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Asthma

By Victor E. Ortega, MD, PhD, Assistant Professor, Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy, and Immunologic Diseases, Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine ; Emily J. Pennington, MD, Pulmonologist, Wake Forest School of Medicine

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Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea, chest tightness, cough, and wheezing. The diagnosis is based on history, physical examination, and pulmonary function tests. Treatment involves controlling triggering factors and drug therapy, most commonly with inhaled beta-2agonists and inhaled corticosteroids. Prognosis is good with treatment.

Epidemiology

The prevalence of asthma has increased continuously since the 1970s, and the WHO estimates that 235 million people worldwide are affected. More than 25 million people in the US are affected. Asthma is one of the most common chronic diseases of childhood, affecting more than 6 million children in the US; it occurs more frequently in boys before puberty and in girls after puberty. It also occurs more frequently in non-Hispanic blacks and Puerto Ricans.

Despite its increasing prevalence, however, there has been a recent decline in mortality. In the US, about 3400 deaths occur annually as a result of asthma. However, the death rate is 2 to 3 times higher for blacks than for whites. Asthma is the leading cause of hospitalization for children and is the number one chronic condition causing elementary school absenteeism. Asthma is estimated to cost the US $56 billion/yr in medical care and lost productivity.

Etiology

Development of asthma is multifactorial and depends on the interactions among multiple susceptibility genes and environmental factors.

Susceptibility genes are thought to include those for T-helper cells types 1 and 2 (Th1 and Th2), IgE, interleukins (IL-3, -4, -5, -9, -13), granulocyte-monocyte colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-α), and the ADAM33 gene, which may stimulate airway smooth muscle and fibroblast proliferation or regulate cytokine production.

Environmental factors may include the following:

  • Allergen exposure

  • Diet

  • Perinatal factors

Evidence clearly implicates household allergens (eg, dust mite, cockroach, pet) and other environmental allergens in disease development in older children and adults. Diets low in vitamins C and E and in omega–3 fatty acids have been linked to asthma, as has obesity. Asthma has also been linked to perinatal factors, such as young maternal age, poor maternal nutrition, prematurity, low birthweight, and lack of breastfeeding.

On the other hand, endotoxin exposure early in life can induce tolerance and may be protective. Air pollution is not definitively linked to disease development, although it may trigger exacerbations. The role of childhood exposure to cigarette smoke is controversial, with some studies finding a contributory and some a protective effect.

Genetic and environmental components may interact, thereby determining the balance between Th1 and Th2 cell lineages. Infants may be born with a predisposition toward proallergic and proinflammatory Th2 immune responses, characterized by growth and activation of eosinophils and IgE production. Early childhood exposure to bacterial and viral infections and endotoxins may shift the body to Th1 responses, which suppresses Th2 cells and induce tolerance. Trends in developed countries toward smaller families with fewer children, cleaner indoor environments, and early use of vaccinations and antibiotics may deprive children of these Th2-suppressing, tolerance-inducing exposures and may partly explain the continuous increase in asthma prevalence in developed countries (the hygiene hypothesis).

Reactive airways dysfunction syndrome (RADS)

Indoor exposures to nitrogen oxide and volatile organic compounds (eg, from paints, solvents, adhesives) are implicated in the development of RADS, a persistent asthma-like syndrome in people with no history of asthma (see Occupational Asthma). RADS appears to be distinct from asthma and may be, on occasion, a form of environmental lung disease. However, RADS and asthma have many clinical similarities (eg, wheezing, dyspnea, cough), and both may respond to corticosteroids.

Pathophysiology

Asthma involves

  • Bronchoconstriction

  • Airway edema and inflammation

  • Airway hyperreactivity

  • Airway remodeling

In patients with asthma, Th2 cells and other cell types—notably, eosinophils and mast cells, but also other CD4+ subtypes and neutrophils—form an extensive inflammatory infiltrate in the airway epithelium and smooth muscle, leading to airway remodeling (ie, desquamation, subepithelial fibrosis, angiogenesis, smooth muscle hypertrophy). Hypertrophy of smooth muscle narrows the airways and increases reactivity to allergens, infections, irritants, parasympathetic stimulation (which causes release of pro-inflammatory neuropeptides, such as substance P, neurokinin A, and calcitonin gene-related peptide), and other triggers of bronchoconstriction.

Additional contributors to airway hyperreactivity include loss of inhibitors of bronchoconstriction (epithelium-derived relaxing factor, prostaglandin E2) and loss of other substances called endopeptidases that metabolize endogenous bronchoconstrictors. Mucus plugging and peripheral blood eosinophilia are additional classic findings in asthma and may be epiphenomena of airway inflammation. However, not all patients with asthma have eosinophilia.

Asthma triggers

Common triggers of an asthma exacerbation include

  • Environmental and occupational allergens (numerous)

  • Infections

  • Exercise

  • Inhaled irritants

  • Emotion

  • Aspirin

  • Gastroesophageal reflux disease (GERD)

Infectious triggers in young children include respiratory syncytial virus, rhinovirus, and parainfluenza virus infection. In older children and adults, URIs (particularly with rhinovirus) and pneumonia are common infectious triggers. Exercise can be a trigger, especially in cold or dry environments. Inhaled irritants, such as air pollution, cigarette smoke, perfumes, and cleaning products, are often involved. 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-sensitive asthma is typically accompanied by nasal polyps with nasal and sinus congestion.

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.

Response

In the presence of triggers, there is reversible airway narrowing and uneven lung ventilation. Relative perfusion exceeds relative ventilation in lung regions distal to narrowed airways; thus, alveolar oxygen tensions fall and alveolar carbon dioxide tensions rise. 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.

Classification

Unlike hypertension (eg, in which one parameter [BP] defines the severity of the disorder and the efficacy of treatment), asthma causes a number of clinical and testing abnormalities. Also, unlike most types of hypertension, asthma manifestations typically wax and wane. Thus, monitoring (and studying) asthma requires a consistent terminology and defined benchmarks.

The term status asthmaticus describes severe, intense, prolonged bronchospasm that is resistant to treatment.

Severity

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.

Classification of Asthma Severity*

Components of Severity

Intermittent

Mild Persistent

Moderate Persistent

Severe Persistent

Symptoms and risk measures

All ages: ≤ 2 days/week

All ages: > 2 days/week, not daily

All ages: Daily

All ages: Throughout the day

Nighttime awakenings

Adults and children ≥ 5 yr: ≤ 2x/month

Children 0–4 yr: 0

Adults and children ≥ 5 yr: 3–4x/month

Children 0–4 yr: 1–2x/month

Adults and children ≥ 5 yr: >1x/week but not nightly

Children 0–4 yr: 3–4x/month

Adults and children ≥ 5 yr: Often 7x/week

Children 0–4 yr: >1x/week

SABA rescue inhaler use for symptoms (not to prevent EIB)

≤ 2 days/week

Adults and children ≥ 5 yr: > 2 days/week but not daily

Children 0–4 yr: > 2 days/week but not daily

Daily

Several times per day

Interference with normal activity

None

Minor limitation

Some limitation

Extreme limitation

FEV1

Adults and children ≥ 5 yr: > 80%

Children 0–4 yr: Not applicable

Adults and children ≥ 5 yr: > 80%

Children 0–4 yr: Not applicable

Adults and children ≥ 5 yr: 60–80%

Children 0–4 yr: Not applicable

Adults and children ≥ 5 yr: < 60%

Children 0–4 yr: Not applicable

FEV1/FVC

Adults and children ≥ 12 yr: Normal

Children 5–11 yr: > 85%

Children 0–4 yr: Not applicable

Adults and children ≥ 12 yr: Normal

Children 5–11 yr: > 80%

Children 0–4 yr: Not applicable

Adults and children ≥ 12 yr: Reduced 5%

Children 5–11 yr: 75–80%

Children 0–4 yr: Not applicable

Adults and children ≥ 12 yr: Reduced > 5%

Children 5–11 yr: < 75%

Children 0–4 yr: Not applicable

Risk of an asthma exacerbations requiring oral corticosteroid bursts

0–1/year

Adults and children ≥ 5 yr: ≥ 2/year

Children 0–4 yr: ≥ 2 in 6 months or wheezing ≥ 4x/year lasting >1 day AND risk factors for persistent asthma

More frequent and intense events indicate greater severity

More frequent and intense events indicate greater severity

*Severity is categorized based on degree of impairment and risk of exacerbations requiring oral corticosteroids. Impairment is assessed over the previous 2–4 weeks, and risk is assessed over the past year. Severity is best classified at the first visit before a controller therapy is initiated (not SABA or systemic corticosteroid bursts for symptoms or exacerbations).

Evidence for airflow obstruction is based on an FEV1/FVC ratio less than expected normal values by age group. Normal FEV1/FVC ratios by age group: 8–19 years = 85%; 20–39 years = 80%; 40–59 years = 75%; 60–80 years = 70%.

At present, there are inadequate data to correlate frequencies of exacerbations with different levels of asthma severity. In general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate greater underlying disease severity. For treatment purposes, patients with ≥ 2 exacerbations may be considered to have persistent asthma.

EIB = exercise-induced bronchospasm; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ICS = inhaled corticosteroid; SABA = short-acting beta-2 agonist.

Adapted from National Heart, Lung, and Blood Institute: Expert Panel Report 3: Guidelines for the diagnosis and management of asthma—full report 2007. August 28, 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.

Control

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 Table: Classification of Asthma Severity* and see Table: Classification of Asthma Control*, ).

Classification of Asthma Control*,

Component

Well-Controlled

Not Well-Controlled

Very Poorly Controlled

Symptoms

All ages except children 5–11 yr: 2 days/wk

Children 5–11 yr: 2 days/wk but not >once/day

All ages except children 5–11 yr: > 2 days/wk

Children 5–11 yr: > 2 days/wk or multiple times on ≤ 2 days/wk

For all ages: Throughout the day

Nighttime awakenings

Adults and children ≥ 12 yr: ≤ 2/mo

Children 5–11 yr: 1 /mo

Children 0–4 yr: 1 /mo

Adults and children ≥ 12 yr: 1–3/wk

Children 5–11 yr: ≥ 2/mo

Children 0–4 yr: > 1/mo

Adults and children ≥ 12 yr: ≥ 4/wk

Children 5–11 yr: 2/wk

Children 0–4 yr: > 1/wk

Interference with normal activity

None

Some limitation

Extreme limitation

Use of short-acting beta-2 agonist for symptom control (not prevention of exercise-induced asthma)

2 days/wk

> 2 days/wk

Several times/day

FEV1 or peak flow

> 80% predicted/personal best

60–80% predicted/personal best

< 60% predicted/personal best

FEV1/FVC (children 5–11 yr)

> 80%

75–80%

< 75%

Exacerbations requiring oral systemic corticosteroids

0–1/yr

Adults and children ≥ 5 yr: ≥ 2/yr

Children 0–4 yr: 2–3/yr

Adults and children ≥ 5 yr: ≥ 2/yr

Children 0–4 yr:> 3/yr

Validated questionnaires:

  • ATAQ

0

1–2

3−4

  • ACQ

0.75

1.5

Ν/Α

  • ACT

20

16−19

15

Recommended action

Maintain current step

Follow up every 1–6 mo

Consider step down if well controlled for 3 mo

Step up 1 step

Reevaluate in 2–6 wk

For adverse effects, consider treatment options

Consider short course of systemic corticosteroids

Step up 1 or 2 steps

Re-evaluate in 2 wk

For adverse effects, consider treatment options

*All ages unless specified differently.

Level of control is based on the most severe impairment or risk category. Additional factors to consider are progressive loss of lung function on pulmonary function tests, significant adverse effects, and severity and interval between exacerbations (ie, one exacerbation requiring intubation or 2 hospitalizations within 1 mo may be considered very poor control).

At present, there are inadequate data to correlate frequencies of exacerbations with different levels of asthma control. In general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer asthma control.

ACQ = asthma control questionnaire; ACT = asthma control test; ATAQ = asthma therapy assessment questionnaire; FEV1 = forced expiratory volume in 1 sec; FVC = forced vital capacity.

Adapted from National Heart, Lung, and Blood Institute: Expert Panel Report 3: Guidelines for the diagnosis and management of asthma—full report 2007. August 28, 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.

Impairment

Impairment refers to the frequency and intensity of patients' symptoms and functional limitations (see Table: Classification of Asthma Severity*). Impairment differs from severity by its emphasis on symptoms and functional limitations rather than the intrinsic intensity of the disease process. Impairment can be measured by spirometry, mainly forced expiratory volume in 1 sec (FEV1), and the ratio of FEV1 to forced vital capacity (FVC), but is manifested as 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

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 ICU admission

  • Need for intubation

Symptoms and Signs

Patients with mild asthma are typically asymptomatic between exacerbations. Patients with more severe disease and those with exacerbations experience dyspnea, chest tightness, audible wheezing, and coughing. Coughing may be the only symptom in some patients (cough-variant asthma). Symptoms can follow a circadian rhythm and worsen during sleep, often around 4 am. Many patients with more severe disease waken during the night (nocturnal asthma).

Signs include wheezing, pulsus paradoxus (ie, a fall of systolic BP > 10 mm Hg during inspiration), tachypnea, tachycardia, and visible efforts to breathe (use of neck and suprasternal [accessory] muscles, upright posture, pursed lips, inability to speak). The expiratory phase of respiration is prolonged, with an inspiratory:expiratory ratio of at least 1:3. Wheezes can be present through both phases or just on expiration, but patients with severe bronchoconstriction may have no audible wheezing because of markedly limited airflow.

Patients with a severe exacerbation and impending respiratory failure typically have some combination of altered consciousness, cyanosis, pulsus paradoxus > 15 mm Hg, oxygen saturation <90%, Paco2> 45 mm Hg, or hyperinflation. Rarely, pneumothorax or pneumomediastinum is seen on chest x-ray.

Symptoms and signs disappear between exacerbations, although soft wheezes may be audible during forced expiration at rest, or after exercise, in some asymptomatic patients. Hyperinflation of the lungs may alter the chest wall in patients with long-standing uncontrolled asthma, causing a barrel-shaped thorax.

All symptoms and signs are nonspecific, are reversible with timely treatment, and typically are brought on by exposure to one or more triggers.

Diagnosis

  • Clinical evaluation

  • Pulmonary function testing

Diagnosis is based on history and physical examination and is confirmed with pulmonary function tests. Diagnosis of causes and the exclusion of other disorders that cause wheezing are also important. Asthma and COPD are sometimes easily confused; they cause similar symptoms and produce similar results on pulmonary function tests but differ in important biologic ways that are not always clinically apparent.

Asthma that is difficult to control or refractory to commonly used controller therapies should be further evaluated for alternative causes of episodic wheezing, cough, and dyspnea such as allergic bronchopulmonary aspergillosis, bronchiectasis, or vocal cord dysfunction.

Pulmonary function tests

Patients suspected of having asthma should undergo pulmonary function testing to confirm and quantify the severity and reversibility of airway obstruction. Pulmonary function data quality is effort-dependent and requires patient education before the test. If it is safe to do so, bronchodilators should be stopped before the test: 8 h for short-acting beta-2agonists, such as albuterol; 24 h for ipratropium; 12 to 48 h for theophylline; 48 h for long-acting beta-2 agonists, such as salmeterol and formoterol; and 1 week for tiotropium.

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.

Provocative testing, in which inhaled methacholine (or alternatives, such as inhaled histamine, adenosine, or bradykinin, or exercise testing) is used to provoke bronchoconstriction, is indicated for patients suspected of having asthma who have normal findings on spirometry and flow-volume testing and for patients suspected of having cough-variant asthma, provided there are no contraindications. Contraindications include FEV1< 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

Other tests may be helpful in some circumstances:

  • Diffusing capacity for carbon monoxide (DLco)

  • Chest x-ray

  • Allergy testing

DLco testing can help distinguish asthma from chronic obstructive pulmonary disease. 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 (see Drug Treatment of Asthma : Other drugs) 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/μL) and nonspecific IgE (>150 IU) are suggestive but not diagnostic of allergic asthma because they can be elevated in other conditions. However, eosinophilia is not sensitive.

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.

Evaluation of exacerbations

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

  • Pulse oximetry

  • Peak expiratory flow (or FEV1) measurement

These measures can help establish the severity of an exacerbation but are usually used to monitor response to treatment. 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 FEV1 value gives a general idea of airflow limitation but not the individual patient’s degree of worsening.

When measuring FEV1 is impractical (eg, in an emergency department) and baseline PEF is unknown, percent of predicted PEF based on age, height, and sex may be used. Although percent predicted PEF is less accurate than comparison to a personal best, it may be helpful as a baseline to evaluate treatment response. However, the decision to treat an exacerbation should be based primarily on an assessment of signs and symptoms, reserving spirometric and PEF determination for monitoring 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 blood gas measurements should be done in patients with marked respiratory distress or symptoms and signs of impending respiratory failure.

Prognosis

Asthma resolves in many children, but for as many as 1 in 4, wheezing persists into adulthood or relapse occurs in later years. Female sex, smoking, earlier age of onset, sensitization to household dust mites, and airway hyperresponsiveness are risk factors for persistence and relapse.

Although a significant number of deaths each year are attributable to asthma, most of these deaths are preventable with treatment. Thus, the prognosis is good with adequate access and adherence to treatment. Risk factors for death include increasing requirements for oral corticosteroids before hospitalization, previous hospitalization for acute exacerbations, and lower PEF values at presentation. Several studies show that use of inhaled corticosteroids decreases hospital admission and mortality rates.

Over time, the airways in some patients with asthma undergo permanent structural changes (remodeling) that prevent return to normal lung functioning. Early aggressive use of anti-inflammatory drugs may help prevent this remodeling.

Treatment

  • Control of triggers

  • Drug therapy

  • Monitoring

  • Patient education

  • Treatment of acute exacerbations

Treatment objectives are to minimize impairment and risk, including preventing exacerbations and minimizing chronic symptoms, including nocturnal awakenings; to minimize the need for emergency department visits or hospitalizations; to maintain baseline (normal) pulmonary function and activity levels; and to avoid adverse treatment effects.

Control of triggering factors

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 is 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 wine.

Nonallergenic triggers, such as cigarette smoke, strong odors, irritant fumes, cold temperatures, high humidity, and exercise, should also be avoided or controlled when possible. Limiting exposure to people with viral URIs is also important.

Patients with aspirin-sensitive asthma can use acetaminophen, choline magnesium salicylate, or celecoxib in place of NSAIDs.

Asthma is a relative contraindication to the use of nonselective beta-blockers, including topical formulations, but cardioselective drugs (eg, metoprolol, atenolol) probably have no adverse effects.

Drug therapy

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

  • Bronchodilators (beta-2 agonists, anticholinergics)

  • Corticosteroids

  • Leukotriene modifiers

  • Mast cell stabilizers

  • Methylxanthines

  • Immunomodulators

Drugs in these classes (see Table: Drug Treatment of 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

Bronchial thermoplasty (BT) 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.

Criteria for consideration of BT 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 BT. The long-term efficacy and safety of BT 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.

Monitoring response to treatment

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 yr 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 airflow obstruction (see Table: Classification of Asthma Control*, . Outside the office, home 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.

Patient education

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.

Treatment of acute asthma exacerbation

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

  • Inhaled bronchodilators (beta-2 agonists and anticholinergics)

  • Usually systemic corticosteroids

Details of the treatment of acute asthma exacerbations are discussed elsewhere.

Treatment of chronic asthma

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, GERD, COPD, obstructive sleep apnea, vocal cord dysfunction) are reviewed. These factors should be addressed before increasing drug therapy. Once asthma has been well controlled for at least 3 mo, drug therapy is reduced if possible to the minimum that maintains good control (step-down). For specific drugs and doses, see Table: Drug Treatment of Asthma*.

Steps of Asthma Management*

Step

Preferred Treatment

Alternate Treatment

1 (starting point for intermittent asthma)

Short-acting beta-2 agonist prn

2 (starting point for mild persistent asthma)

Low-dose inhaled corticosteroid

Mast cell stabilizer, leukotriene receptor antagonist, or theophylline

3 (starting point for moderate persistent asthma)

Medium-dose inhaled corticosteroid

or

Low-dose inhaled corticosteroid plus long-acting beta-2 agonist

Low-dose inhaled corticosteroid plus one of the following: a leukotriene receptor antagonist, theophylline, or zileuton

4

Medium-dose inhaled corticosteroid plus long-acting beta-2 agonist

Medium-dose inhaled corticosteroid plus one of the following: leukotriene receptor antagonist, theophylline, or zileuton

5 (starting point for severe persistent asthma)

High-dose inhaled corticosteroid plus long-acting beta-2 agonist and

Possibly omalizumab for patients with allergic asthma

6

High-dose inhaled corticosteroid plus long-acting beta-2 agonist plus oral corticosteroid and

Possibly omalizumab, mepolizumab, or reslizumab for patients with evidence of allergic asthma

*Before stepping up, adherence, environmental factors (eg, trigger exposure), and comorbid conditions should be reviewed and managed if needed.

A short-acting beta-2 agonist is indicated to provide quick relief at all steps and to prevent exercise-induced asthma.

Exercise-induced asthma

Exercise-induced asthma can generally be prevented by 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 severe symptoms, the patient likely has more severe asthma than was initially recognized and requires controller therapy.

Aspirin-sensitive asthma

The primary treatment for aspirin-sensitive asthma is avoidance of NSAIDs. Celecoxib does not appear to be a trigger. Leukotriene modifiers can blunt the response to NSAIDs. Alternatively, inpatient desensitization has been successful in a few patients.

Future therapies

Multiple therapies are being developed to target specific components of the inflammatory cascade. Therapies directed at IL-4, IL-13, tumor necrosis factor-alpha, other chemokines, and cytokines or their receptors are all under investigation or consideration as therapeutic targets.

Special Populations

Infants, children, and adolescents

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 MDI with a holding chamber with or without a face mask. Infants and children <5 yr requiring treatment > 2 times/wk should be given daily anti-inflammatory therapy with inhaled corticosteroids (preferred), leukotriene receptor antagonists, or cromolyn.

Children > 5 yr and adolescents with asthma can be treated similarly to adults. They should be encouraged to maintain physical activities, exercise, and sports participation. Predicted norms for pulmonary function tests in adolescents are closer to childhood (not adult) standards. Adolescents and mature younger children should participate in developing their own asthma management plans and establishing their own goals for therapy to improve adherence. The action plan should be understood by teachers and school nurses to ensure reliable and prompt access to rescue drugs. Cromolyn and nedocromil are often tried in this group but are not as beneficial as inhaled corticosteroids. Long-acting drugs prevent the problems (eg, inconvenience, embarrassment) of having to take drugs at school.

Pregnant women

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. 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.

Pearls & Pitfalls

  • Suspect carbon dioxide retention and respiratory failure in pregnant women with uncontrolled asthma and PCO2levels near 40 mm Hg.

Elderly patients

The elderly have a high prevalence of other obstructive lung disease (eg, COPD), so it is important to determine the magnitude of the reversible component of airflow obstruction (eg, by a 2- to 3-wk trial of inhaled corticosteroids or pulmonary function testing with bronchodilator challenge). The elderly may be more sensitive to adverse effects of beta-2 agonists and inhaled corticosteroids. Patients requiring inhaled corticosteroids, particularly those with risk factors for osteoporosis, may benefit from measures to preserve bone density (eg, calcium and vitamin D supplements, bisphosphonates).

Key Points

  • Asthma triggers range from environmental allergens and respiratory irritants to infections, aspirin, exercise, emotion, and GERD.

  • Consider asthma in patients who have unexplained persistent coughing, particularly at night.

  • If asthma is suspected, arrange pulmonary function testing, with methacholine provocation if necessary.

  • Educate patients on how to avoid triggers.

  • Control chronic asthma with drugs that modulate the allergic and immune response—usually inhaled corticosteroids—with other drugs (eg, long-acting bronchodilators, mast cell stabilizers, leukotriene inhibitors) added based on asthma severity.

  • Treat acute exacerbations with inhaled beta-2 agonists and anticholinergic drugs, systemic corticosteroids, and sometimes injected epinephrine.

  • If mechanical ventilation is necessary, consider using high inspiratory flow rates (to prolong expiration) with low tidal volumes, even at the cost of a slight increase in PCO2 (permissive hypercapnia).

  • Treat asthma aggressively during pregnancy.

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