Adapted from National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma: Expert panel report 3, NIH publication 08-4051. Bethesda, MD: National Institutes of Health; 2007 and Reddel HK, Bacharier LB, Bateman ED, et al. Global Initiative for Asthma Strategy 2021: Executive Summary and Rationale for Key Changes. Am J Respir Crit Care Med. 2022;205:17-35.

Diagnostic approach

A clinical history of reversible episodes of dyspnea and wheezing brought on by characteristic triggers is often crucial to the diagnosis of asthma. Other helpful features in the history include other evidence for atopy (e.g., hay fever or eczema) or a family history of allergies or asthma. Physical examination demonstrating wheezes during an attack often provides confirmatory evidence for airflow obstruction.

The chest radiograph, although sometimes useful for excluding other causes of wheezing or complications of asthma, generally is not particularly helpful in the diagnosis. It usually shows normal findings but may demonstrate a flattened diaphragm suggestive of air trapping.

If the patient is producing sputum, microscopic examination of the sputum frequently shows many eosinophils on the smear. An increased number of eosinophils in peripheral blood is also relatively common, even when the asthma has no clear relationship to allergies.

The clinical usefulness of skin testing and inhalation testing with allergens in an attempt to identify antigens to which the patient is sensitized is controversial. Allergy skin testing with antigens and blood testing for specific IgE antibodies are available to help confirm or refute suspected allergic sensitivities to common aeroallergens. Unfortunately, neither is useful for the diagnosis of asthma, because persons with asthma may have no allergic sensitivities, and persons with allergic sensitivities may not have asthma but rather manifest with symptoms affecting the nose and conjunctivae.

A measure of airway inflammation that is sometimes used clinically is the fraction of exhaled nitric oxide (FENO). Nitric oxide, which is produced and released by airway epithelial cells, is increased in exhaled gas in the presence of airway inflammation, particularly with eosinophils. This occurs as a result of augmenting the levels of the inducible nitric oxide synthase (iNOS) enzyme in the airway epithelium. This measure of eosinophilic airway inflammation has been used as a marker of how active the inflammatory response is, as a guide to the likelihood of response to corticosteroids, and as an indicator of response to therapy.

Although the diagnosis of asthma is usually made based on clinical features, spirometry, and response to therapy, provocation tests are sometimes used to establish or confirm the diagnosis of asthma. These tests rely on the principle that persons with asthma have hyperreactive airways. Therefore, when tested with inhalation of methacholine (a cholinergic agent) or histamine, persons with asthma develop bronchoconstriction to lower doses of either agent compared with normals. Inhalation of cold air at high minute ventilations with PCO2 kept constant (termed isocapnic hyperpnea) can also be used as a challenge test to induce transient bronchoconstriction in patients in whom the diagnosis of asthma is uncertain.

Measurements of pulmonary function, especially FEV1 and FVC, are particularly useful in the patient with suspected or known asthma. Documentation of reversible airflow obstruction, either during attacks or with a challenge test, is frequently sufficient to make the diagnosis. In practice, the diagnosis of asthma is most commonly made by the history of episodic dyspnea, wheezing, or cough, with documentation of reversible airflow obstruction by pulmonary function testing.

A diagnosis of asthma includes a history of episodic dyspnea, wheezing, or cough, along with

reversible airflow obstruction documented by pulmonary function testing.

Patients can conveniently test their own pulmonary function through measurement of the peak expiratory flow rate on a simple, inexpensive hand-held device. Such testing is particularly useful for monitoring the course of the disease and alerting the patient to adjust the medication regimen, seek attention from a physician, or both. In addition, the efficacy of treatment or changes in the therapeutic regimen can readily be assessed by serial measurement of the peak expiratory flow rate.

Treatment

The major categories of drugs used to treat asthma are those that dilate smooth muscle of the bronchial wall and those that have an anti-inflammatory action. Agents that decrease the production or activity of specific mediators and are developed from biological sources are termed biologic agents, and include monoclonal antibodies against IgE, IL-5, and other important mediators of asthmatic inflammation. The main categories of drugs used to treat asthma are listed in Table 5.4. Several of the drugs are also used for treatment of other types of pulmonary disease, particularly COPD, and are mentioned in other chapters.

TABLE 5.4

Drug Therapy in Asthma

cAMP, cyclic adenosine monophosphate; IgE, immunoglobulin E; IL-4, interleukin-4; IL-5, interleukin-5; IL-13, interleukin-13; TSLP, thymic stromal lymphopoietin.

Bronchodilators

The most common bronchodilator agents used for the treatment of asthma are the sympathomimetic agents, which act on β2-receptors to activate adenylate cyclase and increase intracellular cyclic adenosine monophosphate (cAMP). Increased levels of cAMP in bronchial smooth muscle, resulting specifically from stimulation of β2-receptors, activate protein kinase A, which phosphorylates several regulatory proteins that mediate bronchodilation. In addition, β-receptor stimulation increases intracellular cAMP in mast cells, inhibiting release of chemical mediators that secondarily cause bronchoconstriction. Specific examples of available sympathomimetic drugs are listed in Table 5.4. To avoid some of the adverse

cardiac effects induced by stimulation of β1-receptors (primarily tachycardia), the preferred agents act preferentially on β2-receptors. The β2-specific agents most commonly used are albuterol (short-acting β2- agonist) and salmeterol or formoterol (long-acting β2-agonists), and the typical route of administration is inhalation. In addition to its long duration, formoterol also has a rapid onset of action. Although some sympathomimetic agents can be given orally or parenterally, the inhaled route is preferred because it has fewer systemic side effects and provides direct delivery to the site of action in the airways.

Sympathomimetic agents increase intracellular cAMP by activating adenylate cyclase. Preferred agents preferentially stimulate β2-receptors and decrease potential adverse cardiac effects caused by stimulation of β1-receptors.

Short-acting inhaled β2-agonists, such as albuterol, are typically used on an as-needed basis to reverse an acute episode of bronchoconstriction. They may be the only agents needed to control the patient’s asthma when episodes are infrequent. Short-acting β2-agonist drugs can also be used prophylactically before activities or exposure to stimuli known to precipitate bronchoconstriction, such as exercise. Effects of the long-acting β2-agonists salmeterol, formoterol, and arformoterol last for approximately 12 hours, whereas newer ultra-long-acting β2-agonists such as vilanterol can last up to 24 hours. If asthma severity necessitates frequent use of an inhaled β2-agonist, then an anti-inflammatory agent (see following section) should be incorporated in the treatment regimen.

The second class of bronchodilator agents, which are less commonly used in asthma, consists of drugs that have an anticholinergic action. Anticholinergic agents dilate bronchial smooth muscle by decreasing bronchoconstrictor cholinergic tone to airways. Ipratropium, available as an aerosol for inhalation, is the primary short-acting example of this class of agents. The major use of ipratropium for asthma has been as adjunctive therapy to inhaled β2-agonists in patients during a severe acute asthma attack. Tiotropium, a long-acting anticholinergic agent frequently used in patients with COPD, is also used in patients with asthma and has been increasingly used as adjunctive therapy in patients with severe asthma already on an inhaled glucocorticoid and a long-acting β2-agonist.

The third class of bronchodilator agents, the methylxanthines, is used much less frequently than either β2-agonists or anticholinergic agents. Theophylline, the prototype of this class, is generally believed to act by inhibiting the enzyme phosphodiesterase (PDE), which is normally responsible for metabolic degradation of cAMP. When degradation is inhibited, the levels of cAMP in smooth muscle and mast cells increase, resulting again in bronchodilation and decreased mediator release from mast cells. However, the serum levels of methylxanthines needed to inhibit PDE are higher than those actually achieved in patients, so whether PDE inhibition is the major or exclusive mechanism of action of theophylline as a bronchodilator is uncertain. In addition, theophylline may have a component of anti-inflammatory activity, mediated by inhibition of the PDE-4 isozyme in inflammatory cells. Theophylline is available only for oral administration, whereas aminophylline (a water-soluble salt of theophylline) can be given orally or intravenously. Because methylxanthines can be administered only systemically (as opposed to locally in the airway), systemic side effects (gastrointestinal, cardiac, neurologic) are more problematic than with inhaled sympathomimetic or anticholinergic agents. In addition, methylxanthines have a narrow therapeutic window and require monitoring of serum levels. For these reasons, methylxanthines are now used relatively infrequently compared with other medications.

Methylxanthines (aminophylline, theophylline) increase cAMP by inhibiting the enzyme PDE, which

degrades cAMP. This mechanism may be responsible for bronchodilation.

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Anti-inflammatory drugs

As opposed to the bronchodilator agents, which act by relaxing bronchial smooth muscle, antiinflammatory agents are targeted to control the underlying process of airway inflammation and are therefore categorized as controller medications. The primary category of anti-inflammatory controller agents are corticosteroids, ideally given by inhalation. They suppress the inflammatory response by decreasing the number of eosinophils and lymphocytes infiltrating the airway and decrease production of a number of inflammatory mediators. Despite the general rationale for corticosteroid use, many aspects of their anti-inflammatory action remain poorly understood. Glucocorticoids are thought to bind to a cytoplasmic receptor present in nearly all cell types. After the receptor binds to its glucocorticoid ligand, it moves to the cell nucleus, where it interacts with transcription factors such as activator protein (AP)-1 and nuclear factor (NF)-κB, which regulate transcription of other target genes. Important target genes whose transcription is suppressed by the action of glucocorticoids include a variety of inflammatory cytokines (e.g., IL-1, IL-3, IL-4, IL-5, IL-6, and tumor necrosis factor [TNF]-α), the inducible form of iNOS, and an inducible form of cyclooxygenase.

Because airway inflammation plays an important role in asthma pathogenesis, particularly in the patient with more frequent attacks or more persistent airflow obstruction, inhaled corticosteroids have assumed a central role in the management of most cases of asthma. By decreasing airway inflammation, inhaled corticosteroids are thought to ameliorate the underlying disease process in asthma, not just the bronchoconstriction resulting from airway inflammation.

Corticosteroids have an important place in both management of acute asthma exacerbations and as part of maintenance therapy. Frequently, systemic corticosteroids such as prednisone or methylprednisolone are started at high doses during an acute attack and then tapered relatively rapidly. Because of the potential for significant adverse effects with long-term use of systemic (oral) corticosteroids, chronic administration of oral corticosteroids is avoided if the asthma can be managed with other modes of therapy. Foremost among these alternative forms of therapy are inhaled forms of corticosteroids that deliver the drug locally to the airway but have minimal systemic absorption and limited side effects. Inhaled corticosteroids are currently incorporated into the regimen of most patients with asthma. Traditionally, scheduled daily use of an inhaled corticosteroid was started if the condition required more than infrequent use of a short-acting β-agonist. More recently, the field has moved toward using inhaled corticosteroids in conjunction with formoterol (a long-acting β-agonist with an onset of action that is short enough to be used for quick relief) on an as-needed basis if possible, rather than committing patients with less severe asthma to scheduled daily inhaled corticosteroids. However, patients with more severe asthma may require daily in addition to as-needed therapy with a combination corticosteroid-formoterol inhaler. This latter approach has been called SMART (Single Maintenance And Reliever Therapy).

Systemic and inhaled corticosteroids have an important role in acute therapy and preventive management, respectively.

A different anti-inflammatory drug that is rarely used is disodium cromoglycate (cromolyn). Its mode of action was traditionally thought to be inhibition of mediator release from mast cells, but this mechanism has been disputed. Alternative mechanisms proposed include inhibitory effects on other types of inflammatory cells or on the action of tachykinins. Cromolyn is available in most countries only as a solution for inhalation using a nebulizer; it is not a bronchodilator and therefore has no role in the treatment of acute attacks. Rather, it is given as an ongoing medication, with the goal of preventing future exacerbations.

Anti-inflammatory therapy is important when treatment of asthma requires more than infrequent use of an inhaled β2-agonist.

Agents with specific targeted action

Agents are increasingly being developed that block the synthesis or action of a particular type of mediator. Accompanying the recent interest in identifying discrete asthma phenotypes is a goal of targeting therapy toward individual mediators that may have a central role in one or more underlying endotypes. This rationale is supported by the observation that such agents are often effective only in specific subgroups of patients with asthma. We will consider three categories of chemical mediators in asthma that are the targets of currently available drugs—leukotrienes, IgE, and cytokines that are important in the asthmatic response.

Drugs that are directed at modifying leukotrienes or leukotriene pathways include zafirlukast and montelukast, which antagonize the action of leukotrienes at their receptor, and zileuton, which inhibits the enzyme 5-lipoxygenase and thus limits leukotriene production. Because of their mode of action, drugs that either block leukotriene synthesis or antagonize their action have a particularly important role in patients who are sensitive to aspirin or other NSAIDs.

Omalizumab, a monoclonal antibody to IgE, prevents binding of IgE to receptors on mast cells, thus inhibiting the release of mast cell mediators which are important components of the pathobiology of allergic asthma. Omalizumab is administered every 2 to 4 weeks by subcutaneous injection in a healthcare setting (e.g., outpatient medical office) and is expensive. Its use has been limited to selected patients with particularly severe asthma who have elevated levels of IgE and continue to be symptomatic and prone to asthmatic attacks despite other treatment.

More recently, monoclonal antibodies against important cytokine mediators of asthma, such as IL-4, IL- 5, IL-13, and thymic stromal lymphopoietin, have become available and reduce TH2-related inflammation. Like omalizumab, these drugs are extremely expensive. They are administered subcutaneously or intravenously and have limited use, but can be very effective in some patients with severe asthma, particularly when requiring ongoing treatment with corticosteroids. Of note, the effectiveness of some of these agents is limited to specific phenotypes of asthma based on eosinophil count and other factors.

Bronchial thermoplasty

In bronchial thermoplasty, a relatively new procedure performed via a flexible bronchoscope, thermal energy is delivered to the airways in an effort to reduce airway smooth muscle mass. Studies indicate that the procedure can produce sustained benefit in patients with moderate and severe asthma, but experience is limited. Further trials should better define the optimal role of this procedure in asthma management.

Management strategy

At present, the overall strategy for management of asthma commonly proceeds in the following manner. In a patient with relatively infrequent attacks and with symptom-free periods and normal pulmonary function between attacks, preferred management is with the use of an inhaled β2-agonist or a combined inhaled corticosteroid and β2-agonist on an as-needed basis. These drugs are used both for management of bronchospasm once it occurs and before exposure to stimuli often known to precipitate attacks (e.g., exercise or allergen exposure). These general guidelines are summarized in Table 5.3 according to the categories of clinical severity of disease.

When a patient’s asthma cannot be managed successfully with just infrequent use of an as-needed

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