophil chemotactic factor is believed to play a role. Even some patients with exercise-induced asthma experience a late reaction.

In growing recognition of the heterogeneity of asthma’s pathogenesis and pathophysiology and until validated means of genotyping and biomarking emerge, phenotyping represents an opportunity to unravel the heterogeneity of asthma and better classify patients, under the assumption they are likely to share mechanisms of disease and responses to treatment.

Traditionally, asthma has been divided phenotypically on the basis of age of onset and presence of atopy into childhoodonset/atopic asthma and adult-onset/nonatopic asthma. These are sometimes referred to as allergic and nonallergic asthma (see later discussion). However, patients in both groups have demonstrated reactivity related to IgE, which challenges the notion of separate allergen-related and non-allergen-related categories of this reactive airway disease.

Others have suggested phenotyping by degree of eosinophilia, one characterized by prominence of tissue and sputum eosinophils and associated with greater airway remodeling and more exacerbations and the other with little eosinophilia and greater obstruction to airflow.

Cluster analysis has been applied to asthma phenotyping, identifying as many as six distinct clusters of patients, in which members of each share important clinical characteristics. Easily ascertainable domains for use in clustering have been identified by discriminant analysis and include not only age of onset and atopy status but also gender, race, body mass index, duration, and
baseline and maximal pulmonary function measures. Members in each cluster manifest similar clinical courses and responses to therapy, suggesting a shared pathogenesis and/or pathophysiology.

Although refinement and revisions are almost certain and linking to specific inflammatory pathways and mediators remains a major unfinished task, this exercise in phenotyping points the way toward design of more targeted, personalized approaches to asthma treatment. The work presented here derives from the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program (SARP)—a collaborative effort that, despite its name, encompasses the full spectrum of asthma patients. Since such clustering represents a work in progress, it would be premature to consider each cluster a well-defined subgroup requiring a particular approach to management, but this effort is presented to provide the reader with a foundation for understanding future asthma categorization and subsequent management. Of particular note was the finding of the SARP investigators that 80% of patients could be accurately categorized by consideration of just baseline pulmonary function (pre- and postbronchodilator FEV₁% predicted) and age of onset, suggesting a potentially useful approach to future phenotyping. Two other observations of potential prognostic importance are (a) that the likelihood of change in cluster over time varies according to atopy status (persons without atopy are at greater risk for progression to a more severe disease cluster), and (b) that disease severity is greatest and prognosis is poorest for persons with the poorest prebronchodilator and postbronchodilator measurements a time of diagnosis (baseline and best FEV _1< <68% predicted) whereas a prebronchodilator FEV₁ ≥80% predicted identifies persons with a favorable prognosis.

A number of comorbidities are associated with asthma, especially with increasing age and severity. These include gastroesophageal reflux disease (GERD), sinus disease, pneumonia, obstructive sleep apnea, and hypertension. While not directly participating in asthma’s pathophysiology, they can interact with it and have important impacts on clinical presentation, course, severity of symptoms, and response to treatment.

Patients with so-called allergic asthma typically give a history of atopy, onset of symptoms during childhood or adolescence, predictable seasonal occurrence, and hyperresponsiveness to environmental allergens. However, the condition can occur at any age, and attacks may take place seasonally or year-round, precipitated by such common household allergens as dust mites (in beds and living room rugs, carpets, drapes, stuffed furniture), animal dander, and fungal spores.

Anxiety, inhalation of airway irritants, and exposure to perfumes and strong household odors can also precipitate asthmatic episodes in these patients, since they suffer from the hyperresponsiveness characteristic of all asthmatics. The course of attacks is usually self-limited, although some patients have severe bouts requiring hospitalization. Prognosis is relatively good, with 70% found to be symptom free 20 years after onset.

Patients with nonallergic asthma usually begin having symptoms in the third or fourth decade. Although no identifiable extrinsic allergen is associated with attacks in these patients, they do demonstrate elevations in serum IgE, similar to those of patients with “allergic” disease. Sputum production can be considerable, so that differentiation from chronic bronchitis is sometimes difficult. Minor upper respiratory tract infections often precipitate attacks. Some of these patients present with exertional dyspnea or cough and no demonstrable wheezing, although expiratory flow rates are significantly reduced. “Intrinsic” asthma is sometimes more refractory to treatment than is “extrinsic” disease.

Postexertional asthma is a form of airway hyperreactivity most common in children and adolescents. The stimulus is believed to be a reduction in the temperature of inhaled air, which leads to mediator release (especially leukotrienes) in susceptible patients. Both initial and late-phase reactions have been identified. Vigorous exercise on a cold, dry day is particularly apt to trigger an attack; airway temperature can become quite low in such circumstances. Although bronchospasm does not occur during exercise, it becomes marked shortly after exercise ends and can last for up to 1 hour.

Occupational asthma has gained increasing recognition as an important cause of work-related disability. True occupational asthma involves the development of sensitization through inhalation exposure to an occupationally related allergen. Exposure to irritant or toxic pollutants in the workplace can also trigger bronchospasm, especially in a person with preexisting airway hyperresponsiveness. Cold air, sulfur dioxide in low concentrations, fluorocarbons, and inert dusts are common irritants that stimulate reflex bronchospasm. Toxic gases such as sulfur dioxide in high concentrations, halogens, ammonia, acid fumes, and solvent vapors cause inflammatory bronchoconstriction. Important allergens include animal proteins, enzymes, grain and cereal dusts, seeds, vegetable gums, and legumes. Other substances have pharmacologic activity; histamine-releasing compounds are present in cotton dust, organic acids are found in wood dust, and numerous chemicals have anticholinesterase activity. Some agents provoke asthma through multiple mechanisms; toluene diisocyanate has reflex, pharmacologic, β-blocking, and IgE effects.

Patients with occupational asthma caused by toxic or irritant substances characteristically report a direct relation between exposure and onset of symptoms. Those with allergen-induced disease note no symptoms at the time of the first exposure but marked wheezing after even minor repeated contact with the allergen (anamnestic response). Typically, patients with occupational asthma are symptom-free during days off from work, only to have a flare-up on returning (see Chapter 39).

Nasal polyps and aspirin sensitivity comprise a curious but important familial asthma syndrome. The bronchospasm associated with aspirin intake may be marked. The finding of nasal polyps in a person with a history of asthma should lead to consideration of aspirin sensitivity. Aspirin sensitivity can be demonstrated with oral provocation testing among 21% of adults with asthma. Almost all patients with aspirin sensitivity have cross-reactivity with nonsteroidal anti-inflammatory agents. Only 7% of those with aspirin sensitivity have cross-reactivity with acetaminophen.

In some cases, chronic cough may be the principal or only manifestation of asthma. Such “cough variant asthma” is found mostly in children, but adults may present with it. On spirometry, there is typical reversible airflow obstruction and hyperresponsiveness demonstrated. Response to treatment is similar to that for other forms of asthma.

For management purposes (see later discussion), four categories or steps of asthma according to disease severity have been defined to help guide treatment. A shortcoming of such a categorization is the likely heterogeneity of patients within each step or stage of disease, which could affect response to treatment and natural history of disease. Nonetheless, this categorization remains a key element of currently recommended treatment guidelines.

In obtaining the history, particular note should be taken of any cough or wheezing that is recurrent and may be accompanied by shortness of breath or chest tightness, worse at night or awakening the patient, and occurring or worsened by exercise or viral infection. Also useful is checking for exacerbations brought on by contact with hairy or furry animals or exposure to house dusts, airborne chemicals or dusts, smoke (tobacco or wood), mold, or pollens, which not only helps establish the diagnosis but also provides potentially useful information for prevention. Any triggering by changes in weather, emotional outbursts, or menstrual cycle should also be noted since these are characteristic features in subsets of patients.

Age at onset, duration of symptoms, and history of hay fever or eczema or family history of atopy are useful elements of the history for phenotyping, though not for diagnosis. Similarly, checking history for comorbidities such as obstructive sleep apnea (see Chapter 46), GERD (see Chapter 60), sinus disease (see Chapter 219), and hypertension (see Chapter 19) facilitates management, because their presence can hinder treatment and/or exacerbate symptoms.

Review of the patient’s medication list is also indicated. Concurrent use of noncardioselective beta-blockers in asthmatics with underlying hypertension or cardiovascular disease can cause bronchospasm and blunt the bronchodilating effects of β₂-agonists. Concern about beta-blocker therapy has been reduced by the advent and judicious use of cardioselective (β₁) beta-blockers (e.g., atenolol, metoprolol). Meta-analytic work found only a 7.5% reduction in FEV₁ in mild to moderate asthmatic patients with the addition of a cardioselective beta-blocker and no impairment of the bronchodilating effects of beta-agonist therapy. Most asthmatic patients with a clear indication for beta-blockade (i.e., those with hypertension, coronary disease, or heart failure) need not forego or stop beta-blocker therapy as long as cardioselective preparations are used and doses are kept low. However, the safety of cardioselective beta-blockade in those with severe asthma is not well established.

Spirometry is essential to the diagnosis of asthma. The key measurement of impaired airway function is the reduction in forced expiratory volume in 1 second (FEV₁) expressed either as a percent of the predicted value or as a proportion of the forced vital capacity (FEV₁/FVC). The latter calculation is the more accurate since it corrects for conditions other than airflow obstruction that might affect the FEV₁, such as generalized debility or chest wall deformity.

Determinations are made before and after the patient inhales a short-acting bronchodilator (e.g., two to four puffs of albuterol). Reversibility, a key determinant for the diagnosis of asthma, is defined by an increase in FEV₁ of >200 mL, a ≥12% increase from baseline, or an increase ≥10% of predicted FEV₁.

The degree of airflow obstruction and short-term reversibility as measured objectively also correlates with degree of inflammation and prognosis—patient perception of disease severity is often discordant with actual measurements. Patients with the greatest degree of baseline airflow obstruction appear to have the worst prognosis. Those with the greatest reversibility are often at greatest risk of developing fixed airflow obstruction and the greatest loss of lung function.

Biomarkers have been sought as a more convenient way to confirm the diagnosis, determine disease severity, and predict prognosis. Among those measures studied include blood or sputum eosinophils or eosinophilic cationic protein (ECP), fractional exhaled nitric oxide concentration (FeNO), serum immunoglobulin E (IgE), number of positive skin tests, cytokine levels, and exhaled breath condensate (EBC). To date, none have proved superior to spirometry. Chest imaging studies are useful in conditions that might mimic asthma, but there are no findings diagnostic of asthma, although the plain film of the chest might show some hyperinflation during an exacerbation.

Because a high degree of treatment compliance and self-monitoring is required for effective implementation and maintenance of an asthma treatment program, it is essential to assess and support the patient’s capacity to carry out these functions (see also Patient Education). This requires inquiry into the patient’s knowledge of the condition as well as an estimate of skills and aptitude for self-management. Review of any prior experience with a medical regimen for control of a chronic illness having exacerbations and remissions can be very helpful in this regard.

As the treatment of asthma shifted over the past two decades from a focus on bronchospasm to amelioration of inflammation, the National Institutes of Health convened expert panels to develop clinical practice guidelines for asthma management and published them as the National Asthma Education and Prevention Program (NAEPP). These prescribe the stepped approach to care noted earlier. Oral steroids, other anti-inflammatory agents, and other bronchodilators are used in adjunctive fashion. Patient education is a central feature of the guidelines. Underuse of anti-inflammatory therapy and failure to monitor peak flows correlate strongly with an increased number of emergency department visits and hospitalizations.

Like most practice guidelines, many of the NAEPP recommendations are supported by the results of randomized, controlled trials. Primary care physicians may need to customize for individual patients those elements that pertain to patient self-monitoring and self-treatment of an exacerbation. Surveys indicate that fewer than 50% of asthma patients who should take inhaled steroids daily do so and fewer than 20% measure their peak flow regularly. Some have suggested that time pressures and staffing limitations in primary care practices may limit the teaching effort and contribute to inadequate outcomes. They propose disease management strategies, which emphasize the use of information technology to identify patients, customize the teaching intervention, monitor care, and control costs. The efficacy of the disease management approach is still being evaluated, but many studies have shown reductions in rates of emergency room visits and hospitalizations, especially when integrated with the work of the primary care practice.