Asthma

Practice Essentials

Asthma is a common chronic disease worldwide and affects approximately 26 million persons in the United States. It is the most common chronic disease in childhood, affecting an estimated 7 million children. The pathophysiology of asthma is complex and involves airway inflammation, intermittent airflow obstruction, and bronchial hyperresponsiveness. See the image below.

View Image

Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading to airway inflammation and asthma....

Signs and symptoms

Signs and symptoms of asthma include the following:

Wheezing
Coughing
Shortness of breath
Chest tightness/pain

Other nonspecific symptoms in infants or young children may be a history of recurrent bronchitis, bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling.

See Clinical Presentation for more detail.

Diagnosis

Updated guidelines from the National Asthma Education and Prevention Program (NAEPP) highlight the importance of correctly diagnosing asthma, by establishing the following^[1]:

Episodic symptoms of airflow obstruction are present
Airflow obstruction or symptoms are at least partially reversible
Exclusion of alternative diagnoses

Spirometry with postbronchodilator response should be obtained as the primary test to establish the asthma diagnosis. Pulse oximetry measurement is desirable in all patients with acute asthma to exclude hypoxemia. The chest radiograph remains the initial imaging evaluation in most individuals with symptoms of asthma, but in most patients with asthma, chest radiography findings are normal or may indicate hyperinflation. Exercise spirometry is the standard method for assessing patients with exercise-induced bronchoconstriction.

See Workup for more detail.

Management

For all but the most severely affected patients, the ultimate goal is to prevent symptoms, minimize morbidity from acute episodes, and prevent functional and psychological morbidity to provide a healthy (or near healthy) lifestyle appropriate to the age of child.

Pharmacologic treatment

The pharmacologic treatment of asthma is based on stepwise therapy. Asthma medications should be added or deleted as the frequency and severity of the patient's symptoms change.

Allergen avoidance

Environmental exposures and irritants can play a strong role in symptom exacerbations. The use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on how to avoid them. Efforts should focus on the home, where specific triggers include dust mites, animals, cockroaches, mold, and pollen.

See Treatment and Medication for more detail.

References

Background

Asthma is a common chronic disease worldwide and affects approximately 26 million persons in the United States. It is the most common chronic disease in childhood, affecting an estimated 7 million children, and it is a common cause of hospitalization for children in the United States.

The pathophysiology of asthma is complex and involves airway inflammation, intermittent airflow obstruction, and bronchial hyperresponsiveness. The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edema and mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway remodeling are present.^{[2, 3]}

Airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cells or nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with the clinical severity of asthma.

Physical findings vary with the severity of the asthma and with the absence or presence of an acute episode and its severity. The severity of asthma is classified as intermittent, mild persistent, moderate persistent, or severe persistent. Patients with asthma of any level of severity may have mild, moderate, or severe exacerbations.

Pharmacologic management includes the use of relief and control agents. Control agents include inhaled corticosteroids, long-acting bronchodilators (beta-agonists and anticholinergics), theophylline (Theo-24, Theochron, Uniphyl), leukotriene modifiers, anti-IgE antibodies, anti–IL-5 antibodies, and anti–IL-4/IL-13 antibodies. Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium (Atrovent). With severe exacerbations, indications for hospitalization are based on findings after the patient receives 3 doses of an inhaled bronchodilator. In general, patients should be assessed every 1-6 months for asthma control.

References

Pathophysiology

The 2007 Expert Panel Report 3 (EPR-3) of the National Asthma Education and Prevention Program (NAEPP) noted several key changes in the understanding of the pathophysiology of asthma^[1]:

The critical role of inflammation has been further substantiated, but evidence is emerging for considerable variability in the pattern of inflammation, thus indicating phenotypic differences that may influence treatment responses
Of the environmental factors, allergic reactions remain important. Evidence also suggests a key and expanding role for viral respiratory infections in these processes
The onset of asthma for most patients begins early in life, with the pattern of disease persistence determined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parental history of asthma
Current asthma treatment with anti-inflammatory therapy does not appear to prevent progression of the underlying disease severity

The pathophysiology of asthma is complex and involves the following components:

Airway inflammation
Intermittent airflow obstruction
Bronchial hyperresponsiveness

Airway inflammation

The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edema and mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees of mononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth muscle hyperplasia, and airway remodeling are present.^[2]See the image below.

View Image

Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading to airway inflammation and asthma....

Some of the principal cells identified in airway inflammation include mast cells, eosinophils, epithelial cells, macrophages, and activated T lymphocytes. T lymphocytes play an important role in the regulation of airway inflammation through the release of numerous cytokines. Other constituent airway cells, such as fibroblasts, endothelial cells, and epithelial cells, contribute to the chronicity of the disease. Other factors, such as adhesion molecules (eg, selectins, integrins), are critical in directing the inflammatory changes in the airway. Finally, cell-derived mediators influence smooth muscle tone and produce structural changes and remodeling of the airway.

The presence of airway hyperresponsiveness or bronchial hyperreactivity in asthma is an exaggerated response to numerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cells or nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with the clinical severity of asthma.

A study by Balzar et al reported changes in airway resident mast cell populations from a large group of subjects with asthma and normal control subjects.^[5]A greater proportion of chymase-positive mast cells in the airways and increased prostaglandin D2 levels were identified as important predictors of severe asthma as compared with other steroid-treated subjects with asthma.

Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses, cold air, or exercise. In some patients with chronic asthma, airflow limitation may be only partially reversible because of airway remodeling (hypertrophy and hyperplasia of smooth muscle, angiogenesis, and subepithelial fibrosis) that occurs with chronic untreated disease.

Airway inflammation in asthma may represent a loss of normal balance between two "opposing" populations of Th lymphocytes. Two types of Th lymphocytes have been characterized: Th1 and Th2. Th1 cells produce interleukin (IL)-2 and IFN-α, which are critical in cellular defense mechanisms in response to infection. Th2, in contrast, generates a family of cytokines (IL-4, IL-5, IL-6, IL-9, and IL-13) that can mediate allergic inflammation. A study by Gauvreau et al found that IL-13 has a role in allergen-induced airway responses.^[6]

The current "hygiene hypothesis" of asthma illustrates how this cytokine imbalance may explain some of the dramatic increases in asthma prevalence in westernized countries.^[7]This hypothesis is based on the concept that the immune system of the newborn is skewed toward Th2 cytokine generation (mediators of allergic inflammation). Following birth, environmental stimuli such as infections activate Th1 responses and bring the Th1/Th2 relationship to an appropriate balance. However, unequivocal support for the "hypgiene hypothesis" has not been demonstrated.^[8]

Airflow obstruction

Airflow obstruction can be caused by a variety of changes, including acute bronchoconstriction, airway edema, chronic mucous plug formation, and airway remodeling. Acute bronchoconstriction is the consequence of immunoglobulin E-dependent mediator release upon exposure to aeroallergens and is the primary component of the early asthmatic response. Airway edema occurs 6-24 hours following an allergen challenge and is referred to as the late asthmatic response. Chronic mucous plug formation consists of an exudate of serum proteins and cell debris that may take weeks to resolve. Airway remodeling is associated with structural changes due to long-standing inflammation and may profoundly affect the extent of reversibility of airway obstruction.^[9]

Airway obstruction causes increased resistance to airflow and decreased expiratory flow rates. These changes lead to a decreased ability to expel air and may result in hyperinflation. The resulting overdistention helps maintain airway patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases the work of breathing.

Bronchial hyperresponsiveness

Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volume approaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes in airflow resistance, the resulting uneven distribution of air, and alterations in circulation from increased intra-alveolar pressure due to hyperinflation all lead to ventilation-perfusion mismatch. Vasoconstriction due to alveolar hypoxia also contributes to this mismatch. Vasoconstriction is also considered an adaptive response to ventilation/perfusion mismatch.

In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the ready diffusion of carbon dioxide across alveolar capillary membranes. Thus, patients with asthma who are in the early stages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggered by the hypoxic drive also causes a decrease in PaCO₂. An increase in alveolar ventilation in the early stages of an acute exacerbation prevents hypercarbia. With worsening obstruction and increasing ventilation-perfusion mismatch, carbon dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis results from hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output result in metabolic acidosis. Respiratory failure leads to respiratory acidosis due to retention of carbon dioxide as alveolar ventilation decreases.

References

Etiology

Factors that can contribute to asthma or airway hyperreactivity may include any of the following:

Environmental allergens (eg, house dust mites; animal allergens, especially cat and dog; cockroach allergens; and fungi)
Viral respiratory tract infections
Exercise, hyperventilation
Gastroesophageal reflux disease
Chronic sinusitis or rhinitis
Aspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, sulfite sensitivity
Use of beta-adrenergic receptor blockers (including ophthalmic preparations)
Obesity^[10]
Environmental pollutants, tobacco smoke
Occupational exposure
Irritants (eg, household sprays, paint fumes)
Various high- and low-molecular-weight compounds (eg, insects, plants, latex, gums, diisocyanates, anhydrides, wood dust, and fluxes; associated with occupational asthma)
Emotional factors or stress
Perinatal factors (prematurity and increased maternal age; maternal smoking and prenatal exposure to tobacco smoke; breastfeeding has not been definitely shown to be protective)

Aspirin-induced asthma

The triad of asthma, aspirin sensitivity, and nasal polyps affects 5-10% of patients with asthma. Most patients experience symptoms during the third to fourth decade. A single dose can provoke an acute asthma exacerbation, accompanied by rhinorrhea, conjunctival irritation, and flushing of the head and neck. It can also occur with other nonsteroidal anti-inflammatory drugs and is caused by an increase in eosinophils and cysteinyl leukotrienes after exposure.^[11]

A study by Beasley et al demonstrated some epidemiological evidence that exposure to acetaminophen is associated with an increased risk of asthma.^[12]However, no clinical studies have directly linked asthma symptoms with acetaminophen use.

Primary treatment is avoidance of these medications, but leukotriene antagonists have shown promise in treatment, allowing these patients to take daily aspirin for cardiac or rheumatic disease. Aspirin desensitization has also been reported to decrease sinus symptoms, allowing daily dosing of aspirin.^[13]

Gastroesophageal reflux disease

The presence of acid in the distal esophagus, mediated via vagal or other neural reflexes, can significantly increase airway resistance and airway reactivity. Patients with asthma are 3 times more likely to also have GERD.^[14]Some people with asthma have significant gastroesophageal reflux without esophageal symptoms. Gastroesophageal reflux was found to be a definite asthma-causing factor (defined by a favorable asthma response to medical antireflux therapy) in 64% of patients; clinically silent reflux was present in 24% of all patients.^[14]

Work-related asthma

Occupational factors are associated with 10-15% of adult asthma cases. More than 300 specific occupational agents have been associated with asthma. High-risk jobs include farming, painting, janitorial work, and plastics manufacturing. Given the prevalence of work-related asthma, the American College of Chest Physicians (ACCP) supports consideration of work-related asthma in all patients presenting with new-onset or worsening asthma. An ACCP consensus statement defines work-related asthmas as including occupational asthma (ie, asthma induced by sensitizer or irritant work exposures) and work-exacerbated asthma (ie, preexisting or concurrent asthma worsened by work factors).^[15]

Two types of occupational asthma are recognized: immune-related and non-immune-related. Immune-mediated asthma has a latency of months to years after exposure. Non-immune-mediated asthma, or irritant-induced asthma (reactive airway dysfunction syndrome), has no latency period and may occur within 24 hours after an accidental exposure to high concentrations of respiratory irritants. Pay careful attention to the patient's occupational history. Those with a history of asthma who report worsening of symptoms during the week and improvement during the weekends should be evaluated for occupational exposure. Peak-flow monitoring during work (optimally, at least 4 times a day) for at least 2 weeks and a similar period away from work is one recommended method to establish the diagnosis.^[15]

To see complete information on Allergic and Environmental Asthma, please go to the main article by clicking here.

Viral exposure in children

Evidence suggests that rhinovirus illness during infancy is a significant risk factor for the development of wheezing in preschool children and a frequent trigger of wheezing illnesses in children with asthma.^[16]Human rhinovirus C (HRVC) is a newly identified genotype of HRV found in patients with respiratory tract infections. A study of children with acute asthma who presented to the emergency department found HRVC present in the majority of patients. The presence of HRVC was also associated with more severe asthma.^[17]

Approximately 80-85% of childhood asthma episodes are associated with prior viral exposure. Prior childhood pneumonia due to infection by respiratory syncytial virus, Mycoplasma pneumoniae, and/or Chlamydia species was found in more than 50% of a small sample of children aged 7-9 years who later had asthma.^[18]Treatment with antibiotics appropriate for these organisms improves the clinical signs and symptoms of asthma.

Sinusitis

Of patients with asthma, 50% have concurrent sinus disease. Sinusitis is the most important exacerbating factor for asthma symptoms. Either acute infectious sinus disease or chronic inflammation may contribute to worsening airway symptoms. Treatment of nasal and sinus inflammation reduces airway reactivity. Treatment of acute sinusitis requires at least 10 days of antibiotics to improve asthma symptoms.^[19]

Exercise-induced asthma

Exercise-induced asthma (EIA), or exercise-induced bronchoconstriction (EIB), is an asthma variant defined as a condition in which exercise or vigorous physical activity triggers acute bronchoconstriction in persons with heightened airway reactivity. It is observed primarily in persons who have asthma (exercise-induced bronchoconstriction in asthmatic persons) but can also be found in patients with normal resting spirometry findings with atopy, allergic rhinitis, or cystic fibrosis and even in healthy persons, many of whom are elite or cold weather athletes (exercise-induced bronchoconstriction in athletes). Exercise-induced bronchoconstriction is often a neglected diagnosis, and the underlying asthma may be silent in as many as 50% of patients, except during exercise.^{[20, 21]}

The pathogenesis of exercise-induced bronchoconstriction is controversial. The disease may be mediated by water loss from the airway, heat loss from the airway, or a combination of both. The upper airway is designed to keep inspired air at 100% humidity and body temperature at 37°C (98.6°F). The nose is unable to condition the increased amount of air required for exercise, particularly in athletes who breathe through their mouths. The abnormal heat and water fluxes in the bronchial tree result in bronchoconstriction, occurring within minutes of completing exercise. Results from bronchoalveolar lavage studies have not demonstrated an increase in inflammatory mediators. These patients generally develop a refractory period, during which a second exercise challenge does not cause a significant degree of bronchoconstriction.

Factors that contribute to exercise-induced bronchoconstriction symptoms (in both persons with asthma and athletes) include the following:

Exposure to cold or dry air
Environmental pollutants (eg, sulfur, ozone)
level of bronchial hyperreactivity
Chronicity of asthma and symptomatic control
Duration and intensity of exercise
Allergen exposure in atopic individuals
Coexisting respiratory infection

The assessment and diagnosis of exercise-induced bronchoconstriction is made more often in children and young adults than in older adults and is related to high levels of physical activity. Exercise-induced bronchoconstriction can be observed in persons of any age based on the level of underlying airway reactivity and the level of physical exertion.

Genetics

Research on genetic mutations casts further light on the synergistic nature of multiple mutations in the pathophysiology of asthma. Polymorphisms in the gene that encodes platelet-activating factor hydrolase, an intrinsic neutralizing agent of platelet-activating factor in most humans, may play a role in susceptibility to asthma and asthma severity.^[22]

Evidence suggests that the prevalence of asthma is reduced in association with certain infections (Mycobacterium tuberculosis, measles, or hepatitis A); rural living; exposure to other children (eg, presence of older siblings and early enrollment in childcare); and less frequent use of antibiotics. Furthermore, the absence of these lifestyle events is associated with the persistence of a Th2 cytokine pattern. Under these conditions, the genetic background of the child, with a cytokine imbalance toward Th2, sets the stage to promote the production of immunoglobulin E (IgE) antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, and possibly cats). Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generating IgE, and sensitization occurs.

A reciprocal interaction is apparent between the 2 subpopulations, in which Th1 cytokines can inhibit Th2 generation and vice versa. Allergic inflammation may be the result of an excessive expression of Th2 cytokines. Alternatively, studies suggest the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished.^[23]

In addition, some studies highlight the importance of genotypes in children's susceptibility to asthma and response to specific antiasthma medications.^{[24, 25, 26, 27]}

Obesity

A study by Cottrell et al explored the relationship between asthma, obesity, and abnormal lipid and glucose metabolism.^[28]The study found that community-based data linked asthma, body mass, and metabolic variables in children. Specifically, these findings described a statistically significant association between asthma and abnormal lipid and glucose metabolism beyond body mass association. Evidence is accumulating that individuals with a high body mass index have worse asthma control and sustained weight loss improves asthma control.^[29]

Accelerated weight gain in early infancy is associated with increased risks of asthma symptoms according to one study of preschool children.^[30]

References

History

A detailed assessment of the medical history should address the following:

Whether symptoms are attributable to asthma
Whether findings support the likelihood of asthma (eg, family history)
Asthma severity
Identification of possible precipitating factors

Family history may be pertinent for asthma, allergy, sinusitis, rhinitis, eczema, and nasal polyps. The social history may include home characteristics, smoking, workplace or school characteristics, educational level, employment, social support, factors that may contribute to nonadherence of asthma medications, and illicit drug use.

The patient’s exacerbation history is important with respect to the following:

Usual prodromal signs or symptoms
Rapidity of onset
Associated illnesses
Number in the last year
Need for emergency department visits, hospitalizations, ICU admissions, intubations
Missed days from work or school or activity limitation

The patient’s perception of his or her asthma is important regarding knowledge of asthma and treatment, use of medications, coping mechanisms, family support, and economic resources.

General manifestations of asthma

Wheezing, a musical, high-pitched, whistling sound produced by airflow turbulence, is one of the most common symptoms. In the mildest form, wheezing is only end expiratory. As severity increases, the wheeze lasts throughout expiration. In a more severe asthmatic episode, wheezing is also present during inspiration. During a most severe episode, wheezing may be absent because of the severe limitation of airflow associated with airway narrowing and respiratory muscle fatigue.

Asthma can occur without wheezing when obstruction involves predominantly the small airways. Thus, wheezing is not necessary for the diagnosis of asthma. Furthermore, wheezing can be associated with other causes of airway obstruction, such as cystic fibrosis and heart failure. Patients with vocal cord dysfunction, now referred to as inducible laryngeal obstruction (ILO), have a predominantly inspiratory monophonic wheeze (different from the polyphonic wheeze in asthma), which is heard best over the laryngeal area in the neck. Patients with excessive dynamic airway collapse (EDAC), bronchomalacia, or tracheomalacia also have an expiratory monophonic wheeze heard over the large airways. In exercise-induced bronchoconstriction, wheezing may be present after exercise, and in nocturnal asthma, wheezing is present during the night.

Cough may be the only symptom of asthma, especially in cases of exercise-induced or nocturnal asthma. Usually, the cough is nonproductive and nonparoxysmal. Children with nocturnal asthma tend to cough after midnight and during the early hours of morning. Chest tightness or a history of tightness or pain in the chest may be present with or without other symptoms of asthma, especially in exercise-induced or nocturnal asthma.

Other nonspecific symptoms in infants or young children may be a history of recurrent bronchitis, bronchiolitis, or pneumonia; a persistent cough with colds; and/or recurrent croup or chest rattling. Most children with chronic or recurrent bronchitis have asthma. Asthma is also the most common underlying diagnosis in children with recurrent pneumonia; older children may have a history of chest tightness and/or recurrent chest congestion.

Exercise-induced bronchoconstriction

In patients with exercise-induced bronchoconstriction, the clinical history findings are typical of asthma but are associated only with exercise. Typical symptoms include cough, wheezing, shortness of breath, and chest pain or tightness. Some individuals also may report sore throat or GI upset. Initially, airway dilation is noted during exercise. If exercise continues beyond approximately 10 minutes, bronchoconstriction supervenes, resulting in asthma symptoms. If the exercise period is shorter, symptoms may develop up to 5-10 minutes after completion of exercise. Higher intensity levels of exercise result in a more intense attack, with running producing more symptoms than walking.

Patients may note asthma symptoms are related to seasonal changes or the ambient temperature and humidity in the environment in which a patient exercises. Other triggers may be pollutants (eg, sulfur, nitrous oxide, ozone) or upper respiratory tract infections. Cold, dry air generally provokes more obstruction than warm, humid air. Consequently, many athletes have good exercise tolerance in sports such as swimming. A prospective longitudinal study in Britain found that swimming was associated with increased lung function and lower risk of asthma-related symptoms, especially among children with respiratory conditions.^[44]

Athletes who are more physically fit may not notice the typical asthma symptoms and may report only a reduced or more limited level of endurance. Several modifiers in the history should prompt an evaluation for causes other than exercise-induced bronchoconstriction. While patients may report typical obstructive symptoms, a history of a choking sensation with exercise, inspiratory wheezing, or stridor should prompt an evaluation for evidence of vocal cord dysfunction.

References

Physical Examination

The guidelines from the National Asthma Education and Prevention Program highlight the importance of correctly diagnosing asthma, by establishing the following^[1]:

Episodic symptoms of airflow obstruction are present
Airflow obstruction or symptoms are at least partially reversible
Exclusion of alternative diagnoses.

Manifestations of an acute episode

Acute episodes can be mild, moderately severe, severe, or characterized by imminent respiratory arrest.

Mild episodes

During a mild episode, patients may be breathless after physical activity such as walking; they can talk in sentences and lie down; and they may be agitated. Patients with mild acute asthma are able to lie flat. In a mild episode, the respiratory rate is increased, and accessory muscles of respiration are not used. The heart rate is less than 100 bpm, and pulsus paradoxus (an exaggerated fall in systolic blood pressure during inspiration) is not present. Auscultation of the chest reveals moderate wheezing, which is often end expiratory. Rapid forced expiration may elicit wheezing that is otherwise inaudible, and oxyhemoglobin saturation with room air is greater than 95%.

Moderately severe episodes

In a moderately severe episode, the respiratory rate also is increased. Typically, accessory muscles of respiration are used. In children, also look for supraclavicular and intercostal retractions and nasal flaring, as well as abdominal breathing. The heart rate is 100-120 bpm. Loud expiratory wheezing can be heard, and pulsus paradoxus may be present (10-20 mm Hg). Oxyhemoglobin saturation with room air is 91-95%. Patients experiencing a moderately severe episode are breathless while talking, and infants have feeding difficulties and a softer, shorter cry. In more severe cases, the patient assumes a sitting position.

Severe episodes

In a severe episode, patients are breathless during rest, are not interested in eating, sit upright, talk in words rather than sentences, and are usually agitated. In a severe episode, the respiratory rate is often greater than 30 per minute. Accessory muscles of respiration are usually used, and suprasternal retractions are commonly present. The heart rate is more than 120 bpm. Loud biphasic (expiratory and inspiratory) wheezing can be heard, and pulsus paradoxus is often present (20-40 mm Hg). Oxyhemoglobin saturation with room air is less than 91%. As the severity increases, the patient increasingly assumes a hunched-over sitting position with the hands supporting the torso, termed the tripod position.

Imminent respiratory arrest

When children are in imminent respiratory arrest, in addition to the aforementioned symptoms, they are drowsy and confused, but adolescents may not have these symptoms until they are in frank respiratory failure. In status asthmaticus with imminent respiratory arrest, paradoxical thoracoabdominal movement occurs. Wheezing may be absent (associated with most severe airway obstruction), and severe hypoxemia may manifest as bradycardia. Pulsus paradoxus noted earlier may be absent; this finding suggests respiratory muscle fatigue.

As the episode becomes more severe, profuse diaphoresis occurs, with the diaphoresis presenting concomitantly with a rise in PCO₂ and hypoventilation. In the most severe form of acute asthma, patients may struggle for air, act confused and agitated, and pull off their oxygen, stating, "I can’t breathe." These are signs of life-threatening hypoxia. With advanced hypercarbia, bradypnea, somnolence, and profuse diaphoresis may be present; almost no breath sounds may be heard; and the patient is willing to lie recumbent.

References

Bronchoprovocation

Methacholine/histamine challenge

Bronchoprovocation testing with either methacholine or histamine is useful when spirometry findings are normal or near normal, especially in patients with intermittent or exercise-induced asthma symptoms. Bronchoprovocation testing helps determine if airway hyperreactivity is present, and a negative test result usually excludes the diagnosis of asthma. Methacholine is a direct stimulant that acts directly on acetylcholine receptors on smooth muscle, causing contraction and airway narrowing. Methacholine has been reported to have a high sensitivity to identify airway hyperresponsiveness and a negative test is often used to exclude asthma.

Trained individuals should perform this asthma testing in an appropriate facility and in accordance with the guidelines of the American Thoracic Society published in 1999.^[64]Methacholine is administered in incremental doses up to a maximum dose of 16 mg/mL, and a 20% decrease in FEV₁, up to the 4 mg/mL level, is considered a positive test result for the presence of bronchial hyperresponsiveness. The presence of airflow obstruction with an FEV₁ less than 65-70% at baseline is generally an indication to avoid performing the test.

Eucapnic hyperventilation

Eucapnic hyperventilation with either cold or dry air is an alternative method of bronchoprovocation testing. It has been used to evaluate patients for exercise-induced asthma and has been shown to produce results similar to those of methacholine-challenge asthma testing.

Exercise testing

Exercise spirometry is the standard method for assessing patients with exercise-induced bronchoconstricition. Testing involves 6-10 minutes of strenuous exertion at 85-90% of predicted maximal heart rate and measurement of postexercise spirometry for 15-30 minutes. The defined cutoff for a positive test result is a 15% decrease in FEV₁ after exercise.

Exercise testing may be accomplished in 3 different ways, using cycle ergometry, a standard treadmill test, or free running exercise. This method of testing is limited because laboratory conditions may not subject the patient to the usual conditions that trigger exercise-induced bronchoconstriction symptoms, and results have a lower sensitivity for asthma than other methods.

Allergen-inhalation challenge

Allergen-inhalation challenges can be performed in selected patients but are generally not needed or recommended. This test requires an available allergen solution and specialized centers able to handle potentially significant reactions. A negative test finding may allow continued exposure to an allergen (eg, family pet); a positive test finding can dramatically indicate that the patient should avoid a particular allergen. This test is often needed to help diagnose occupational asthma

Mannitol

Mannitol is a provocation test that uses indirect stimuli, causing smooth muscle contraction by release of endogenous mediators, including prostaglandins, leukotrienes, and histamine. Mannitol is equivalent for the diagnosis of asthma compared with methacholine but is not currently available for use in the United States.^[65]

References

Approach Considerations

Medical care includes treatment of acute asthmatic episodes and control of chronic symptoms, including nocturnal and exercise-induced asthmatic symptoms. Pharmacologic management includes the use of control agents such as inhaled corticosteroids, long-acting bronchodilators (beta-agonists and anticholinergics), theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (IgE) antibodies (omalizumab), anti–IL5 antibodies, and anti–IL4/IL13 antibodies in selected patients. Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium.

A stepwise (step-up if necessary and step-down when possible) approach to asthma management continues to be used in the current guidelines and is now divided into 3 groups based on age (0-4 y, 5-11 y, 12 y and older).^[1]

For all patients, quick-relief medications include rapid-acting beta₂ agonists as needed for symptoms. The intensity of treatment depends on the severity of symptoms. If rapid-acting beta₂ agonists are used more than 2 days a week for symptom relief (not including use of rapid-acting beta₂ agonists for prevention of exercise-induced symptoms), stepping up on treatment may need be considered.

A study by Price et al randomly assigned patients to 2 years of open-label therapy with leukotriene antagonists (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and a leukotriene antagonist (170 patients) or long-acting beta-agonists (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial.^[71]The results of these two trials suggests that a leukotriene antagonist is equivalent to both comparison drugs with regard to asthma-related quality of life at 2 months, but equivalence was not proven at 2 years.

A Cochrane review found that inhaled corticosteroids are superior to anti-leukotrienes when used as monotherapy in adults and children with persistent asthma. The superiority of inhaled corticosteroids is most pronounced in asthma patients with moderate airway obstruction.^[72]The 2019 Global Initiative for Asthma (GINA) guidelines identify inhaled corticosteroids as the preferred controller medication of choice for children and adults.

In general, patients should be assessed every 1-6 months for asthma control. At every visit, adherence, environmental control, and comorbid conditions should be checked. If the patient has good control of their asthma for at least 3 months, treatment can be stepped down; however, the patient should be reassessed in 2-4 weeks to make sure that control is maintained with the new treatment.

A study by Bruzzese et al assessed the Asthma Self-Management for Adolescents (ASMA) approach, which is a school-based intervention for adolescents and medical providers.^[73]The study found that ASMA helped improve self-management and reduced morbidity and urgent health care use in low-income, urban, minority adolescents.

References

Environmental Control

Environmental exposures and irritants can play a strong role in symptom exacerbations. Therefore, in patients who have persistent asthma, the use of skin testing or in vitro testing to assess sensitivity to perennial indoor allergens is important. Once the offending allergens are identified, counsel patients on avoidance from these exposures. In addition, education to avoid tobacco smoke (both first-hand and second-hand exposure) is important for patients with asthma.

Allergen avoidance takes different forms, depending on the specific allergen size and characteristic. Improvement in symptoms after avoidance of the allergen should result rather rapidly, though the allergen itself (eg, cat dander) may linger in the environment for months after primary removal of the source. A multifaceted approach is necessary, as individual interventions are rarely successful by themselves.

Comprehensive allergen avoidance during the first year of life effectively prevents the onset of asthma in individuals with a high genetic risk, with the effect occurring early in childhood and persisting through adulthood, according to one study. In the trial, 120 children at high risk for allergic disorders were randomized into prophylactic (n=58) and control (n=62) groups. The infants in the intervention group were either breast fed (with the mother on a low allergen diet) or given an extensively hydrolyzed formula. The control group followed standard advice. At age 18, a significantly lower prevalence of asthma was observed in the intervention arm compared to the control group (10.7% and 25.9%, respectively). An overall reduction in asthma prevalence from 1 to 18 years was also observed in assessments performed at ages 1, 2, 4, 8 and 18 years.^[74]

Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their homes regularly.^[75]If a patient cannot avoid vacuuming, he or she should use a face mask or a double-bagged vacuum with a high-efficiency particulate air filter. If possible, consideration can be given to moving to a higher floor in the house (less dust and mold) or different neighborhood (fewer cockroaches). Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven to be effective for people with chronic asthma, and the generation of ozone by these machines may be harmful to some. Specific factors related to the home include dust mites, animals, cockroaches, mold, and pollen (see Indoor Aeroallergens for more details).

Air pollution caused by traffic may increase the risk of asthma and wheezing, especially in individuals with EPHX1 gene and enzyme activity.^[76]This can be mediated through airway oxidative stress generation.

Dust mites

In the case of dust mites (Dermatophagoides pteronyssinus and farina, size 30 μm), the primary allergen is an intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air filtration is not very effective. Measures to avoid dust mites include using impervious covers (eg, on mattresses, pillows, comforters, the most important intervention), washing other bedding in hot water (130°F [54.4°C] most effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically put them in the freezer. Decrease room humidity (< 50%).

A Cochrane Review noted that most trials to date have been small and of poor methodologic quality. Therefore, clinicians cannot easily offer definitive recommendations on the role of house dust mite avoidance measures in the management of perennial allergic rhinitis that is sensitive to house dust mites. Conclusions from this analysis suggest that acaricides and extensive bedroom-based environmental control programs may help reduce rhinitis symptoms. If such measures are considered appropriate, they should be the interventions of choice. However, analysis also indicated that isolated use of bedding that is impermeable to house dust mites is not likely to be effective in reducing rhinitis symptoms caused by dust mites.^[77]

Animals

Because of the small size (1-20 μm) of dander, saliva, urine, or serum proteins of cats and other animals, these allergens are predominantly airborne indoor allergens. Avoidance involves removing animals from the home (or at least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and dogs as often as twice weekly. The antigens may remain in a home for 6 months or more after cats are removed from the home, and cat antigen may be found in homes and offices where cats were never present, highlighting the importance of frequent cleaning.

Cockroaches

Twenty percent of homes without visible infestation still produce sensitizing levels of cockroach allergen (size 30 μm). Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches, exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.

Mold

For indoor molds (size 1-150 μm), avoidance includes keeping areas dry (eg, remove carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.

Pollen

Pollen (size 1-150 μm) avoidance is difficult or impossible, but efforts to reduce exposure include closing windows and doors, using air conditioning and high-efficiency particulate air filters in the car and home, staying inside during the midday and afternoon when pollen counts are highest, wearing glasses or sunglasses, and wearing a face mask over the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing in a different ecosystem during pollen season.

References

Allergen Immunotherapy

The use of immunotherapy for the treatment of asthma is controversial. Several large, well-conducted studies did not demonstrate any benefit, but a meta-analysis of 75 randomized controlled trials confirmed efficacy in asthma.^[78]The National Asthma Education and Prevention Program Expert Panel Report recommends that immunotherapy be considered if the following criteria are fulfilled:

A relationship is clear between symptoms and exposure to an unavoidable allergen to which the patient is sensitive.
Symptoms occur all year or during a major portion of the year.
Symptoms are difficult to control with pharmacologic management because the medication is ineffective, multiple medications are required, or the patient is not accepting of medication.

Repeated injections of small doses of allergen have been used for more than almost 100 years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting (hymenoptera venom) reactions. The role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative indication to no indication. Benefit has been shown in individuals with allergy-induced asthma.^[79]

Supporters argue that compliance can be ensured, and evidence shows that the underlying disease process can be modified or even prevented (eg, preventing asthma in children with allergic rhinitis). Acquisition of new sensitivities can be reduced or eliminated with immunotherapy of monosensitized or oligosensitized children.

Immunotherapy decreased asthma symptoms and the need for medication in a 2003 meta-analysis of 75 randomized controlled trials by Abramson et al.^[80]Another study showed improved peak expiratory flow rate (PEFR) and decreased use of medications in a highly selected group of children, but only for the first year of therapy.

Patients receiving subcutaneous immunotherapy (SCIT) demonstrated improved medical outcomes and cost savings in one study designed to evaluate the cost-effectiveness of SCIT in addition to symptomatic therapy (ST), compared with ST alone.^[78]

Allergen immunotherapy should be considered if specific allergens have a proven relationship to symptoms and a vaccine to the allergen is available; the individual is sensitized (ie, positive skin test or RAST findings); the allergen cannot be avoided and is present year-round (eg, industrial); or symptoms are poorly controlled with medical therapy. As discussed above, this treatment is especially useful if asthma is associated with allergic rhinitis.

Referral to an allergist is required, and the patient must commit to a course of 3-5 years of therapy (although a trial of several months can be considered).

Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment are required. Also, allergen immunotherapy should be avoided if the patient is taking beta blockers or is having an asthma exacerbation (ie, PEFR < 70% of patient’s personal best) or has moderate or worse fixed obstruction. A major risk factor for immunotherapy-related fatalities includes uncontrolled asthma; therefore, appropriate caution should be exercised.

Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units (PNU), but "major allergen content" may be a more standardized and reliable method of dosing and characterizing allergen extracts; however, not all allergens have been standardized. Extracts with modifications that decrease allergenicity (adverse reactions) without reducing immunogenicity (effectiveness) are under investigation.

Sublingual immunotherapy (SLIT) has been shown to improve allergic rhinitis symptoms, including in pediatric patients and allergic asthma. While adverse reactions do occur, SLIT is safe enough for home administration. Based on limited data, sublingual therapy, at least in the short term, may be about half as effective as traditional subcutaneous injection. While SLIT is widely used in European, South American, and Asian countries, as of early 2016, it is not FDA approved and remains off-label use in the United States.

References

Monoclonal Antibody Therapy

Omalizumab

Omalizumab is indicated for adults and children aged 6 years or older with moderate-to-severe persistent asthma who have a positive skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Patients should have IgE levels between 30 and 700 IU and should not weigh more than 150 kg.

This is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell receptor, thereby preventing cell degranulation without causing degranulation itself.

Therapy has been shown to decrease free IgE antibody levels by 99% and cell receptor sites for IgE antibody by 97%. This decrease, in turn, is associated with reduced histamine production (90%), early-phase bronchospasm (40%), and late-phase bronchospasm (70%), as well as a decrease in the number, migration, and activity of eosinophils. Levels drop quickly and remain low for at least a month. This therapy is also effective for allergic rhinitis.

Multiple phase 3 trials show that compared to placebo injections, treatment is associated with larger median inhaled steroid dose reduction (83% vs 50%), higher percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and the emergency department may also be improved. Omalizumab has been shown to reduce the number of asthma exacerbations.

Prescribers must be prepared and equipped to recognize and treat anaphylaxis should it occur. Adverse effects are rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1% in studies and 0.2% in postmarketing surveillance). Transient thrombocytopenia has also been noted but not in humans. Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune complex deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit one’s ability to fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has not been seen in the postmarketing data.

Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight. Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $6,110 to $36,600 annually, so omalizumab is a second-line therapy for patients with moderate-to-severe persistent allergic asthma that is not fully controlled on standard therapy.^[81]

A study by Busse et al found that omalizumab further improved asthma control, nearly eliminated seasonal exacerbation peaks, and reduced the need for other medications to control asthma when added to a regimen of guidelines-based therapy in inner-city children, adolescents, and young adults.^[82]

A study by Hanania et al found that omalizumab provided additional benefit in patients with severe allergic asthma that is insufficiently controlled with inhaled corticosteroids and long-acting beta2-agonists.^[83]However, the results of the study were limited by early patient discontinuation (20.8%) and were limited because the study was not powered to detect rare safety events or treatment effect in the corticosteroid group.

Mepolizumab

Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin 5 (IL-5). Mepolizumab binds to IL-5 and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding to eosinophils reduces blood, tissue, and sputum eosinophil levels. It is indicated for add-on maintenance treatment of patients with severe asthma aged 12 years or older and with an eosinophilic phenotype.

Approval was based on three key phase 3 trials (DREAM, MENSA, and SIRIUS). Each trial demonstrated statistically significant improvement in decreasing asthma exacerbations and emergency department visits or hospitalization. Mean reduction in glucocorticoid use was 50% in the mepolizumab group, while also reducing the asthma exacerbation rate. Significant improvement in FEV₁ was also observed compared with placebo.^{[84, 85, 86]}

Reslizumab

Reslizumab is an IgG kappa monoclonal antibody that inhibits IL-5. It was approved by the FDA in March 2016 and is indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype. It is administered as an intravenous infusion every 4 weeks. Approval was based on three multicenter, international trials in patients with asthma who had elevated eosinophils. In two of these studies (n = 953), patients who received reslizumab had a significant reduction in the frequency of asthma exacerbations of up to 59% (study 1: rate ratio, 0.50 [95% confidence interval, 0.37-0.67]; study 2: rate ratio, 0.41 [95% confidence interval, 0.28-0.59]; both P < .0001) compared with those receiving placebo.^[87]

Benralizumab

Benralizumab is an IL-5 receptor, alpha-directed cytolytic mAb (IgG1, kappa) approved by the FDA in November 2017. The IL-5 receptor is expressed on the surface of eosinophils and basophils. Benralizumab reduces eosinophils and basophils through antibody-dependent cell-mediated cytotoxicity (ADCC). It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.

Approval was based on results from the WINDWARD clinical trial program, including the phase III exacerbation trials, SIROCCO and CALIMA, and the phase III oral corticosteroid (OCS)–sparing trial, ZONDA.^{[88, 89, 90]}

Results for the 8-week benralizumab dosing regimen from these trials showed the following:

Up to 51% reduction in the annual asthma exacerbation rate (AAER) compared with placebo
Significant improvement in lung function as measured by forced expiratory volume in one second (FEV₁) of up to 159 mL compared with placebo
Seventy-five percent median reduction in daily OCS use and discontinuation of OCS use in 52% of eligible patients

Dupilumab

Approval for dupilumab was based on the LIBERTY QUEST (n=1902) and VENTURE (n=210) phase 3 clinical trials.

In the LIBERTY QUEST trial, patients with moderate-to-severe uncontrolled asthma were administered dupilumab add-on therapy to current maintenance therapy every 2 weeks or matched placebo. Those receiving a 200-mg dose demonstrated a 47.7% lower rate of annualized severe asthma exacerbations compared with placebo add-on (P< .001). The 300-mg dose showed a similar response.^[91]

In the LIBERTY VENTURE trial, patients with oral corticosteroid–dependent severe asthma were administered dupilumab add-on therapy or matched placebo to current maintenance therapy every 2 weeks for 24 weeks or matched placebo. Corticosteroid doses were gradually decreased from week 4 to week 20 and then maintained for 4 weeks. Patients receiving dupilumab had a 70.1% greater corticosteroid dose reduction compared with 41.9% for placebo add-on (P< .001). Additionally, patients receiving dupilumab had a 59% (95% confidence interval, 37-74) lower rate of severe asthma exacerbations than those taking placebo add-on.^[92]

References

Acute Exacerbation

Prehospital care

The mainstay of ED therapy for acute asthma is inhaled beta₂ agonists. The most effective particle sizes are 1-5 μm. Larger particles are ineffective because they are deposited in the mouth and central airways. Particles smaller than 1 μm are too small to be effective because they move in the airways by Brownian motion and do not reach the lower airways.

Although studies in patients with COPD reported increased rates of pneumonia associated with inhaled corticosteroid use, a study by O’Byrne et al found no increased risk in patients with asthma in clinical trials using budesonide.^[97]

Standard delivery systems and routes

Albuterol is administered 2.5-5 mg every 20 minutes for 3 doses, then 2.5-10 mg every 1-4 hours as needed; dilution of 2.5 mg in 3-4 mL of saline or use of premixed nebules is standard. Oxygen or compressed air delivery of the inhaled beta agonists should be at a rate of 6-8 L/min. For children, use 0.15 mg/kg (minimum dose 2.5 mg) every 20 minutes for 3 doses, then 0.15-0.3 mg/kg up to 10 mg every 1-4 hours as needed.

An equivalent method of beta-agonist delivery in mild-to-moderate exacerbations is the metered-dose inhaler (MDI) used in conjunction with a spacer or holding chamber. For severe exacerbations, it is less clear if nebulized versus MDI/spacer delivery is truly equivalent. Each puff delivers a standard 90 μg of albuterol. The dose is 4-8 puffs every 20 minutes up to 4 hours, then every 1-4 hours as needed. A potential advantage of the MDI/holding chamber is that it requires little or no assistance from the respiratory therapist once the patient understands how to use the medication; the patient can be discharged from the ED with the same spacer and albuterol canister. This modality is especially effective in areas where patients may be unable to afford their inhaled beta agonists.

Side effects may include tremor and a slight tendency toward tachycardia. However, many patients who present with acute asthma and tachycardia actually decrease their heart rate with inhaled beta-agonist therapy. In addition, inhaled beta agonists decrease potassium by an average of 0.4 mEq/L.

Patients who respond poorly or not at all to an inhaled beta-agonist regimen may respond to parenteral beta₂ agonists, such as 0.25 mg terbutaline or 0.3 mg of 1:1000 concentration of epinephrine administered subcutaneously. This treatment should be reserved for patients who are seriously ill and not responding to serial treatments with inhaled beta-agonist/anticholinergic therapy and other more established therapies.

Ipratropium 0.5 mg has had variable benefit in controlled trials, demonstrating most consistent efficacy in children and smokers with comorbid COPD. The current NAEPP guidelines (2007) recommend its use in severe exacerbations only.^[1]Ipratropium should be given in combination with albuterol every 20 minutes for 3 doses, then as needed. The addition of ipratropium has not been shown to provide further benefit once the patient is hospitalized.

Nebulizer therapy

Continuous nebulization may be superior to the MDI/holding chamber method in a patient with severe exacerbations (eg, PEF < 200 L/min). The dose of albuterol is 10-15 mg in 70 mL of isotonic saline. For children, this method is reserved for severe asthma at an albuterol dose of 0.5 mg/kg/h. Based on meta-analyses, there is no advantage of intravenous albuterol over inhaled albuterol, even in severe asthma. However, the role of parenteral beta agonists in addition to inhaled beta-agonist treatments is uncertain.

A study by Dhuper et al found no evidence that nebulizers were more effective than MDI/spacer beta agonist delivery in emergency management of acute asthma in an inner-city adult population.^[98]Thus, because they are more cost effective, MDI/spacer may be a better alternative to nebulizer delivery for some individuals.

Intravenous/oral steroids

Although use of systemic corticosteroids is recommended early in the course of acute exacerbations in patients with an incomplete response to beta agonists, oral administration is equivalent in efficacy to intravenous administration. Corticosteroids speed the resolution of airway obstruction and prevent a late-phase response.^{[99, 100]}

In children, long-term use of high-dose steroids (systemic or inhaled) may lead to adverse effects that include growth failure. However, long-term use of inhaled steroids (budesonide) was shown to have no sustained adverse effect on growth in children, according to the Childhood Asthma Management Program (CAMP).^{[101, 102]}

In preschool children with asthma, 2 years of inhaled corticosteroid therapy did not change the asthma symptoms or lung function during a third, treatment-free year. This suggests that no disease-modifying effect of inhaled corticosteroids is present after the treatment is discontinued.^[103]

Complications of long-term corticosteroid use may include osteoporosis, immunosuppression, cataracts, myopathy, weight gain, addisonian crisis, thinning of skin, easy bruising, avascular necrosis, diabetes, and psychiatric disorders.

Heliox

Heliox is a helium-oxygen (80:20 or 70:30) mixture that may provide dramatic benefit for ED patients with severe exacerbations. Helium is about 10% as dense as room air and, consequently, travels more easily down narrowed passages. This property makes heliox of particular value to patients at risk of intubation—by quickly decreasing the work of breathing and, when the gas mixture is used to drive the nebulizer, by better delivery of the inhaled bronchodilator.

Despite considerable promise, the literature shows mixed results. Potential explanations include the large number of small trials (low statistical power) and suboptimal delivery of albuterol to the patient. Briefly, heliox-driven nebulizer treatments should have the gas set at a rate of 8-10 L/min and with double the usual amount of albuterol. These adjustments result in the delivery of the appropriate amount of albuterol to the patient but with particles being delivered in the heliox mixture instead of oxygen or room air. When patients need supplemental oxygen, one can deliver it via nasal prong. Of course, as the supplemental oxygen is increased, the benefits of using heliox decrease. Oxygen requirements should determine the ideal mix. The role of heliox in acute asthma remains under investigation.

Indications for intubation

Despite the best efforts of the ED, some patients require endotracheal intubation. Approximately 5-10% of all hospital admissions for asthma are to an intensive care unit—for further care of already intubated patients or for close supervision of patients at very high risk of intubation. Mechanical ventilation of patients with acute asthma presents special challenges, such as the risk of high pressures lowering systemic blood pressure (auto-PEEP) and, less commonly, complications such as barotrauma, pneumothorax, or pneumomediastinum. The role of permissive hypercapnia goes beyond the scope of this article but is a ventilator strategy used in the ICU management of some patients with severe asthma exacerbations.

Indications for hospitalization

Indications for hospitalization are based on findings from the repeat assessment of a patient after the patient receives 3 doses of an inhaled bronchodilator. The decision whether to admit is based on the following:

Duration and severity of asthma symptoms
Severity of airflow obstruction
Course and severity of prior exacerbations
Medication use and access to medications
Adequacy of support and home conditions
Presence of psychiatric illness

Admit the patient to the ICU for close observation and monitoring in certain situations, such as the following:

Rapidly worsening asthma or a lack of response to the initial therapy in the emergency department
Confusion, drowsiness, signs of impeding respiratory arrest, or loss of consciousness
Impending respiratory arrest, as indicated by hypoxemia (PO₂< 60 mm Hg) despite supplemental oxygen and/or hypercarbia with PCO₂ greater than 45 mm Hg
Intubation is required because of the continued deterioration of the patient's condition despite aggressive treatments.

Status asthmaticus

Status asthmaticus, or an acute severe asthmatic episode that is resistant to appropriate outpatient therapy, is a medical emergency that requires aggressive hospital management. This may include admission to an ICU for the treatment of hypoxia, hypercarbia, and dehydration and possibly for assisted ventilation because of respiratory failure.

References

Classification Guidelines

The 2007 NAEPP guidelines^[1]and the 2009 VA/DoD asthma management guidelines^[43]use the severity of asthma classification below, with features of asthma severity divided into three charts to reflect classification in different age groups (0-4 y, 5-11 y, and 12 y and older). Classification includes (1) intermittent asthma, (2) mild persistent asthma, (3) moderate persistent asthma, (4) and severe persistent asthma.

Intermittent asthma is characterized as follows:

Symptoms of cough, wheezing, chest tightness, or difficulty breathing less than twice a week
Flare-ups are brief, but intensity may vary
Nighttime symptoms less than twice a month
No symptoms between flare-ups
Lung function test FEV₁ is 80% or more above normal values
Peak flow has less than 20% variability am-to-am or am-to-pm, day-to-day

Mild persistent asthma is characterized as follows:

Symptoms of cough, wheezing, chest tightness, or difficulty breathing 3-6 times a week
Flare-ups may affect activity level
Nighttime symptoms 3-4 times a month
Lung function test FEV₁ is 80% or more above normal values
Peak flow has less than 20-30% variability

Moderate persistent asthma is characterized as follows:

Symptoms of cough, wheezing, chest tightness, or difficulty breathing daily
Flare-ups may affect activity level
Nighttime symptoms 5 or more times a month
Lung function test FEV₁ is above 60% but below 80% of normal values
Peak flow has more than 30% variability

Severe persistent asthma is characterized as follows:

Symptoms of cough, wheezing, chest tightness, or difficulty breathing that are continual
Frequent nighttime symptoms
Lung function test FEV₁ is 60% or less of normal values
Peak flow has more than 30% variability

In contrast, the 2019 Global Initiative for Asthma (GINA) guidelines categorize asthma severity as mild, moderate, or severe. Severity is assessed retrospectively from the level of treatment required to control symptoms and exacerbations, as follows^[106]:

Mild asthma: Well-controlled with as-needed reliever medication alone or with low-intensity controller treatment such as low-dose inhaled corticosteroids (ICSs), leukotriene receptor antagonists, or chromones
Moderate asthma: Well-controlled with low-dose ICS/long-acting beta2-agonists (LABA)
Severe asthma: Requires high-dose ICS/LABA to prevent it from becoming uncontrolled, or asthma that remains uncontrolled despite this treatment

The 2013 joint European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines on evaluation and treatment of severe asthma reserves the definition of severe asthma for patients with refractory asthma and those in whom response to treatment of comorbidities is incomplete.^[108]

The 2019 GINA guidelines stress the importance of distinguishing between severe asthma and uncontrolled asthma, as the latter is a much more common reason for persistent symptoms and exacerbations, and it may be more easily improved. The most common problems that need to be excluded before a diagnosis of severe asthma can be made are the following^[106]:

Poor inhaler technique
Poor medication adherence
Incorrect diagnosis of asthma, with symptoms due to alternative conditions such as upper airway dysfunction, cardiac failure, or lack of fitness
Comorbidities and complicating conditions such as rhinosinusitis, gastroesophageal reflux, obesity, and obstructive sleep apnea
Ongoing exposure to sensitizing or irritant agents in the home or work environment.

References

Management Guidelines

The goals for successful management of asthma outlined in the 2007 NHLBI publication "Global Strategy for Asthma Management and Prevention" (see the images below) include the following^[1]:

Achieve and maintain control of asthma symptoms
Maintain normal activity levels, including exercise
Maintain pulmonary function as close to normal as possible
Prevent asthma exacerbations
Avoid adverse effects from asthma medications
Prevent asthma mortality

View Image

Asthma symptoms and severity. Recommended guidelines for determination of asthma severity based on clinical symptoms, exacerbations, and measurements ....

View Image

Stepwise approach to pharmacological management of asthma based on asthma severity. Adapted from Global Strategy for Asthma Management and Prevention:....

Stepwise pharmacologic therapy

The pharmacologic treatment of asthma is based on stepwise therapy. Asthma medications should be added or deleted as the frequency and severity of the patient's symptoms change. The 2007 NAEPP guidelines offer the recommendations below.^[1]

Step 1 for intermittent asthma is as follows:

Controller medication not indicated
Reliever medication is a short-acting beta-agonist (SABA) as needed for symptoms

Step 2 for mild persistent asthma is as follows:

Preferred controller medication is a low-dose inhaled corticosteroid
Alternatives include cromolyn, leukotriene receptor antagonist (LTRA),^[109]or theophylline

Step 3 for moderate persistent asthma is as follows:

Preferred controller medication is either a low-dose inhaled corticosteroid (ICS) plus a long-acting beta-agonist (LABA) (combination medication is the preferred choice to improve compliance)^[110]or an inhaled medium-dose corticosteroid
Alternatives include a low-dose ICS plus either an LTRA or theophylline

Step 4 for moderate-to-severe persistent asthma is as follows:

Preferred controller medication is an inhaled medium-dose corticosteroid plus a LABA (combination therapy)
Alternatives include an inhaled medium-dose corticosteroid plus either an LTRA or theophylline

Step 5 for severe persistent asthma is as follows:

Preferred controller medication is an inhaled high-dose corticosteroid plus LABA

Step 6 for severe persistent asthma is as follows:

Preferred controller medication is an inhaled high-dose corticosteroid plus LABA plus oral corticosteroid

The 2019 GINA guidelines include the stepwise recommendations below for medication and symptom control.^[106]

The preferred reliever medication is specified as low-dose ICS-formoterol, which is an off-label use. Other reliever options include as-needed SABA. See the following stepwise approach:

Step 1: As-needed low-dose ICS-formoterol (off-label); other options are low dose ICS taken whenever SABA is taken
Step 2: Daily low-dose ICS, or as-needed low-dose ICS-formoterol (off-label); other options are leukotriene receptor antagonist (LTRA) or low-dose ICS taken whenever SABA is taken
Step 3: Low-dose ICS/LABA; other options include medium-dose ICS or low-dose ICS + LTRA
Step 4: Medium-dose ICS-LABA; other options are high-dose ICS, add-on tiotropium, or add-on LTRA
Step 5: High-dose ICS-LABA; refer for phenotypic assessment with or without add-on therapy (eg, tiotropium, anti-IgE, anti-IL5/5R, and IL4R; other options are to add low-dose OCS, but consider adverse effects

The change in GINA guidelines from SABA to ICS-formoterol as the recommended as-needed inhaler was based on the SYGMA I/II trials published in 2018. SYGMA I showed that as-needed budesonide-formoterol was superior to as-needed terbutaline but was inferior to budesonide maintenance therapy. Exacerbation rates were similar for budesonide-containing strategies, both of which were lower than terbutaline. SYGMA II concluded that as needed budesonide-formoterol was noninferior to budesonide maintenance therapy for the rate of severe exacerbations but was inferior for controlling asthma symptoms. Both trials showed a reduction in overall ICS exposure with as-needed budesonide/formoterol.

The 2013 joint European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines include the following additional recommendations for treatment of severe asthma^[108]:

For severe allergic asthma, a therapeutic trial of omalizumab
Do not use methotrexate or macrolide antibiotics to treat severe asthma
For severe asthma and recurrent exacerbations of allergic bronchopulmonary aspergillosis (ABPA), antifungal agents should be given
Do not use antifungal agents for severe asthma without ABPA irrespective of sensitization to fungi (ie, positive skin prick test or fungus-specific immunoglobulin E in serum)

References

Medication Summary

Asthma medications are generally divided into two categories:

Quick relief (also called reliever medications)
Long-term control (also called controller medications)

Quick relief medications are used to relieve acute asthma exacerbations and to prevent exercise-induced bronchoconstriction (EIB) symptoms. These medications include short-acting beta agonists (SABAs), anticholinergics (used only for severe exacerbations), and systemic corticosteroids, which speed recovery from acute exacerbations.

Long-term control medications include inhaled corticosteroids (ICSs),^{[99, 100]} long-acting beta agonists (LABAs), long-acting anticholinergics, combination inhaled corticosteroids and long-acting beta agonists, methylxanthines, and leukotriene receptor antagonists. Inhaled corticosteroids are considered the primary drug of choice for control of chronic asthma, but unfortunately the response to this treatment is characterized by wide variability among patients. A study by Tantisira et al showed the glucocorticoid-induced transcript 1 gene (GLCCI1) to be the cause of this decrease in response.^[112]

In a study by Peters et al, the use of the anticholinergic agent tiotropium in 210 asthmatic patients resulted in a superior outcome compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow and other secondary outcomes. The addition of tiotropium in this study was also shown to be noninferior to the addition of salmeterol.^[113]

Kerstjens et al evaluated 912 patients already taking an ICS/LABA combination who were randomized to 48 weeks of tiotropium versus placebo in two replicate, randomized, controlled trials. The patients had a mean baseline FEV₁ of 62% of the predicted value. The use of tiotropium compared to placebo increased the time to first exacerbation (282 versus 226 days) and resulted in a higher peak change in FEV₁ from baseline of 86 ± 34 mL (Trial 1) and 154 ± 32 mL (Trial 2) for those patients taking tiotropium.^[114]

In a cross-sectional population-level comparison study of asthmatics from 1997-1998 and 2004-2005, researchers evaluated controller-to-total asthma medication ratio (greater than 0.5) with asthma exacerbation rates (dispensing of systemic corticosteroid or emergency department visit/hospitalization for asthma). They were able to demonstrate an increased use of asthma controllers based on a 16% increase in controller-to-total asthma medication ratio. However, there was no change in annual asthma exacerbation rates (0.27/year to 0.23/year) despite this improvement in controller use.^[115]

Two systematic reviews indicate that the regular use of ICSs for the treatment of pediatric asthma may suppress linear growth in the first year of treatment, but lower ICS doses may minimize such effects.^{[1, 2, 116]}The investigators of both reviews also noted that head-to-head comparison trials are needed to assess the effects of different ICSs, ICS doses, inhalation devices, and patient ages on growth suppression over time.

References

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treatment of Asthma?Which medications in the drug class Long-acting beta2 agonists are used in the treatment of Asthma?Which medications in the drug class Beta2-Agonist/Corticosteroid Combinations are used in the treatment of Asthma?Which medications in the drug class Nonselective Phosphodiesterase Enzyme Inhibitors are used in the treatment of Asthma?Which medications in the drug class Mast cell stabilizers are used in the treatment of Asthma?Which medications in the drug class Corticosteroid, Inhalant are used in the treatment of Asthma?Which medications in the drug class Leukotriene Receptor Antagonist are used in the treatment of Asthma?Which medications in the drug class Monoclonal Antibodies, Anti-asthmatics are used in the treatment of Asthma?

References

Author

Michael J Morris, MD, FACP, FCCP, Clinical Faculty, Pulmonary Disease/Critical Care Service, Department of Medicine, Brooke Army Medical Center; Assistant Dean for Research, SAUSHEC, Brooke Army Medical Center; Clinical Professor, University of Texas School of Medicine at San Antonio; Professor, Uniformed Services University of the Health Sciences

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Janssen Pharmaceuticals; Glaxo Smith Kline.

Coauthor(s)

Daniel J Pearson, MD, Chief of Pulmonary Medicine, Wright-Patterson Medical Center

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Regeneron; Sanofi Genzyme.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine