Asthma

1. 1. Pate CA, Zahrn HS, Qin X, et al: Asthma Surveillance — United States, 2006–2018. MMWR Surveill Summ 70(No. SS-5):1–32, 2021. doi: 10.15585/mmwr.ss7005a1

2. 2. Centers for Disease Control and Prevention: CDC Healthy Schools: Asthma. Updated June 14, 2021. Accessed January 21, 2022.

3. 3. Allergy and Asthma Foundation of America: Cost of asthma on society. Accessed January 21, 2022. https://www.aafa.org/cost-of-asthma-on-society

4. 4. Peters U, Dixon AE, Forno E: Obesity and asthma. J Allergy Clin Immunol 141(4):1169–1179, 2018. doi: 10.1016/j.jaci.2018.02.004

Reactive airways dysfunction syndrome (RADS) is the rapid onset (minutes to hours, but not > 24 hours) of an asthma-like syndrome that

• Develops in people with no history of asthma

• Occurs following a single, specific inhalation exposure to a significant amount of an irritating gas or particulate

• Persists for ≥ 3 months

Numerous substances have been implicated, including chlorine gas, nitrogen oxide, and volatile organic compounds (eg, from paints, solvents, adhesives). The exposure event is usually obvious to the patient, particularly when symptoms begin almost immediately.

Irritant-induced asthma refers to a similar, persistent asthma-like response following multiple or chronic inhalational exposure to high levels of similar irritants. Manifestations are sometimes more insidious, and thus the connection to the inhalational exposure is clear only in retrospect.

RADS and chronic irritant-induced asthma have many clinical similarities to asthma (eg, wheezing, dyspnea, cough, presence of airflow limitation, bronchial hyperresponsiveness) and respond significantly to bronchodilators and often corticosteroids. Unlike in asthma, the reaction to the inhaled substance is not thought to be an IgE-mediated allergy; low-level exposures do not cause RADS or irritant-induced asthma. However, repeated exposure to the initiating agent may trigger additional symptoms.

Common triggers of an asthma exacerbation include

• Environmental and occupational allergens (numerous)

• Cold, dry air

• Infections

• Exercise

• Inhaled irritants

• Emotion

• Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs)

• Gastroesophageal reflux disease (GERD)

Infectious triggers in young children include respiratory syncytial virus, rhinovirus, and parainfluenza virus infection. In older children and adults, upper respiratory infections (particularly with rhinovirus) and pneumonia are common infectious triggers. Exercise can be a trigger, especially in cold or dry environments, and cold air alone can also trigger symptoms. Inhaled irritants, such as air pollution, cigarette smoke, perfumes, and cleaning products can also trigger symptoms in patients with asthma. (Inhaled irritants that trigger asthma exacerbations do so by inducing a T2 response, in contrast to what happens in reactive airways dysfunction syndrome and chronic irritant-induced asthma.) Emotions such as anxiety, anger, and excitement sometimes trigger exacerbations.

Aspirin is a trigger in up to 30% of patients with severe asthma and in < 10% of all patients with asthma. Aspirin

GERD is a common trigger among some patients with asthma, possibly via esophageal acid-induced reflex bronchoconstriction or by microaspiration of acid. However, treatment of asymptomatic GERD (eg, with proton pump inhibitors) does not seem to improve asthma control.

Allergic rhinitis often coexists with asthma; it is unclear whether the two are different manifestations of the same allergic process or whether rhinitis is a discrete asthma trigger.

In the presence of triggers, there is reversible airway narrowing and uneven lung ventilation. In lung regions distal to narrowed airways, relative perfusion exceeds relative ventilation; thus, alveolar oxygen tensions fall and alveolar carbon dioxide tensions rise. Usually, such regional hypoxia and hypercarbia trigger compensatory pulmonary vasoconstriction to match regional ventilation and perfusion; however, these compensatory mechanisms fail during an asthma exacerbation due to the vasodilatory effects of prostaglandins that are upregulated during an exacerbation. Most patients can compensate by hyperventilating, but in severe exacerbations, diffuse bronchoconstriction causes severe gas trapping, and the respiratory muscles are put at a marked mechanical disadvantage so that the work of breathing increases. Under these conditions, hypoxemia worsens and PaCO2 rises. Respiratory acidosis and metabolic acidosis may result and, if left untreated, cause respiratory and cardiac arrest.

Severity is the intrinsic intensity of the disease process (ie, how bad it is—see table Classification of Asthma Severity). Severity can usually be assessed directly only before treatment is started, because patients who have responded well to treatment by definition have few symptoms. Asthma severity is categorized as

• Intermittent

• Mild persistent

• Moderate persistent

• Severe persistent

It is important to remember that the severity category does not predict how serious an exacerbation a patient may have. For example, a patient who has mild asthma with long periods of no or mild symptoms and normal pulmonary function may have a severe, life-threatening exacerbation.

Control is the degree to which symptoms, impairments, and risks are minimized by treatment. Control is the parameter assessed in patients receiving treatment. The goal is for all patients to have well-controlled asthma regardless of disease severity. Control is classified as

• Well controlled

• Not well controlled

• Very poorly controlled

Severity and control are assessed in terms of patient impairment and risk (see tables Classification of Asthma Severity and Classification of Asthma Control).

Impairment refers to the frequency and intensity of patients' symptoms and functional limitations (see table Classification of Asthma Severity). Impairment is assessed using similar criteria to severity, but differs from severity by its emphasis on symptoms and functional limitations rather than the intrinsic intensity of the disease process. Lung function or physiologic, objective impairment can be measured by spirometry, mainly forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC), which correlate strongly with subjective components of asthma control that includes symptoms and clinical features such as

• How often symptoms are experienced

• How often the patient awakens at night

• How often the patient uses a short-acting beta-2 agonist for symptom relief

• How often asthma interferes with normal activity

Risk refers to the likelihood of future exacerbations or decline in lung function and the risk of adverse drug effects. Risk is assessed by long-term trends in spirometry and clinical features such as

• Frequency of need for oral corticosteroids

• Need for hospitalization

• Need for intensive care unit (ICU) admission

• Need for intubation

Patients suspected of having asthma should undergo pulmonary function testing

Spirometry should be done before and after inhalation of a short-acting bronchodilator. Signs of airflow limitation before bronchodilator inhalation include reduced FEV1 and a reduced FEV1/FVC ratio. The FVC may also be decreased because of gas trapping, such that lung volume measurements may show an increase in the residual volume, the functional residual capacity, or both. An improvement in FEV1 of > 12% or an increase ≥ 10% of predicted FEV1 in response to bronchodilator treatment confirms reversible airway obstruction, although absence of this finding should not preclude a therapeutic trial of long-acting bronchodilators.

Flow-volume loops should also be reviewed to diagnose vocal cord dysfunction, a common cause of upper airway obstruction that mimics asthma. However, it should be noted that vocal cord dysfunction is intermittent, and normal flow-volume loops do not exclude this condition.

Provocative testing, < 1 L or < 50% predicted, recent myocardial infarction or stroke, and severe hypertension (systolic BP > 200 mm Hg; diastolic BP > 100 mm Hg). A decline in FEV1 of > 20% on a provocative testing protocol is relatively specific for the diagnosis of asthma. However, FEV1 may decline in response to drugs used in provocative testing in other disorders, such as COPD. If FEV1 decreases by < 20% by the end of the testing protocol, asthma is less likely to be present.

Other tests may be helpful in some circumstances:

• Diffusing capacity for carbon monoxide (DLCO)

• Chest x-ray

• Allergy testing

• Exhaled nitric oxide (FeNO)

DLCO testing can help distinguish asthma from COPD. Values are normal or elevated in asthma and usually reduced in COPD, particularly in patients with emphysema.

A chest x-ray may help exclude some causes of asthma or alternative diagnoses, such as heart failure or pneumonia. The chest x-ray in asthma is usually normal but may show hyperinflation or segmental atelectasis, a sign of mucous plugging. Infiltrates, especially those that come and go and that are associated with findings of central bronchiectasis, suggest allergic bronchopulmonary aspergillosis.

Allergy testing may be indicated for children whose history suggests allergic triggers (particularly for allergic rhinitis) because these children may benefit from immunotherapy. It should be considered for adults whose history indicates relief of symptoms with allergen avoidance and for those in whom a trial of therapeutic anti-IgE antibody therapy is being considered. Skin testing and measurement of allergen-specific IgE via radioallergosorbent testing (RAST) can identify specific allergic triggers.

Blood tests may be done. Elevated blood eosinophils (> 400 cells/mcL [> 0.4 × 10⁹ /L]) and elevated nonspecific IgE levels are suggestive but are neither sensitive nor specific for a diagnosis of allergic asthma. Furthermore, some studies have indicated that eosinophil levels may vary diurnally and with other factors (1). Generally, blood eosinophil levels are higher in the morning, and there may be falsely low eosinophil counts when samples are collected in the afternoon.

In patients ≥ 5 years, fractional exhaled nitric oxide (FeNO) may be used in the evaluation when the diagnosis of asthma is unclear, especially in children, and it can be used as a biomarker to monitor disease severity and therapeutic efficacy (2). FeNO levels > 50 ppb are consistent with allergic airways inflammation, supporting an asthma diagnosis. A level < 25 ppb is more consistent with an alternative diagnosis. Levels between 25 and 50 ppb are indeterminate.

Sputum evaluation for eosinophils is not commonly done; finding large numbers of eosinophils is suggestive of asthma but is neither sensitive nor specific.

Peak expiratory flow (PEF) measurements with inexpensive handheld flow meters are recommended for home monitoring of disease severity and for guiding therapy.

Patients with asthma with an acute exacerbation are evaluated based on clinical criteria but should sometimes also have certain tests:

• Pulse oximetry

• Sometimes peak expiratory flow (PEF) measurement

• FeNO

The decision to treat an exacerbation is based primarily on an assessment of signs and symptoms. PEF measures can help establish the severity of an exacerbation but are most commonly used to monitor response to treatment in outpatients. PEF values are interpreted in light of the patient’s personal best, which may vary widely among patients who are equally well controlled. A 15 to 20% reduction from this baseline indicates a significant exacerbation. When baseline values are not known, the percent predicted PEF based on age, height, and sex may be used, but this is less accurate than a comparison to patient's personal best.

Although spirometry (eg, FEV1) more accurately reflects airflow than PEF, it is impractical in most urgent outpatient and emergency department settings. It may be used for office-based monitoring of treatment or when objective measures are required (eg, when an exacerbation appears to be more severe than perceived by the patient or is not recognized).

Chest x-ray is not necessary for most exacerbations but should be done in patients with symptoms or signs suggestive of pneumonia, pneumothorax, or pneumomediastinum.

Arterial or venous blood gas measurements should be done in patients with marked respiratory distress or symptoms and signs of impending respiratory failure.

Fractional exhaled nitric oxide measurement has been proposed as an adjunct in evaluation of asthma control in patients with confusing or unclear histories or clinical scenarios. No cut off values have been established; however, FeNO-based monitoring of treatment efficacy and compliance has resulted in significant reductions in exacerbation frequency. There are limited data concerning FeNO use in patients taking immunomodulatory drugs (2).

1. 1. Gibson PG: Variability of blood eosinophils as a biomarker in asthma and COPD. Respirology 23(1):12–13, 2018. doi: 10.1111/resp.13200

2. 2. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, Baptist AP, et al: 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 146(6):1217–1270, 2020. doi: 10.1016/j.jaci.2020.10.003

Triggering factors in some patients may be controlled with use of synthetic fiber pillows and impermeable mattress covers and frequent washing of bed sheets, pillowcases, and blankets in hot water. Ideally, upholstered furniture, soft toys, carpets, curtains, and pets should be removed, at least from the bedroom, to reduce dust mites and animal dander. Dehumidifiers should be used in basements and in other poorly aerated, damp rooms to reduce mold. Steam treatment of homes diminishes dust mite allergens. House cleaning and extermination to eliminate cockroach exposure are especially important. Although control of triggering factors is more difficult in urban environments, the importance of these measures is not diminished.

High-efficiency particulate air (HEPA) vacuums and filters may relieve symptoms, but no beneficial effects on pulmonary function and on the need for drugs have been observed.

Sulfite-sensitive patients should avoid sulfite-containing food (eg, certain wine and salad dressings).

Nonallergenic triggers, such as cigarette smoke, strong odors, irritant fumes, cold temperatures, and high humidity should also be avoided or controlled when possible. Limiting exposure to people with viral upper respiratory infections is also important. However, exercise-induced asthma is not treated with exercise avoidance because exercise is important for health reasons. Instead, a short-acting bronchodilator is given prophylactically before exercise and as needed during or after exercise (rescue inhaler); controller therapy (step 2 and above in Table Steps of Asthma Management) should be started if exercise-induced symptoms are not responsive to rescue inhalers or occur daily or more frequently.

Patients with aspirin

Major drug classes commonly used in the treatment of asthma and asthma exacerbations include

• Bronchodilators (beta or beta-2 adrenergic receptor agonists, anticholinergics)

• Corticosteroids

• Leukotriene modifiers

• Mast cell stabilizers

• Methylxanthines

• Immunomodulators

Drugs in these classes (see table Drug Treatment of Chronic Asthma) are inhaled, taken orally, or injected subcutaneously or intravenously; inhaled drugs come in aerosolized and powdered forms. Use of aerosolized forms with a spacer or holding chamber facilitates deposition of the drug in the airways rather than the pharynx; patients are advised to wash and dry their spacers after each use to prevent bacterial contamination. In addition, use of aerosolized forms requires coordination between actuation of the inhaler (drug delivery) and inhalation; powdered forms reduce the need for coordination, because drug is delivered only when the patient inhales. For details, see Drug Treatment of Asthma.

Bronchial thermoplasty is a bronchoscopic technique in which heat is applied through a device that transfers localized controlled radiofrequency waves to the airways. The heat decreases the amount of airway smooth muscle remodeling (and thus the smooth muscle mass) that occurs with asthma. In clinical trials in patients with severe asthma not controlled with multiple therapies, there have been modest decreases in exacerbation frequency and improvement in asthma symptom control. However, some patients have experienced an immediate worsening of symptoms, sometimes requiring hospitalization immediately after the procedure. Expert recommendations are to avoid bronchial thermoplasty unless a patient places a low value on the potential for adverse outcomes and a high value on short-term potential benefits. If possible, bronchial thermoplasty should be done in centers where it is done routinely(1).

Criteria for consideration of bronchial thermoplasty include severe asthma not controlled with inhaled corticosteroids and long-acting beta agonists, intermittent or continuous use of oral corticosteroids, FEV1 ≥ 50% of predicted, and no history of life-threatening exacerbations. Patients should understand the risk of post-procedure asthma exacerbation and need for hospitalization before proceeding with the procedure. The long-term efficacy and safety of bronchial thermoplasty is not known. There are no data in patients with > 3 exacerbations per year or an FEV1 < 50% of predicted because these patients were excluded from the clinical trials.

Guidelines recommend office use of spirometry (FEV1, FEV1/FVC, FVC) to measure airflow limitation and assess impairment and risk. Spirometry should be repeated at least every 1 to 2 years in patients with asthma to monitor disease progression, and a step-up in therapy might be required if lung function declines or becomes impaired with evidence of increased airflow obstruction (see table Classification of Asthma Control). Outside the office, home peak expiratory flow (PEF) monitoring, in conjunction with patient symptom diaries and the use of an asthma action plan, is especially useful for charting disease progression and response to treatment in patients with moderate to severe persistent asthma. When asthma is quiescent, one PEF measurement in the morning suffices. Should PEF measurements fall to < 80% of the patient’s personal best, then twice/day monitoring to assess circadian variation is useful. Circadian variation of > 20% indicates airway instability and the need to re-evaluate the therapeutic regimen.

The importance of patient education cannot be overemphasized. Patients do better when they know more about asthma—what triggers an exacerbation, what drug to use when, proper inhaler technique, how to use a spacer with a metered-dose inhaler (MDI), and the importance of early use of corticosteroids in exacerbations. Every patient should have a written action plan for day-to-day management, especially for management of acute exacerbations, that is based on the patient’s best personal peak flow rather than on a predicted normal value. Such a plan leads to much better asthma control, largely attributable to improved adherence to therapies.

The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes

• Inhaled bronchodilators (beta agonists and anticholinergics)

• Usually systemic corticosteroids

Details of the treatment of acute asthma exacerbations, including of severe attacks requiring hospitalization, are discussed elsewhere.

Current asthma guidelines recommend treatment based on the severity classification. Continuing therapy is based on assessment of control (see table Classification of Asthma Control). Therapy is increased in a stepwise fashion (see table Steps of Asthma Management) until the best control of impairment and risk is achieved (step-up). Before therapy is stepped up, adherence, exposure to environmental factors (eg, trigger exposure), and presence of comorbid conditions (eg, obesity, allergic rhinitis, gastroesophageal reflux disease, chronic obstructive pulmonary disease, obstructive sleep apnea, vocal cord dysfunctionDrug Treatment of Chronic Asthma.

Exercise-induced asthma can generally be prevented by prophylactic inhalation of a short-acting beta-2 agonist or mast cell stabilizer before starting the exercise. If beta-2 agonists are not effective or if exercise-induced asthma causes symptoms daily or more frequently, the patient requires controller therapy.

The primary treatment for aspirinaspirin sensitivity and asthma severity; desensitization has been successful in the majority of patients who are able to continue desensitization treatment for more than one year.

Multiple therapies are being developed to target specific components of the inflammatory cascade. Therapies directed at interleukin 6 (IL-6), thymic stromal lymphopoietin, tumor necrosis factor-alpha, other chemokines, and cytokines or their receptors are all under investigation or consideration as therapeutic targets.

1. 1. Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, Baptist AP, et al: 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 146(6):1217–1270, 2020. doi: 10.1016/j.jaci.2020.10.003

Asthma is difficult to diagnose in infants; thus, under-recognition and undertreatment are common (see also Wheezing and Asthma in Infants and Young Children). Empiric trials of inhaled bronchodilators and anti-inflammatory drugs may be helpful for both. Drugs may be given by nebulizer or metered-dose inhaler (MDI) with a holding chamber with or without a face mask. Infants and children < 5 years who require treatment > 2 times/week should be given daily anti-inflammatory therapy with inhaled corticosteroids (preferred), leukotriene receptor antagonists, or cromolyn.

Children >

About one third of women with asthma who become pregnant notice relief of symptoms, one third notice worsening (at times to a severe degree), and one third notice no change. Gastroesophageal reflux disease (GERD) may be an important contributor to symptomatic disease in pregnancy. Asthma control during pregnancy is crucial because poorly controlled maternal disease can result in increased prenatal mortality, premature delivery, and low birth weight.

Asthma drugs have not been shown to have adverse fetal effects, but safety data are lacking. (See also guidelines from the National Asthma Education and Prevention Program, Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment–Update 2004.) In general, uncontrolled asthma is more of a risk to mother and fetus than adverse effects due to asthma drugs. During pregnancy, normal blood PCO2 level is about 32 mm Hg. Therefore, carbon dioxide retention is probably occurring if PCO2 approaches 40 mm Hg.

Older patients have a high prevalence of other obstructive lung disease (eg, COPD