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.

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

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. 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. 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 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-interleukin (IL)–5 antibodies, and anti–IL-4/IL-13 antibodies. Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium (Atrovent). 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.

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. 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 bronchospasm. 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.

Anatomy The airways of the lungs consist of the cartilaginous bronchi, membranous bronchi, and gas-exchanging bronchi termed the respiratory bronchioles and alveolar ducts. While the first 2 types function mostly as anatomic dead space, they also contribute to airway resistance. The smallest non-gas-exchanging airways, the terminal bronchioles, are approximately 0.5 mm in diameter; airways are considered small if they are less than 2 mm in diameter. [4] Airway structure consists of the following:

• Mucosa, which is composed of epithelial cells that are capable of specialized mucous production and a transport apparatus

• Basement membrane

• A smooth-muscle matrix extending to the alveolar entrances

• Predominantly fibrocartilaginous or fibroelastic-supporting connective tissue.

Cellular elements include mast cells, which are involved in the complex control of releasing histamine and other mediators. Basophils, eosinophils, neutrophils, and macrophages also are responsible for extensive mediator release in the early and late stages of bronchial asthma. Stretch and irritant receptors reside in the airways, as do cholinergic motor nerves, which innervate the smooth muscle and glandular units. In bronchial asthma, smooth muscle contraction in an airway is greater than that expected for its size if it were functioning normally, and this contraction varies in its distribution.

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.

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

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]

Epidemiology Asthma affects 5-10% of the population or an estimated 23.4 million persons, including 7 million children. [15] The overall prevalence rate of exercise-induced bronchospasm is 3-10% of the general population if persons who do not have asthma or allergy are excluded, but the rate increases to 12-15% of the general population if patients with underlying asthma are included. Asthma affects an estimated 300 million individuals worldwide. Annually, the World Health Organization (WHO) has estimated that 15 million disability-adjusted life-years are lost and 250,000 asthma deaths are reported worldwide. [31] In the United States, asthma prevalence, especially morbidity and mortality, is higher in blacks than in whites. Although genetic factors are of major importance in determining a predisposition to the development of asthma, environmental factors play a greater role than racial factors in asthma onset. A national concern is that some of the increased morbidity is due to differences in asthma treatment afforded certain minority groups. Larger asthma-associated lung function deficits are reported in Hispanics, especially females. [32] Asthma is common in industrialized nations such as Canada, England, Australia, Germany, and New Zealand, where much of the asthma data have been collected. The prevalence rate of severe asthma in industrialized countries ranges from 2-10%. Trends suggest an increase in both the prevalence and morbidity of asthma, especially in children younger than 6 years. Factors that have been implicated include urbanization, air pollution, passive smoking, and change in exposure to environmental allergens. Asthma predominantly occurs in boys in childhood, with a male-to-female ratio of 2:1 until puberty, when the male-to-female ratio becomes 1:1. Asthma prevalence is greater in females after puberty, and the majority of adult-onset cases diagnosed in persons older than 40 years occur in females. Boys are more likely than girls to experience a decrease in symptoms by late adolescence. Asthma prevalence is increased in very young persons and very old persons because of airway responsiveness and lower levels of lung function. [33] Two thirds of all asthma cases are diagnosed before the patient is aged 18 years. Approximately half of all children diagnosed with asthma have a decrease or disappearance of symptoms by early adulthood. [34]

Prognosis International asthma mortality is reported as high as 0.86 deaths per 100,000 persons in some countries. US asthma mortality rates in 2009 were reported at 1 death per 100,000 persons. Mortality is primarily related to lung function, with an 8-fold increase in patients in the lowest quartile, but mortality has also been linked with asthma management failure, especially in young persons. Other factors that impact mortality include age older than 40 years, cigarette smoking more than 20 pack-years, blood eosinophilia, forced expiratory volume in one second (FEV1) of 40-69% predicted, and greater reversibility. [35] The estimate of lost work and school time from asthma is approximately 100 million days of restricted activity. Approximately 500,000 annual hospitalizations (40.6% in individuals aged 18 y or younger) are due to asthma. Each year, an estimated 1.7 million people (47.8% of them aged 18 years or younger) require treatment in an emergency department. [36] For 2010, the annual expenditures for health and lost productivity due to asthma was projected to be $20.7 billion. [37] Nearly one half of children diagnosed with asthma will have a decrease in symptoms and require less treatment by late adolescence or early adulthood. In a study of 900 children with asthma, 6% required no treatment after 1 year, and 39% only required intermittent treatment. Patients with poorly controlled asthma develop long-term changes over time (i.e., with airway remodeling). This can lead to chronic symptoms and a significant irreversible component to their disease. Many patients who develop asthma at an older age also tend to have chronic symptoms.

Patient Education The need for patient education about asthma and the establishment of a partnership between patient and clinician in the management of the disease was emphasized by EPR-3. [1] The key points of education include the following:

• Patient education should be integrated into every aspect of asthma care

• All members of the healthcare team, including nurses, pharmacists, and respiratory therapists, should provide education.

• Clinicians should teach patients asthma self-management based on basic asthma facts, self-monitoring techniques, the role of medications, inhaler use, and environmental control measures. [38, 39, 40]

• Treatment goals should be developed for the patient and family.

• A written, individualized, daily self-management plan should be developed.

• Several well-validated asthma action plans are now available and are key in the management of asthma and should therefore be reviewed: ACT (Asthma Control Test), ATAQ (Asthma Therapy Assessment Questionnaire), and ACQ (Asthma Control Questionnaire). [41]

School-based asthma education programs improved knowledge of asthma, self-efficacy, and self-management behaviors in children aged 4-17 years, according to a systematic literature review by Coffman et al, but the programs had less effect on quality of life, days of symptoms, nights with symptoms, and school absences. [42]

Clinical Presentation

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.

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.

Nonpulmonary Manifestations Signs of atopy or allergic rhinitis, such as conjunctival congestion and inflammation, ocular shiners, a transverse crease on the nose due to constant rubbing associated with allergic rhinitis, and pale violaceous nasal mucosa due to allergic rhinitis, may be present in the absence of an acute episode, such as during an outpatient visit between acute episodes. Turbinates may be erythematous or boggy. Polyps may be present. Skin examination may reveal atopic dermatitis, eczema, or other manifestations of allergic skin conditions. Clubbing of the fingers is not a feature of asthma and indicates a need for more extensive evaluation and workup to exclude other conditions, such as cystic fibrosis.

Nocturnal Symptoms A large percentage of patients with asthma experience nocturnal symptoms once or twice a month. Some patients only experience symptoms at night and have normal pulmonary function in the daytime. This is due, in part, to the exaggerated response to the normal circadian variation in airflow. Children with nocturnal asthma tend to cough after midnight and during the early hours of morning. Bronchoconstriction is highest between the hours of 4:00 am and 6:00 am (the highest morbidity and mortality from asthma is observed during this time). These patients may have a more significant decrease in cortisol levels or increased vagal tone at night. Studies also show an increase in inflammation compared with controls and with patients with daytime asthma.

Staging Asthma severity is defined as "the intensity of the disease process" prior to initiating therapy and helps in determining the initiation of therapy in a patient who is not on any controller medications. [1] The severity of asthma is classified as the following:

• Intermittent,

• Mild persistent

• Moderate persistent

• Severe persistent

Patients with asthma of any level of severity may have mild, moderate, or severe exacerbations. Some patients with intermittent asthma have severe and life-threatening exacerbations separated by episodes with almost normal lung function and minimal symptoms; however, they are likely to have other evidence of increased bronchial hyperresponsiveness (BHR; exercise or challenge testing) due to ongoing inflammation. An important point to remember is that the presence of one severe feature is sufficient to diagnose severe persistent asthma. Also, the characteristics in this classification system are general and may overlap because asthma severity varies widely. A patient’s classification may change over time.

Differential Diagnoses

Diagnostic Considerations

Vocal cord dysfunction or inducible laryngeal obstruction (ILO)

Vocal cord dysfunction may exist alone or with asthma, it is caused by paradoxical adduction of the vocal cords during inspiration, and may disappear with panting, speech, or laughing. [45] Patients with chronic symptoms suggestive of asthma, normal spirometry, poor response to asthma medications, and frequent evaluations should be evaluated for vocal cord dysfunction. [46] Usually, the diagnosis can be made using direct laryngoscopy, but only during symptomatic periods or after exercise. The presence of flattening of the inspiratory limb of the flow-volume loop may also suggest vocal cord dysfunction, but this is only seen in 28% of patients at baseline. [47]

Tracheal and bronchial lesions

A variety of airway tumors are reported to manifest with symptoms similar to those of asthma. These tumors include endobronchial carcinoid and mucoepidermoid tumors, as shown in the images below. In one case, a 14-year-old boy with hyperlucency in the left lung was ultimately found to have a bronchial carcinoid in the left mainstem bronchus. [48]

Asthma. High-resolution CT scan of the thorax obtained during inspiration in a patient with recurrent left lower lobe pneumonia shows a bronchial mucoepidermoid carcinoma (arrow).

Asthma. High-resolution CT scan of the thorax obtained during expiration in a patient with recurrent left lower lobe pneumonia shows a bronchial mucoepidermoid carcinoma. Note the normal increase in right lung attenuation during expiration (right arrow). The left lung remains lucent, especially the upper lobe, secondary to bronchial obstruction with airtrapping (left upper arrow). The vasculature on the left is diminutive, secondary to reflex vasoconstriction. Left pleural thickening and abnormal linear opacities are noted in the left lower lobe; these are the result of prior episodes of postobstructive pneumonia (left lower arrow) .

Other tracheal lesions can include bronchocentric granulomatosis, subglottic stenosis, subglottic web, tracheal hamartoma, bronchogenic cysts, leiomyoma, and tracheobronchopathia osteoplastica. All these types of tracheal lesions have been reported with symptoms similar to asthma.

Foreign bodies

Foreign body aspiration may cause not only localized wheezing but also generalized wheezing. Wheezing occurs in toddlers as well as in adults. As described in one patient, foreign body aspiration may necessitate bronchoscopic retrieval before the patient even recalls the inciting event, and as many as 25% of patients may never recall the event. [49] Furthermore, aspirated foreign bodies may be radiolucent and therefore not be visible on a chest radiograph. Radiography may show unilateral hyperinflation (from air trapping), infiltrate (from occlusion of a bronchus), or may be normal.

Pulmonary migraine

Pulmonary migraine consists of combined recurrent asthma; cough with thick mucoid sputum; lower back pain radiating to the shoulder; subtotal or total atelectasis of a segment or lobe; and, occasionally, nausea with vomiting. [50] The symptoms are often accompanied closely in time by focal headache. Spastic narrowing of the bronchi is postulated—along with retained mucous secretions, smooth muscle hypertrophy, and thickened bronchial walls—to cause expiratory collapse of selected airways. Cerebral and abdominal vascular migraine episodes are believed to accompany pulmonary migraine.

Congestive heart failure

Congestive heart failure causes engorged pulmonary vessels and interstitial pulmonary edema, which reduce lung compliance and contribute to the sensation of dyspnea and wheezing. Cardiac asthma is characterized by wheezing secondary to bronchospasm in congestive heart failure, and it is related to paroxysmal nocturnal dyspnea and nocturnal coughing. [51]

Diffuse panbronchiolitis

Diffuse panbronchiolitis is prevalent in Japan and the Far East, and it may mimic bronchial asthma with wheezing, coughing, dyspnea on exertion, and sinusitis. [52] High-resolution CT (HRCT) findings include centrilobular nodules and linear markings that usually are more profuse than the multifocal bronchiolar impaction sometimes observed with asthma.

Aortic arch anomalies

Aortic arch anomalies may occur later in adulthood. In one case, the anomalies, which simulated exercise-induced asthma, were noticed first in a young woman only after a vigorous exercise program. [53] On testing, the flow-volume display of this patient suggested an intrathoracic obstruction. The patient had a right aortic arch with ligamentum arteriosum that extended anterior to the trachea. This condition caused constriction when increased pulmonary blood flow, oxygen demand, and tracheal airflow and decreased intratracheal pressure from downstream turbulence distal to the tracheal ring occurred with exercise; combined, these factors produced wheezing and dyspnea.

Sinus disease

Sinus disease, especially in children, is associated with bronchial asthma and wheezing. Although the association is not strong in patients with CT evidence of mild sinus mucosal thickening, a scoring system developed by Newman et al showed that extensive sinus disease was correlated with a substantially higher extent of wheezing than that in patients with only mild thickening. Of 104 adults, 39% had extensive disease, as visualized on CT scans, which was correlated with asthma and peripheral eosinophilia. [54]

Gastroesophageal reflux

Cough, recurrent bronchitis, pneumonia, wheezing, and asthma are associated with gastroesophageal reflux (GER). [55, 56] The incidence of GER in patients with asthma ranges from 38% in patients with only asthma symptoms to 48% in patients with recurrent pneumonia. Scintigraphic studies performed after technetium-99m sulfur-colloid ingestion have shown radionuclide activity in the lungs the next day, but no causal relationship between reflux and asthma has been established. Nevertheless, evidence suggests that increased pulmonary resistance occurs with symptoms of reflux during acid provocation testing; as some have suggested, the changes may be sufficiently significant to produce clinically evident bronchoconstriction. [55]

Other conditions and factors

Other extrinsic conditions, such as lymphadenopathy from sarcoidosis or Hodgkin lymphoma of the upper mediastinum, can contribute to asthma. In addition, aspirin or NSAID hypersensitivity and reactive airways dysfunction syndrome may be mistaken for asthma. Misdiagnoses as refractory bronchial asthma has resulted in inappropriate long-term treatment with corticosteroids.

A significant history of smoking greater than 20-pack years should make the diagnosis of chronic obstructive pulmonary disease (COPD) a stronger consideration than asthma.

Consideration for alternative diagnoses should be given in all patients, and in particular in those older than 30 years and younger than 2 years with new symptoms suggestive of asthma. An absence of airway obstruction on initial spirometry findings should prompt consideration for alternative diagnoses and additional testing.

Differential Diagnoses

• Allergic and Environmental Asthma

• Alpha1-Antitrypsin (AAT) Deficiency

• Aspergillosis

• Bronchiectasis

• Bronchiolitis

• Chronic Obstructive Pulmonary Disease (COPD)

• Chronic Sinusitis

• Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome)

• Cystic Fibrosis

• Foreign Body Aspiration

• Gastroesophageal Reflux Disease

• Heart Failure

• Pediatric Airway Foreign Body

• Pediatric Tracheomalacia

• Pulmonary Embolism (PE)

• Pulmonary Eosinophilia

• Sarcoidosis

• Upper Respiratory Tract Infection

• Vocal Cord Dysfunction

Workup

Approach Considerations Laboratory assessments and studies are not routinely indicated for the diagnosis of asthma, but they may be used to exclude other diagnoses. Eosinophilia and elevated serum IgE levels may help guide therapy in some cases. Arterial blood gases and pulse oximetry are valuable for assessing severity of exacerbations and following response to treatment.

Blood and Sputum Eosinophils Blood eosinophilia greater than 4% or 300-400/μL supports the diagnosis of asthma, but an absence of this finding is not exclusionary. Eosinophil counts greater than 8% may be observed in patients with concomitant atopic dermatitis. This finding should prompt an evaluation for allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, or eosinophilic pneumonia. In assessing asthma control, the British Thoracic Society recommends using sputum eosinophilia determinations to guide therapy. An improvement in asthma control, a decrease in hospitalizations, and a decrease in exacerbations were noted in those patients in whom sputum-guided therapy was used. [57] A controlled prospective study has shown that adjusting inhaled corticosteroid (ICS) treatment to control sputum eosinophilia—as opposed to controlling symptoms, short-acting beta-agonist (SABA) use, nocturnal awakenings, and pulmonary function—significantly reduced both the rate of asthma exacerbations and the cumulative dose of inhaled corticosteroids. [58] In 2015, mepolizumab (anti-IL-5 antibody) was FDA approved for the treatment of severe asthmatics with an eosinophilic phenotype who have a baseline eosinophil count of 150 cells/μL or an eosinophil count of 300 cells/μL within the past 12 months.

Serum Immunoglobulin E Total serum immunoglobulin E levels greater than 100 IU are frequently observed in patients experiencing allergic reactions, but this finding is not specific for asthma and may be observed in patients with other conditions (eg, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome). A normal total serum immunoglobulin E level does not exclude the diagnosis of asthma. Elevated serum IgE levels are required for chronic asthma patients to be treated with omalizumab (Xolair).

Arterial Blood Gas Arterial blood gas (ABG) measurement provides important information in acute asthma. This test may reveal dangerous levels of hypoxemia or hypercarbia secondary to hypoventilation and, hence, respiratory acidosis. However, the typical finding in the early stages of an acute episode is respiratory alkalosis. Because of the accuracy and utility of pulse oximetry, only patients whose oxygenation is not restored to over 90% with oxygen therapy require an ABG. The clinical picture usually obviates ABGs for most ED patients with acute asthma. Venous levels of PCO2 have been tested as a substitute for arterial measurements, and a venous PCO2 greater than 45 mm may serve as a screening test but cannot substitute for the ABG evaluation of respiratory function. Hypercarbia is of concern in that it reflects inadequate ventilation and may indicate the need for mechanical ventilation if the PCO2 is elevated as a result of patient exhaustion; however, the decision to proceed with endotracheal intubation and mechanical ventilation is a clinical assessment.

Periostin Periostin is a novel biomarker that is currently under investigation as a diagnostic and treatment adjunct. [59] Evidence suggests that periostin is a marker of Th2/eosinophilic inflammation and airway remodeling that occurs with asthma. While there are no therapies currently approved based on periostin testing, several investigational medications are being studied with periostin as a predictor of medication effect. In one phase IIb study, periostin was a good predictor of response to lebrikizumab in patients not controlled on inhaled corticosteroids, with an increase in FEV1 of 8.2% for high periostin levels compared with placebo with an increase in FEV1 of 1.6% for low periostin levels. Currently, there is no clinical role for routine periostin testing.

Pulse Oximetry Assessment Pulse oximetry measurement is desirable in all patients with acute asthma to exclude hypoxemia. The hypoxemia of uncomplicated acute asthma is readily reversible by oxygen administration. Oxygenation decreases 4-10 mm Hg with beta-agonist inhalant therapy due to increases in V/Q mismatch. Therefore, all patients with acute asthma should have oxygen saturation measured by pulse oximetry, or they simply should be placed on oxygen therapy. In children, pulse oximetry is often used to grade severity of acute asthma. Oxygen saturation of 97% or above constitutes mild asthma, 92-97% constitutes moderate asthma, and less than 92% signifies severe asthma. Although an isolated pulse oximetry reading at triage is not predictive in most cases (with the notable exception of severe attacks that usually are self-evident on visual inspection), serial monitoring of pulse oximetry status can provide more subtle evidence for or against the need for hospital admission.

Chest Radiography The chest radiograph remains the initial imaging evaluation in most individuals with symptoms of asthma. The value of chest radiography is in revealing complications or alternative causes of wheezing and the minor importance of wheezing in the diagnosis of asthma and its exacerbations. Chest radiography usually is more useful in the initial diagnosis of bronchial asthma than in the detection of exacerbations, although it is valuable in excluding complications such as pneumonia and asthma mimics, even during exacerbations. In most patients with asthma, chest radiography findings are normal or may indicate hyperinflation. Findings may help rule out other pulmonary diseases such as allergic bronchopulmonary aspergillosis or sarcoidosis, which can manifest with symptoms of reactive airway disease. Chest radiography should be considered in all patients being evaluated for asthma to exclude other diagnoses. Because pneumonia is one of the most common complications of asthma, chest radiography is indicated in patients with fever to rule out pneumonia. With new-onset asthma and eosinophilia, a radiograph may be useful in identifying prominent streaky infiltrates persisting less than 1 month, indicating Loeffler pneumonia. The infiltrates of Loeffler pneumonia are peripheral with central sparing of the lung fields. These findings have been described as the radiographic negative of pulmonary edema. Patients with pleuritic chest pain or those with an acute asthmatic episode that responds poorly to therapy, require a chest film to exclude pneumothorax or pneumomediastinum, particularly if subcutaneous emphysema is present.

Chest CT Scanning High-resolution CT (HRCT) is a second-line examination. It is useful in patients with chronic or recurring symptoms and in those with possible complications such as allergic bronchopulmonary aspergillosis and bronchiectasis. [60] In the last decade, the role of CT in the imaging of airway disease increased after the development of lung HRCT. The technical progress of thin-section acquisition, high-spatial-frequency data reconstruction (ie, bone algorithm technique), and targeted reconstruction has allowed the visualization of finer details on HRCT scans; these details include airtrapping, measurable bronchial wall thickening, atelectasis, centrilobular nodules due to mucous plugging, and acinar nodules due to low-grade inflammatory changes. [61] HRCT findings in bronchial asthma include the following:

• Bronchial wall thickening

• Bronchial dilatation

• Cylindrical and varicose bronchiectasis

• Reduced airway luminal area

• Mucoid impaction of the bronchi

• Centrilobular opacities, or bronchiolar impaction

• Linear opacities

• Airtrapping, as demonstrated or exacerbated with expiration

• Mosaic lung attenuation, or focal and regional areas of decreased perfusions

Note the images below.

High-resolution CT scan of the thorax obtained during inspiration demonstrates airtrapping in a patient with asthma. Inspiratory findings are normal.

High-resolution CT scan of the thorax obtained during expiration demonstrates a mosaic pattern of lung attenuation in a patient with asthma. Lucent areas (arrows) represent areas of airtrapping (same patient as in the previous image)

Electrocardiography Patients with asthma who are severely symptomatic should undergo ECG monitoring, as with any seriously ill patient. Sinus tachycardia and ECG evidence of right heart strain are common in patients with acute asthma. The use of beta2 -agonist therapy will cause a paradoxical decrease in heart rate as pulmonary function improves and symptoms are relieved. Supraventricular tachycardia raises the consideration of theophylline toxicity. Arrhythmias, other than supraventricular tachycardia, are rare.

MRI Aside from cardiovascular applications, MRI of the thorax is used primarily as a problem-solving modality in the workup of patients with lung, mediastinal, or pleural lesions. MRI is a useful alternative to CT pulmonary angiography in evaluating possible pulmonary embolic disease in patients in whom iodinated contrast agent cannot be administered and when the avoidance of ionizing radiation is preferred. In bronchial asthma, the most promising work appears to involve the use of special paramagnetic gases, which amplify the low signal-to-noise ratio of conventional spin-echo and gradient-echo techniques by several thousand times. The use of such gases offsets the disadvantages of the large magnetic susceptibility states with consequent shortened T2 signals induced by the air-alveolar interfaces.

Nuclear Imaging Nuclear medicine technology has been used in the study of aerosol and particulate distribution in the airways. Technetium-99m DTPA radioaerosol lung scintigraphy is a classic technique that shows the extent of major airway distribution, peripheral distribution (depending on particle size), and absorption in the oronasal air passages. Technetium-99m radioaerosol has been used to show improved peripheral lung distribution of corticosteroid both in normal persons and in persons treating their asthma using dry-powder inhalers as opposed to pressurized metered-dose inhalers (pMDIs) with a spacer device. Ventilation scanning with Technetium-99m DTPA has also been used as an indicator of ventilation defects in asthmatic children.

Allergy Skin Testing Allergy skin testing is a useful adjunct in individuals with atopy. Results help guide indoor allergen mitigation or help diagnose allergic rhinitis symptoms. The allergens that most commonly cause asthma are aeroallergens such as house dust mites, animal danders, pollens, and mold spores. Two methods are available to test for allergic sensitivity to specific allergens in the environment: allergy skin tests and blood radioallergosorbent tests (RASTs). Allergy immunotherapy may be beneficial in controlling allergic rhinitis and asthma symptoms for some patients.

Pulmonary Function Testing Spirometry assessments should be obtained as the primary test to establish the asthma diagnosis. Spirometry should be performed prior to initiating treatment in order to establish the presence and determine the severity of baseline airway obstruction. [62] Optimally, the initial spirometry should also include measurements before and after inhalation of a short-acting bronchodilator in all patients in whom the diagnosis of asthma is considered. Spirometry measures the forced vital capacity (FVC), the maximal amount of air expired from the point of maximal inhalation, and the forced expiratory volume in one second (FEV1). A reduced ratio of FEV1 to FVC, when compared with predicted values, demonstrates the presence of airway obstruction. Reversibility is demonstrated by an increase of 12% and 200 mL after the administration of a short-acting bronchodilator. As a preliminary assessment for exercise-induced asthma (EIA), or exercise-induced bronchospasm (EIB), perform spirometry in all patients with exercise symptoms to determine if any baseline abnormalities (ie, the presence of obstructive or restrictive indices) are present. The assessment and diagnosis of asthma cannot be based on spirometry findings alone because many other diseases are associated with obstructive spirometry indices. Single-breath counting (SBC) is a novel technique for measuring pulmonary function in children. SBC is the measurement of how far an individual can count using a normal speaking voice after one maximal effort inhalation. The count is in cadence to a metronome that is set at 2 beats per second. A study by Ali et al determined that SBC correlates well with standard measures of pulmonary function. [63] However, further studies are needed to establish values and to evaluate the use in an ED population of patients with acute asthma exacerbation.

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]

Peak Flow Monitoring Peak expiratory flow (PEF) measurement is common in the ED because it is inexpensive and portable. Serial measurements document response to therapy and, along with other parameters, are helpful in determining whether to admit the patient to the hospital or discharge from the ED. A limitation of PEF is that it is dependent on effort by the patient. FEV1 is also effort dependent but less so than PEF. FEV1 is not often used in the ED except in research settings. PEF in the ED can be compared with asymptomatic (baseline) PEF, if known. Unfortunately, patients often do not know their asymptomatic PEF. Moreover, the reference group for the ideal PEF percent predicted (based on age, sex, height) may not be accurate for the patient population seen in many inner-city EDs, since most equations are based on white populations.

Impulse Oscillometry Impulse oscillometry (IOS) is gaining attention for the evaluation of obstructive lung disease, including asthma. IOS uses a speaker to produce pressure oscillations within the airway, resulting in measurement of pressure changes and flows with calculation of resistance, reactance, and resonance. Different frequencies are used to assess large and small airways, which is helpful to determine where the primary obstruction is occurring. For example, a patient with asthma would demonstrate increased resistance at 5 Hz (R5, distal airways) with a normal resistance at 20 Hz (R20, central airways). The primary benefit of IOS is the effort-independent nature of the test, such that small children and frail adults can easily perform the test. Therefore, in patients unable to perform spirometry or with normal spirometry but symptoms suggestive of asthma, IOS could be used to determine if there is increased airway resistance or a bronchodilator response compatible with bronchial hyperreactivity. IOS is also very quickly obtained, but provides no information on lung volumes or oxygen diffusion capacity. Currently, routine use of IOS is limited by a lack of universally accepted reference values across all patient populations.

Exhaled Nitric Oxide Exhaled nitric oxide analysis has been shown to predict airway inflammation and asthma control; however, it is technically more complex and not routinely used in the monitoring of patients with asthma. A prospective, controlled study has shown that when inhaled corticosteroid asthma treatment was adjusted to control the fraction of exhaled nitric oxide, as opposed to controlling the standard indices of asthma, the cumulative dose of ICS was reduced, with no worsening of the frequency of asthma exacerbations. [66]

Sinus CT Scanning Sinus CT scanning may be useful to help exclude acute or chronic sinusitis as a contributing factor. In patients with chronic sinus symptoms, CT scanning of the sinuses can also help rule out chronic sinus disease. Conventional wisdom regarding the sinus radiographic evaluation of chronic coughing and asthma suggests that a workup for chronic coughing should be performed first, as outlined in a Finnish study of hospital admissions for acute asthma. Admission chest radiographs showed abnormalities in 50% of the patients and resulted in treatment changes in 5%. The numbers were more remarkable when a paranasal sinus series was obtained in unselected patients who presented primarily because of asthma. A sinus abnormality of any kind was found in 85% of patients; maxillary sinus abnormalities occurred alone in 63%. In 29% of patients with a sinus abnormality, treatment was immediately altered. All abnormalities were identified on the Waters view alone, which is 6 times more useful than chest radiography in directing the treatment of acute asthma. [67, 68]

24-Hour pH Monitoring A 24-hour pH probe can be used to help diagnose gastroesophageal reflux disease (GERD) if a patient’s condition is refractory to asthma therapy. Empirical medical therapy is often tried without performing diagnostic tests for GERD, especially if a patient has symptoms of GERD. In cases of GERD, a prolonged trial of therapy may be necessary. The median time to improvement of GERD-induced cough has been reported as 3 months. [69] A 2012 study of severe asthmatics demonstrated that GERD was a significant component in these patients. [70]

Histologic Findings Asthma is an inflammatory disease characterized by the recruitment of inflammatory cells, vascular congestion, increased vascular permeability, increased tissue volume, and the presence of an exudate. Eosinophilic infiltration, a universal finding, is considered a major marker of the inflammatory activity of the disease. Histologic evaluations of the airways in a typical patient reveal infiltration with inflammatory cells, narrowing of airway lumina, bronchial and bronchiolar epithelial denudation, and mucus plugs. Additionally, a patient with severe asthma may have a markedly thickened basement membrane and airway remodeling in the form of subepithelial fibrosis and smooth muscle hypertrophy or hyperplasia.

Treatment & Management

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. 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. 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.

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.

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.

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 (FEV 1) 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]

Bronchial Thermoplasty Bronchial thermoplasty (BT) is a novel intervention for asthma in which controlled thermal energy is delivered to the airway wall during a series of bronchoscopy procedures. A group of patients (AIR2 Trial Study Group) with severe asthma who remained symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta2 agonists underwent BT and showed superior improvement from baseline in their score on the Asthma Quality of Life Questionnaire (AQLQ) (BT, 1.35±1.10; sham, 1.16±1.23). Changes in AQLQ of 0.5 or greater were seen in 79% of BT and in 64% of sham subjects. Although the hospitalization rate was 6% higher among BT subjects during the treatment period (up to 6 wk after BT), in the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department visits, and days missed from work/school compared with the sham group. [93] Further results from the AIR2 study showed lasting efficacy at 5 years, as well as a reduction in maintenance treatment and healthcare utilization. The study also highlights the possibility that more patients may benefit from this treatment. [94] Wechsler and colleagues examined the long-term safety and effectiveness of bronchial thermoplasty in 162 patients with severe persistent asthma from the Asthma Intervention Research 2 (AIR2) trial, which showed a 32% reduction in severe asthma exacerbations, an 84% reduction in respiratory symptom-related emergency department visits, a 73% reduction in hospitalizations for respiratory symptoms, and a 66% reduction in time lost from work/school/other daily activities because of asthma symptoms. [95, 96]

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.

Asthma in Pregnancy Asthma complicates 4-8% of pregnancies. Mild and well-controlled moderate asthma can be associated with excellent maternal and perinatal pregnancy outcomes. Severe and poorly controlled asthma may be associated with increased prematurity and other perinatal complications, to include maternal morbidity and mortality. Optimal management of asthma during pregnancy includes objective monitoring of lung function, avoiding or controlling asthma triggers, patient education, and individualized pharmacologic therapy. Inhaled corticosteroids are the preferred medication for all levels of persistent asthma during pregnancy. For pregnant women with asthma, it is safer to be treated with asthma medications than to have asthma symptoms and exacerbations. The ultimate goal of asthma therapy is to maintain adequate oxygenation of the fetus by prevention of hypoxic episodes in the mother. With the exception of alpha-adrenergic compounds other than pseudoephedrine and some antihistamines, most drugs used to treat asthma and allergic rhinitis have not been shown to increase any risk to the mother or fetus. The National Institute of Health stated that albuterol (Proventil HFA), beclomethasone (QVAR), budesonide (Pulmicort Flexhaler or Respules), prednisone (Deltasone, Orasone), and theophylline, when clinically indicated, are considered appropriate for the treatment of asthma in pregnancy. The American College of Obstetrics and Gynecology issued updated clinical guidelines for 2008. [53] Poorly controlled asthma can result in low birth weight, increased prematurity, and increased perinatal mortality.

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] Aggressive antireflux therapy may improve asthma symptoms and pulmonary function in selected patients. Treatment with proton pump inhibitors, antacids, or H2 blockers may improve asthma symptoms or unexplained chronic cough. The treatment of asthma with agents such as theophylline may lower esophageal sphincter tone and induce GERD symptoms. Some people with asthma have significant gastroesophageal reflux without esophageal symptoms.

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]

Nocturnal Asthma Nocturnal asthma is a significant clinical problem that should be addressed aggressively. Peak-flow meters should be used to allow objective evaluation of symptoms and interventions. Sleep apnea, symptomatic GERD, and sinusitis should be controlled when present. Medications should be appropriately timed, and consideration should be given to the use of a long-acting inhaled or oral beta2 agonist and a leukotriene modifier with inhaled corticosteroids. A once-daily sustained-release theophylline preparation and changing the timing of oral corticosteroids to midafternoon can be also be used.

Long-Term Monitoring For all patients with asthma, monitoring should be performed on a continual basis based on the following parameters, which helps in the overall management of the disease:

• Regarding monitoring of asthma signs and symptoms, patients should be taught to recognize inadequate asthma control, and providers should assess control at each visit.

• To monitor pulmonary function, regularly perform spirometry and peak-flow monitoring.

• For quality of life and functional status, inquire about missed work or school days, reduction in activities, sleep disturbances, or change in caregiver activities.

• To monitor the history of asthma exacerbations, determine whether patients are monitoring themselves to detect asthma exacerbations and if these exacerbations are self-treated or treated by health care providers.

• Regarding monitoring pharmacotherapy, ensure compliance with medications and usage of short-acting beta agonists.

• Monitor patient-provider communication and patient satisfaction

Functional Assessment of Airway Obstruction Perform a functional assessment of airway obstruction with a measurement of the FEV1 or peak expiratory flow (PEF) initially to assess the patient's response to treatment. PEF measurement is inexpensive and portable. Serial measurements document response to therapy and, along with other parameters, are helpful in the ED setting for determining whether to admit the patient to the hospital or discharge from the ED. A limitation of PEF is that it is dependent on effort by the patient. FEV1 is also effort dependent but less so than PEF. A study by van den Berge examined the increased interest in small airway disease and new insights that have been gained about the contribution of small airways to the clinical expression of asthma and COPD. New devices enable drugs to target the small airways and may have implications for treatment of patients with asthma, particularly those who do not respond to large-particle inhaled corticosteroids and patients with uncontrollable asthma. [104]

Perioperative Considerations Asthma-related complications associated with surgery include acute bronchoconstriction resulting from intubation, impaired cough, hypoxemia, hypercapnia, atelectasis, respiratory tract infection, and exposure to latex. The likelihood of these complications occurring depends on the severity of the underlying asthma, the type of surgery (thoracic and upper abdominal), and the type of anesthesia. [105] Patients with asthma should have an evaluation before surgery that includes a review of asthma symptoms, medication use (particularly oral systemic corticosteroids for longer than 2 wk in the past 6 mo), and measurement of pulmonary function. If possible, attempts should be made to improve lung function preoperatively to either predicted values or the personal best level. A short course of oral systemic corticosteroids may be necessary to optimize lung function. If evidence of airflow obstruction (< 80% of baseline values) is present, a brief course of corticosteroids is recommended. Patients who have received oral corticosteroids for an asthma exacerbation in the past 6 months should receive systemic corticosteroids (100 mg hydrocortisone IV q 8 h) in the perioperative period.

Approach to Level of Activity Activity is generally limited by patients' ability to exercise and their response to medications. No specific limitations are recommended for patients with asthma, although they should avoid exposure to agents that may exacerbate their disease. A significant number of patients with asthma also have exercise-induced bronchoconstriction, and baseline control of their disease should be adequate to prevent exertional symptoms. The ability of patients with exercise-induced bronchoconstriction to exercise is based on the level of exertion, degree of fitness, and environment in which they exercise. Many patients have fewer problems when exercising indoors or in a warm, humid environment than they do outdoors or in a cold, dry environment

Dietary Considerations Information from prospective cohort studies and population-based studies in the past several years suggests an association between asthma and obesity. Patients with an elevated body mass index have an increased risk for developing asthma. A prospective cohort study of almost 86,000 adult women in the Nurses' Health Study II observed for 5 years showed a linear relationship between body mass index and the risk of developing asthma. [10] The 2019 GINA guideline adds that obese patients with asthma have lower lung function and more comorbidities than asthma patients who are of normal weight. [106] Asthma is more difficult to control in obese patients, but weight loss of 5-10% can improve asthma control and quality of life. [107] No special diets are generally indicated. Food allergy as a trigger for asthma is uncommon. Unless compelling evidence for a specific allergy exists, milk products do not have to be avoided. Avoidance of foods is recommended after a double-blind food challenge that yields positive results. Sulfites have been implicated in some severe asthma exacerbations and should be avoided in sensitive individuals.

Consultations Refer any patient with moderate-to-severe persistent asthma that is difficult to control to a pulmonologist or allergist to ensure proper stepwise asthma management, or refer for further evaluation to help rule out other diagnoses such as VCD/ILO. Also, abnormalities found on chest radiography screening should prompt referral to a specialist for further evaluation. Refer patients to an allergist or immunologist for skin testing to guide indoor allergen mitigation efforts and consideration of immunotherapy to treat seasonal allergic rhinitis. Refer patients to a pulmonologist for evaluation of symptoms consistent with exercise-induced bronchoconstriction (EIB). These patients should undergo either exercise or bronchoprovocation testing to document evidence of airway hyperreactivity and response to exercise. Refer patients to an otolaryngologist for treatment of nasal obstruction from polyps, sinusitis, or allergic rhinitis or for the diagnosis of upper airway disorders.

Deterrence Control of factors contributing to asthma severity is an essential component in asthma treatment. Exposure to irritants or allergens has been shown to increase asthma symptoms and cause exacerbations. Clinicians should evaluate patients with persistent asthma for allergen exposures and sensitivity to seasonal allergens. Skin testing results should be used to assess sensitivity to perennial indoor allergens, and any positive results should be evaluated in the context of the patient's medical history. All patients with asthma should be advised to avoid exposure to allergens to which they are sensitive, especially in the setting of occupational asthma. Other factors may include the following:

• Environmental tobacco smoke

• Exertion during high levels of air pollution

• Use of beta blockers

• Avoidance of aspirin and other nonsteroidal anti-inflammatory drugs if the patient is sensitive

• Avoidance of sulfites or other food items/additives to which the patient may be sensitive

• Occupational exposures

Asthma Guidelines

Guidelines Summary The following organizations have issued guidelines for the management of asthma:

• National Asthma Education and Prevention Program (NAEPP) [1]

• Veteran’s Administration/Department of Defense (VA/DoD) [43]

• Global Initiative for Asthma (GINA) [106]

• Japanese Society of Allergology (JSA) [108]

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 FEV 1 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 FEV 1 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 FEV 1 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 FEV 1 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. [109] 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.

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

Asthma symptoms and severity. Recommended guidelines for determination of asthma severity based on clinical symptoms, exacerbations, and measurements of airway function. Adapted from Global Strategy for Asthma Management and Prevention: 2002 Workshop Report.

Stepwise approach to pharmacological management of asthma based on asthma severity. Adapted from Global Strategy for Asthma Management and Prevention: 2002 Workshop Report. 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), [110] 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) [111] 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 [109] :

• 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)

Japanese Society of Allergology Guidelines for adult asthma were published in October 2020 by the Japanese Society of Allergology (JSA). [108] Diagnosis The JSA recommends spirometry for assessing the extent of airflow limitation or airway reversibility. The JSA recommends daily measurement of peak expiratory flow for unstable asthma and patients lacking obvious dyspnea during attack. Although useful for diagnosing asthma, the JSA does not recommend assessing bronchial hyperresponsiveness in patients with low FEV1 (≤1 L) or low %FEV1 (≤50%) since excess airway narrowing may occur due to irritant inhalation. Treatment of long-term adult asthma The JSA recommends using a jet nebulizer for budesonide (BUD) inhalation suspension. The JSA recommends adding one or more agents other than inhaled corticosteroids (ICSs), as opposed to increasing the dose of an ICS, to control asthma. The JSA recommends long-acting β2-agonists (LABAs), leukotriene receptor antagonists (LTRAs), sustained-release theophylline, and long-acting muscarinic antagonists as add-on drugs. The JSA recommends that anti-immunoglobulin E antibodies and other biologics as well as oral steroids be reserved for very severe and persistent asthma related to allergic reactions. The JSA recommends inhaled β2-agonists, aminophylline, corticosteroids, adrenaline, oxygen therapy, and other approaches be used as needed during acute exacerbations. Treatment during pregnancy The JSA recommends ICSs as first-line treatment for long-term management of pregnant women with asthma. The JSA recommends a short-acting beta-agonist (SABA) as needed for pregnant women with mild intermittent asthma. The JSA recommends low-dose ICS; LTRA, controlled-release theophylline, and/or disodium cromoglycate (DSCG) as needed in pregnant women with mild persistent asthma. The JSA recommends low-dose ICS and LABA or moderate-dose ICS and LABA in combination with LTRA or controlled-release theophylline as needed in pregnant women with moderate persistent asthma. The JSA recommends high-dose ICS and LABA; oral steroids as needed for pregnant women with severe persistent asthma.

Exercise-Induced Asthma Guidelines In 2013, the American Thoracic Society released clinical guidelines for the management of exercise-induced bronchoconstriction (EIB), which included the following recommendations [112] :

• Administration of an inhaled SABA before exercise (strong recommendation); the SABA is typically administered 15 minutes before exercise

• A controller agent is added whenever SABA therapy is used daily or more frequently

• Interval or combination warm-up exercise before planned exercise (strong recommendation)

• Recommend against daily use of an inhaled long-acting beta2-agonist as single therapy (strong recommendation)

• For patients who continue to have symptoms despite using an inhaled SABA before exercise or who require an inhaled SABA daily or more frequently: (1) Daily ICS (strong recommendation), (2) Daily administration of an LTRA (strong recommendation), (3) Administration of a mast cell‒stabilizing agent before exercise (strong recommendation), and (4) Inhaled anticholinergic agent before exercise (weak recommendation)

• For patients with EIB and allergies who continue to have symptoms despite using an inhaled SABA before exercise or who require an inhaled SABA daily or more frequently consider administration of an antihistamine (weak recommendation)

• For exercise in cold weather, routine use of a device (eg, mask) that warms and humidifies the air during exercise (weak recommendation)

Asthma Medication

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 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 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. [113] 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. [114] 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. [115] 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. [116] 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, 117] 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.

Beta2-adrenergic agonist agents Class Summary Beta2 agonists relieve reversible bronchospasm by relaxing the smooth muscles of the bronchi. These agents act as bronchodilators and are used to treat bronchospasm in acute asthmatic episodes and to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. In December 2018, the US Food and Drug Administration (FDA) approved the ProAir Digihaler (albuterol), the first digital and mobile-connected inhaler. The built-in sensors detect when the device is used and measure the strength of the user’s inhalation. The inhaler sends the user’s data to its mobile app companion and their healthcare provider. Albuterol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA, ProAir RespiClick, ProAir Digihaler)

This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, metered-dose inhaler, oral solution). This is most commonly used in rescue therapy for acute asthmatic symptoms and is used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor down-regulation and receptor hyposensitivity. Levalbuterol (Xopenex, Xopenex HFA)

A nonracemic form of albuterol, levalbuterol (R isomer), is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation).

Anticholinergic Agents Class Summary The long-acting anticholinergic agent, tiotropium, may be considered for long-term maintenance therapy, but not for acute treatment of asthma exacerbations. Tiotropium (Spiriva HandiHaler, Spiriva Respimat)

Tiotropium is a long-acting antimuscarinic agent, often referred to as an anticholinergic. It inhibits M3-receptors at smooth muscle, leading to bronchodilation. It is indicated for long-term, once-daily, maintenance treatment of asthma in patients aged 6 years or older. Ipratropium (Atrovent HFA)

Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. It is approved for COPD, but off-label use for acute exacerbations of asthma in addition to beta2-agonist therapy has been described in the literature. It is a short-acting anticholinergic agent with an onset of 15 minutes.

Anticholinergic agent combinations Class Summary Combination agents with ipratropium and albuterol. A test spray of 3 sprays is recommended before using this combination for the first time and when the aerosol has not be used for more than 24 hours. Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Albuterol is beta-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility. Ipratropium and albuterol (Combivent Respimat)

Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Albuterol is beta-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.

Corticosteroid, oral Class Summary Oral steroids are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2 agonists has been associated with beta2 -receptor subsensitivity and down-regulation; these processes are reversed with corticosteroids. Prednisone (Deltasone, Rayos)

Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)

Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. Prednisolone (Pediapred, Millipred, Orapred ODT)

This glucosteroid occurs naturally and synthetically. It is used for both acute and chronic asthma. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Long-acting beta2 agonists Class Summary Long-acting bronchodilators are not used for the treatment of acute bronchospasm. In combination with corticosteroids, they are used for the preventive treatment of asthma symptoms. Salmeterol (Serevent Diskus)

Salmeterol can relieve bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis. The effect also may facilitate expectoration. Adverse effects are more likely when salmeterol is administered at high doses or more frequent doses than recommended. It is to be used with inhaled corticosteroids and not as monotherapy. Formoterol (Perforomist)

Formoterol is a long acting beta2 agonist. By relaxing the smooth muscles of bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, formoterol can relieve bronchospasms. The effects may also facilitate expectoration. It has been shown to improve symptoms and morning peak flows. Adverse effects are more likely when formoterol is administered at high doses or more frequent doses than recommended. To be used with inhaled corticosteroids and not as monothrapy.

Beta2-Agonist/Corticosteroid Combinations Class Summary These combinations may decrease asthma exacerbations when inhaled short-acting beta2 agonists and corticosteroids have failed. Budesonide/formoterol (Symbicort)

Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in the asthmatic response. Mometasone and formoterol (Dulera)

Combination corticosteroid and long-acting selective beta-2 agonist (LABA) metered-dose inhaler. Mometasone elicits local anti-inflammatory effects to respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation. Indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 3 strengths; each actuation delivers mometasone/formoterol 50 mcg/5 mcg, 100 mcg/5 mcg, or 200 mcg/5 mcg. Salmeterol/fluticasone inhaled (Advair Diskus, Advair HFA, AirDuo RespiClick)

Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, and can relieve bronchospasms. Its effects may also facilitate expectoration. Adverse effects are more likely to occur when the agent is administered at high or more frequent doses than recommended. Vilanterol/fluticasone furoate inhaled (Breo Ellipta)

Indicated for once-daily treatment of asthma for adults not adequately controlled on a long-term asthma control medication (eg, inhaled corticosteroid), or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting beta agonist (LABA). Use prescribed strength (25 mcg/100 mcg or 25 mcg/200 mcg per actuation) once daily via oral inhalation. Fluticasone furoate is a corticosteroid with anti-inflammatory activity. Vilanterol is a long-acting beta agonist (LABA) that stimulates intracellular adenyl cyclase (catalyzes the conversion of ATP to cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Nonselective Phosphodiesterase Enzyme Inhibitors Class Summary These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms. Theophylline (Theo-24, Theochron, Ellixophyllin)

Theophylline is available in short- and long-acting formulations. Because of the need to monitor the drug levels, this agent is used infrequently. The dose and frequency of administration depend on the particular product selected.

Mast cell stabilizers Class Summary These agents (cromolyn sodium) block early and late asthmatic responses, interfere with chloride channels, stabilize the mast cell membrane, and inhibit the activation and release of mediators from eosinophils and epithelial cells. They inhibit acute responses to cold air, exercise, and sulfur dioxide. Cromolyn sodium

Cromolyn sodium (oral inhalation) inhibits the release of histamine, leukotrienes, and other mediators from sensitized mast cells exposed to specific antigens. It has no intrinsic anti-inflammatory, antihistamine, or vasoconstrictive effects.

Corticosteroid, Inhalant Class Summary Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects. Ciclesonide (Alvesco)

Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 years and older. It is not indicated for relief of acute bronchospasm. Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation. Beclomethasone (QVAR Redihaler)

This agent inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. Fluticasone inhaled (Flovent Diskus, Flovent HFA, ArmonAir RespiClick, Arnuity Ellipta)

Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak HPA-axis inhibitory potency when applied topically. It is available as a metered-dose inhaler aerosolized product (HFA) or DPI (Diskus). Budesonide inhaled (Pulmicort, Pulmicort Flexhaler) Leukotriene Receptor Antagonist Class Summary Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration leads to the concept of modifying their action by using pharmacologic agents. Zafirlukast (Accolate)

Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors. Montelukast (Singulair)

Montelukast is the last agent introduced in its class. The advantages are that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

Monoclonal Antibodies, Anti-asthmatics Class Summary Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IgE on the surface of mast cells and basophils. It reduces the release of these mediators that promote an allergic response. Mepolizumab, reslizumab, and benralizumab inhibit IL-5 binding to eosinophils and result in reduced blood, tissue, and sputum eosinophil levels. Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. Omalizumab (Xolair)

Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on the surface of mast cells and basophils. It reduces mediator release, which promotes an allergic response. It is indicated for moderate-to-severe persistent asthma in patients aged 6 years or older who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids. Mepolizumab (Nucala)

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

Reslizumab is an IL-5 antagonist monoclonal antibody (IgG kappa). It is indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype. Benralizumab (Fasenra)

Benralizumab is a humanized monoclonal antibody (IgG1/kappa-class) selective for the IL-5 alpha subunit of basophils and eosinophils. It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype. Dupilumab (Dupixent)

Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This, in turn, reduces the cytokine-induced inflammatory response. It is indicated as an add-on maintenance treatment for moderate-to-severe asthma in patients aged 12 years or older with eosinophilic phenotype or oral corticosteroid–dependent asthma.