What every physician needs to know

Asthma is a chronic inflammatory disease of the airways characterized by at least partially reversible airway obstruction and bronchial hyper-responsiveness. The cause of asthma remains unknown; clearly, both genetic and environmental influences are important. Recent research indicates that asthma is a heterogeneous disease with several phenotypes that likely result from differing underlying etiologies. Asthma is an important public health issue that adversely impacts the global economy through the generation of high direct medical costs and lost work and productivity.

The highly variable clinical presentation of asthma precludes a universal definition that can be applied confidently to all patients who have the disorder. Multiple phenotypes of asthma are recognized, and no unique set of clinical characteristics or any single diagnostic test is specific for asthma. Consequently, asthma can be challenging to diagnose.

In general, asthma is marked by recurrent episodes of wheezing, cough, dyspnea, and chest tightness. Patients may have several or only one of these findings; many report minimal or no wheezing. Hence, it is important to obtain a good history of symptoms in assessing a patient for asthma. Symptoms may occur as a result of exposure to an environmental “trigger,” but such triggers may or may not cause symptoms in individual patients with asthma. Typically, each patient has a unique list of triggers recognized as causing increased symptoms or “flares.” Common triggers include infections, exercise, weather changes, pollen, animal dander, dust mites, and mold. Some patients with asthma experience symptoms with use of aspirin or nonsteroidal antiinflammatory medications (NSAIDS) or with consumption of beer or red wine; some women have worsening symptoms with menses. Patients may be unaware of these associations, so direct questioning regarding unique triggers is required for an accurate diagnosis.

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Most patients with asthma experience onset of symptoms in childhood or adolescence. Atopy is the major predisposing factor for developing asthma as a child; 60 percent of children younger than six years of age who wheeze have associated atopy. Some adolescents may experience “remission” of childhood asthma, but this appears to be the exception rather than the rule. Factors that predict persistence of asthma from childhood into adulthood include female sex, family history of asthma, atopy, bronchial hyper-responsiveness, obesity, and rhinitis/sinusitis. Some individuals who have no history of asthma as a child or teenager develop the disorder as adults (e.g., after age forty), including some with apparently new-onset asthma after age sixty.

Obvious racial and ethnic differences exist with regard to asthma prevalence, healthcare resource utilization in its management, and asthma-related mortality. While most acute exacerbations of asthma can be managed readily on an outpatient basis, some are associated with significant morbidity and mortality. Nationally, thousands of asthma-related deaths are reported annually. In the United States, African Americans have a higher prevalence of asthma, account for greater healthcare use in its management, and experience greater asthma-associated mortality than Caucasian Americans do (African Americans’ asthma mortality rate is 200% that of Caucasians). Socioeconomic issues may explain some of the disparity, but other variables, such as differential response to asthma medications, may be partly responsible. Fortunately, most patients with asthma, if compliant with treatment and afforded proper medical care, live healthy, active lives.

Classification:

Classification of asthma is based on severity of illness prior to initiation of chronic asthma therapy, allowing estimation of treatment duration and intensity required for control of symptoms and preservation of lung function (Figure 1).

Figure 1.

Classification of Asthma Severity.

Asthma guidelines used in the United States and internationally classify disease severity based primarily on frequency of daytime and nighttime symptoms and lung function. Other important parameters include frequency of exacerbations, frequency of rescue inhaler use, and assessment of the disorder’s effect on normal physical activity. Based on these variables, patients are classified into one of four categories:

  • Intermittent asthma

  • Mild persistent asthma

  • Moderate persistent asthma

  • Severe persistent asthma

The particular category is determined by the parameters defining the worst level of severity. Based on available evidence, asthma severity does not appear to change significantly over time, even with use of optimal therapy (see below).

Patients are commonly encountered who have already been prescribed chronic asthma medications prior to classification of asthma severity. Consequently, overestimation or underestimation of true asthma severity may arise, presenting significant challenges to healthcare providers. Under such circumstances, classification of disease severity is likely best avoided. Instead, the focus should be on whether symptoms are controlled adequately or inadequately, as discussed below.

Are you sure your patient has asthma? What should you expect to find?

No definitive test or specific symptom complex is diagnostic for asthma. In making an accurate diagnosis, the clinician should:

  • Determine whether the patient has episodic respiratory symptoms that occur as a result of exposure to an environmental trigger. Classic symptoms include cough, wheezing, dyspnea, and chest tightness.

  • Use pulmonary function testing to demonstrate the presence of airway obstruction that is at least partially reversible after bronchodilator administration.

  • Ensure that alternative diagnoses have been considered and excluded.

A diagnosis of asthma is often made based on the presence of symptoms alone, without appropriate consideration of alternative diagnoses and without pulmonary function testing. As a result, an erroneous diagnosis of asthma may be made, exposing the patient to unnecessary medications and risk.

A variety of asthma phenotypes are recognized, including allergic asthma, adult-onset asthma, steroid-resistant asthma, and exercise-induced asthma. Data also suggest that obesity and female sex can also affect the presentation of asthma. Consequently, entertaining a broad differential diagnosis and performing a thorough history are important when evaluating a patient for asthma. Not all patients will present with the classic history of episodic wheezing and environmental allergies.

Beware: there are other diseases that can mimic asthma:

The differential diagnosis of asthma is somewhat dependent on the age of the patient. Infants and small children have unique anatomical considerations that make the differential diagnosis different than that in adults. In adults, several common diseases must be considered, as it is important to recognize that these conditions may occur concurrently in patients with true asthma, significantly complicating its diagnosis and management. These diseases include:

  • Chronic obstructive pulmonary disease (COPD)

  • Congestive heart failure

  • Gastroesophageal reflux disease (GERD)

  • Medication side effects (e.g., from use of angiotensin-converting enzyme [ACE] inhibitors)

  • Rhinitis/sinusitis

  • Vocal cord dysfunction

Vocal cord dysfunction warrants some additional consideration, as it is an increasingly recognized mimic and significant co-morbid condition in people with asthma. Symptoms are very similar to those of asthma but people with VCD often report failure of albuterol to help, inability to take a breath in, and inspiratory stridor. Stress is common but not always a co-factor, and VCD can also mimic exercise-induced asthma, particularly in teens. VCD is diagnosed by various methods, but direct visualization with some type of provocation that elicits symptoms appears to offer the highest yield for diagnosis. Treatment options, which have not been subjected to any randomized trials, primarily consist of speech therapy.

How and/or why did the patient develop asthma?

The etiology of asthma is unknown, but asthma likely results from complex interactions between multiple genetic and environmental variables. Studies of twins and families with asthmatic members have shown that, in many cases, asthma occurs in a pattern consistent with heritable factors. However, at present, the specific genes responsible for asthma have not been definitively identified. Furthermore, the variety of asthma phenotypes, as described previously, may have distinct etiologies, a focus of much ongoing research.

Which individuals are of greatest risk of developing asthma?

Multiple risk factors are associated with asthma:

  • Family history of asthma in a first-degree relative

  • Abnormal lung function during infancy

  • Allergic conditions, such as atopy or allergic rhinitis (also associated with persistence of asthma from childhood into adulthood)

  • Viral infections during infancy, particularly respiratory syncytial virus (RSV)

  • Obesity as a child or adult

  • Exposure to cigarette smoke (primary or second-hand), including in utero exposure in mothers who smoke during pregnancy

  • Low socioeconomic status and non-white race

  • Exposure to exhaust fumes or other types of air pollution

  • Exposure to occupational triggers, such as chemicals used in farming, hairdressing, and manufacturing

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

No blood tests define the presence or absence of asthma, and no blood tests are available to stratify asthma by severity. However, a complete blood count (CBC), including white blood cell differential analysis, is important in screening for eosinophilia, which can be seen in severe or atypical forms of disorders associated with asthma (e.g., allergic bronchopulmonary aspergillosis [ABPA] or chronic eosinophilic pneumonia. Use of the CBC in screening for anemia also may be helpful in certain cases.

What imaging studies will be helpful in making or excluding the diagnosis of asthma?

Although the chest radiograph is usually of little specific diagnostic value in asthma, all patients with dyspnea or suspected asthma should have a chest radiograph performed on initial evaluation. The presence of infiltrates, consolidation, pleural effusions, or lung nodules should prompt consideration of alternative diagnoses. The chest radiograph can also be helpful in evaluating patients with severe or atypical forms of asthma, such as ABPA or chronic eosinophilic pneumonia.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of asthma?

Although there is no diagnostic test for asthma, several pulmonary tests should be considered in the workup of a patient suspected of having the disorder:

  • Spirometry prior to and following administration of an inhaled bronchodilator. Spirometry allows for documentation of airway obstruction that is at least partially reversible following bronchodilator administration. Obstruction is defined by an FEV1/FVC ratio less than 70 percent; the severity of the obstruction is determined by the magnitude of the decrease in FEV1. Reversibility of obstruction is defined as an improvement of 12 percent or greater and an increase of at least 200 mL, in FEV1 or FVC following bronchodilator administration. Because asthma is episodic in nature, many patients with asthma with stable disease have normal spirometry in the office setting; hence, normal spirometry does not rule out a diagnosis of asthma.

  • Methacholine challenge testing (MCT). MCT is a common method of establishing airway hyper-responsiveness, especially if spirometry is normal at baseline. During the test, increasing concentrations of methacholine are administered via a nebulizer, and spirometry and flow volume loops are obtained following each dose of the drug. A positive test is defined as a 20 percent decline in FEV1 from baseline occurring at a cumulative methacholine dose of 8 mg/ml or less. One cautionary note in using MCT is that some patients without asthma, especially those with atopy, may have a positive test; hence, MCT is not 100 percent diagnostic for asthma. Because of its greater negative predictive value, MCT is much more useful in excluding a diagnosis of asthma. A negative methacholine challenge makes a diagnosis of asthma much less likely, but other diagnoses should also be considered.

  • Measurement of exhaled nitric oxide, a marker of inflammation, has become an accepted adjunctive method in the diagnosis of asthma. Normally, the fractional excretion of exhaled nitric oxide (FENO) is less than 20 parts per billion (ppb). Levels higher than 20 ppb are considered indicative of airway inflammation, which is the pathophysiologic basis of asthma.

  • Allergy skin testing, while not specific for asthma, can be useful in identifying potential environmental triggers and in serving as a guide to immunotherapy in patients with underlying allergic diatheses.

What diagnostic procedures will be helpful in making or excluding the diagnosis of asthma?

No invasive procedures are clinically useful in making or excluding the diagnosis of asthma.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of asthma?

At present, no pathologic, cytologic, or genetic studies are clinically useful in establishing or excluding the diagnosis of asthma. While there is some data to suggest measurement of sputum eosinophils may assist in management of asthma, it appears that a minority of patients have elevated eosinophils in their sputum, and as the process is expensive and requires specialized centers in order to be done in a reliable fashion, it is not currently recommended as standard of care for asthma.

If you decide the patient has asthma, how should the patient be managed?

In a broad context, the goals of chronic asthma management can be divided into two domains: reduction in impairment and reduction in risk. Goals in the domain of reduction in impairment include:

  • Minimization of daytime respiratory symptoms (cough, wheezing, dyspnea)

  • Minimization of nighttime awakenings

  • Minimization of the need for rescue inhaler use

  • Preservation and optimization of lung function

  • Maintenance of ability to perform physical activities, including usual daytime activities and exercise

Goals in the domain of reduction in risk include:

  • Prevention of exacerbations of asthma that require urgent or emergent care or hospitalization

  • Prevention of loss of lung function

  • Prevention of side effects of medications

Clinicians should strive for good asthma symptom control, regardless of the level of asthma severity. Symptom control reflective of well controlled asthma is characterized by lack of asthma interference with normal activity and the “rule of two’s”:

  • Daytime symptoms no more than twice per week

  • Nighttime symptoms no more than twice per month

  • Short-acting bronchodilator (rescue inhaler) use for symptom relief less than twice weekly

If not all of the criteria outlined are met, the patient is considered not well-controlled or poorly (or very poorly) controlled, and augmentation of therapy based on symptoms alone should be considered.

Achieving these goals in asthma management incorporates a multifaceted approach that involves patient education, monitoring of lung function, avoidance of environmental triggers, use of medications, and management of comorbid conditions.

  • Asthma education, a key component of asthma management, is an ongoing process that should be integrated into every patient visit. Use of verbal communication and written educational documents, such as asthma action plans, have been shown to reduce asthma-related morbidity and mortality. Patient education on topics like trigger avoidance, proper inhaler use, and appropriate medication regimens are essential and warrant review at each office visit.

  • Monitoring lung function is also a critical part of asthma management. Asthma guidelines recommend spirometry annually for patients older than age five. Since many patients with asthma perceive symptoms poorly, an objective assessment of asthma control is an essential complement to the subjective symptom assessment described previously. A significant reduction in lung function from baseline may indicate uncontrolled asthma and should prompt consideration of augmentation of the patient’s asthma regimen.

  • Trigger avoidance is important in minimizing asthma flares. Exposure to dust mites, molds, pollens, animal dander, smoke, and fumes should be minimized, if possible, by patients with asthma who are affected by such triggers.

  • Pharmacotherapy is the cornerstone of asthma management. National asthma management guidelines (Figure 2) advocate a stepped approach to treatment–including increases in medications when asthma is not well-controlled and decreases in medications as a means of minimizing adverse drug effects–when asthma is well controlled. Specific asthma medicine regimens are dictated, in part, by both asthma severity and medication tolerance.

  • Management of comorbid conditions that complicate asthma–such as gastroesophageal reflux disease (GERD), allergic rhinitis, sinusitis, obstructive sleep apnea, and depression–is essential.

Figure 2.

Stepwise approach to pharmacologic management of asthma in patients more than twelve years old.

All patients with asthma should have a short-acting inhaled bronchodilator (e.g., albuterol) immediately available at all times. Patients with asthma who are classified as having intermittent asthma can often be managed with short-acting bronchodilators alone. Patients with asthma who are classified as having persistent asthma should be on a daily, long-term, asthma-controller regimen. Inhaled corticosteroids (ICS) are recommended as the initial controller medication. Regular use of ICS has been shown to reduce the frequency of symptoms, improve overall asthma-related quality of life, and decrease risk of asthma exacerbations. Alternative controllers for persistent asthma include leukotriene receptor antagonists (LTRA), theophylline, and cromolyn compounds. Among these alternatives, LTRA are preferred; however, none of the alternatives are as effective as ICS.

Patients with asthma who are classified as having severe, persistent asthma may require multiple asthma-controller medications. In moderate to severe asthma, a combination of ICS and long-acting beta agonist (LABA) is the preferred initial controller regimen. LABA should not be used as monotherapy because of the risk of adverse cardiovascular events. LABA should be used in conjunction with ICS. Additional controllers may be required, along with ICS/LABA combination inhalers. If patients are uncontrolled on ICS/LABA combination therapy, referral to an asthma specialist should be considered.

Patients with very severe asthma may require additional therapy, including monoclonal IgE injections (omalizumab) or oral corticosteroids. Oral corticosteroids are given either in a short burst to stop serious asthma flare-ups or on a low dosage as maintenance for patients with severe asthma to prevent symptoms. Consideration of oral steroids should be given when short bursts of higher doses of oral steroids are required every two to three months despite high-dose inhaled steroids, long-acting inhaled beta agonist, and trials of other asthma-controller medications. In most cases, these therapeutic approaches require management by asthma specialists.

Bronchial thermoplasty (BT) is a technique for treatment of adults with severe, uncontrolled asthma. Bronchial thermoplasty is a bronchoscopic procedure for severe persistent asthma in patients who are eighteen years and older and whose asthma is not well controlled with inhaled corticosteroids and long-acting beta-agonists. During the procedure, the bronchoscopist delivers thermal energy to the airway wall in a precisely controlled manner in order to reduce excessive airway smooth muscle. Reducing airway smooth muscle decreases the ability of the airways to constrict, thereby reducing the frequency of asthma attacks. BT has been shown to reduce exacerbations and emergency room visits that are due to asthma.

Occasionally, management of acute exacerbations of asthma may be required. In most cases, these are managed on an outpatient basis with a short burst of higher dose oral steroids. In some cases, inpatient management may be required if outpatient treatment fails. Patients who require beta 2-agonist therapy more often than every two to three hours, who have not clinically improved after administration of systemic glucocorticoids, or who require supplemental oxygen should be admitted to the hospital.

What is the prognosis for patients managed in the recommended ways?

Asthma is typically a chronic disorder, although long periods of remission may occasionally occur. The long-term prognosis generally depends on disease severity and optimization of patient management according to published guidelines:

  • In mild to moderate cases, asthma is usually easily controlled; patients may be symptom-free.

  • In severe cases, with appropriate management the majority of patients experience some improvement, depending on the initial degree of airway obstruction.

  • In a small subset of severe, persistent cases, inflammatory changes in the airway mucosa may lead to permanent airway remodeling, resulting in progressive and irreversible declines in lung function, even with aggressive medical management.

Approximately 3000-4000 people die from asthma in the United States every year, with an in-hospital mortality rate of 1-5 percent. Patients with asthma who have severe exacerbation with intubation and admission to an ICU have an increased mortality of 10-25 percent. The biggest risk for death from asthma is a prior history of near-fatal or severe asthma attack. More than two hospitalizations or more than three ER visits for asthma in one year also increase the risk of fatal asthma. African Americans and those of Puerto Rican or Cuban ancestry or lower socioeconomic status, women, and people older than age sixty-five have also been reported to have a high mortality rate from asthma. Additional risk factors/signs include frequent use of short-acting beta agonists, history of illicit drug use, and history of psychiatric illness.

Some patients appear to lack the ability to perceive asthma symptoms, so they often wait too long before seeking medical attention. A written action plan with peak flow monitoring could help this population to avoid severe exacerbations.

What other considerations exist for patients with asthma?

Unfortunately, 25-30 percent of patients with asthma smoke cigarettes. Cigarette smoke increases airway inflammation and may decrease the effectiveness of anti-inflammatory therapies, such as inhaled corticosteroids. Aggressive smoking cessation techniques should be considered for patients with asthma who are addicted to cigarettes.

Many patients with asthma are reluctant to exercise because of exercise’s role as a potential asthma trigger. Exercise-induced asthma is usually responsive to pre-treatment with one or two inhalations of albuterol 15-20 minutes prior to exercise. Exercise has many general health benefits, and some research suggests that it may have specific benefits for patients with asthma. Patients with asthma should be educated on prophylaxis of exercise-induced asthma and encouraged to participate in regular physical activity.

What’s the evidence?

“GINA report: global strategy for asthma management and prevention”. 2011. (International reference guide for the diagnosis and management of asthma.)

“National Institutes of Health. Expert panel report 3: guidelines for the diagnosis and management of asthma”. 2011. (United States reference guide for the diagnosis and management of asthma.)

“Centers for Disease Control. Vital signs: asthma prevalence, disease characteristics, and self management education – United States, 2001-2009”. MMWR. vol. 60. 2011. pp. 1-7. (This reference and the following reference provide the latest and most frequently utilized statistics on asthma in the United States from the CDC.

Chung, KF, Wenzel, SE, Brozek, JL, Bush, A, Castro, M, Sterk, PJ, Adcock, IM, Bateman, ED, Bel, EH, Bleecker, ER, Boulet, LP, Brightling, C, Chanez, P, Dahlen, SE, Djukanovic, R, Frey, U, Gaga, M, Gibson, P. “International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma”. Eur Respir J. vol. 43. 2014. pp. 343-73. (Comprehensive, evidence-based review of severe asthma.)

Parsons, JP, Hallstrand, TS, Mastronarde, JG, Kaminsky, DA, Rundell, K, Hull, JH, Storms, WW, Weiler, JM, Cheek, FM, Wilson, KC, Anderson, SD. “An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction”. Am J Respir Crit Care Med. vol. 187. 2013. pp. 1016-27. (Comprehensive, evidence-based review of exercise-induced asthma.)

Akinbami, LJ, Morrman, JE, Liu, X. “Asthma prevalence, health care use, and mortality: United States, 2005-2006”. National Health Statistics Report No. 32. vol. 12. 2011. pp. 1-15.

Petsky, JL, Cates, CJ, Lasserson, TJ, Li, AM, Turner, C, Kynaston, JA, Chang, AB. “A systematic review and meta-analysis: tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils)”. Thorax. vol. 67. 2012. pp. 199-208. (Good review and evaluation of the data pertaining to the routine use of exhaled nitric oxide and sputum eosinophils tests in practice.)

Benninger, C., Parsons, JP, Mastronarde, JG. “Vocal cord dysfunction and asthma”. Curr Opin Pulm Med. vol. 17. 2011. pp. 45-9. (Review of data and thoughts on the relationship of VCD to asthma.)

Castro, M, Rubin, AS, Laviolette, M, Fiterman, J, De Andrade Lima, M, Shah, PL, Fiss, E, Olivenstein, R, Thomson, NC, Niven, RM, Pavord, ID, Simoff, M, Duhamel, DR, McEvoy, C, Barbers, R, ten Hacken, NHT, Wechsler, ME, Holmes, M, Phillips, MJ, Erzurum, S, Lunn, W, Israel, E, Jarjour, N, Kraft, M, Shargill, NS, Quiring, J, Berry, SM, Cox, G. “for the AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind sham-controlled clinical trial”. Am J Respir Crit Care Med. vol. 181. 2010. pp. 116-124. (One of the seminal papers on the use of bronchial thermoplasty in asthma.)

Denner, DR, Doeing, DC, Hogarth, DK, Dugan, K, Naureckas, ET, White, SR. “Airway inflammation after bronchial thermoplasty for severe asthma”. Ann Am Thorac Soc. 2015. (Paper that shows first characterization of significant changes in airway inflammation in the first weeks after thermoplasty.)

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