Approximately 25.7 million people in the United States have asthma, with a prevalence of 9.5% and 7.7% in children 0 to 17 years and adults 18+ years, respectively (Moorman et al., 2012). Asthma is more common in persons below 100% of the federal poverty rate and in persons living in the northeast United States (Moorman et al., 2012). Asthma prevalence is greater in blacks than in whites (11.2% vs. 7.7%), in boys than in girls (11.1% vs. 7.8%), and in women than in men (9.7% vs. 5.7%) (Moorman et al., 2012). In 2009, asthma accounted for 10.6 million office visits, 2.1 million emergency department visits, and 479,300 hospitalizations (Moorman et al., 2012). The cost of asthma in the United States is approximately $56 billion per year (Centers for Disease Control and Prevention [CDC], 2013b). The noneconomic costs of asthma are high. Nine persons with asthma die from asthma every day and nearly one in three adults and one in two children miss 1 day or more of work or school for asthma-related reasons (CDC, 2013b).
The current National Asthma Education and Prevention Program (NAEPP) guidelines for the diagnosis and management of asthma were released in 2007 (NAEPP, 2007). The guidelines, originally developed in 1997 by an expert panel commissioned by the NAEPP Coordinating Committee of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), were updated in 2002 and 2007. The 1993 Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention report, an international collaboration of the NHLBI and the World Health Organization, is updated annually (GINA, 2014).
CAUSES
Asthma is a heterogeneous chronic inflammatory medical condition of unknown etiology. The hygiene hypothesis theorizes that a lack of exposure to a variety of microbiological agents at a young age creates a predominant T helper cell type-2 (Th2) lymphocyte immune response that is associated with allergy (Brown et al., 2013). Some genetic associations have been identified. For example, although there is no single “asthma gene,” more than 100 single nucleotide polymorphisms (SNPs) of the gene that encodes the ADAM metallopeptidase domain 33 gene (ADAM33) have been identified. Smooth muscle, fibroblasts, and myofibroblasts express ADAM-related proteins with a variety of signaling, adhesion, and fusion functions that influence the epithelial-mesenchymal unit (EMTU). Additionally, more than 25 polymorphic genes expressed in the EMTU have been identified.
Common asthma phenotypes include allergic asthma, nonallergic asthma, late-onset asthma, asthma with fixed airflow limitation, and asthma with obesity. Symptom triggers include upper respiratory tract viral infections, allergens, exercise, changes in the weather, laughter, exposure to inhaled irritants (e.g., smoke, vehicle exhaust fumes, strong smells), gastroesophageal reflux disease (GERD), aspirin (in individuals sensitive to aspirin), stress, and exposure to sulfites. Hormonal changes during a woman’s menstrual cycle or during pregnancy may trigger or worsen asthma symptoms.
PATHOPHYSIOLOGY
Asthma is characterized by airway narrowing and airway hyperresponsiveness. The chronic airway inflammation and structural airway changes characteristic of asthma are the result of interactions between the activated EMTU and inflammatory mediators (Holgate, 2008). Key cellular mediators include chemokines, cysteinyl leukotrienes, cytokines, histamine, nitric oxide, and prostaglandins. Sources of these mediators include airway epithelial cells, mast cells, eosinophils, and T lymphocytes. In the presence of these cellular mediators, airway smooth muscle cells proliferate, hypertrophy, and express inflammatory proteins; endothelial cells recruit circulatory inflammatory cells; and fibroblasts and myofibroblasts produce collagens and proteoglycans (components of connective tissue). Cellular mediators activate airway cholinergic nerves causing bronchoconstriction and mucous secretion and airway sensory nerves causing cough and the sensation of chest tightness.
Chronic airway structural changes, including subepithelial fibrosis, increased airway smooth muscle, increased airway wall blood vessels, increased airway epithelium goblet cells, and submucosal gland hypertrophy, are the result of airway inflammation and other mechanisms independent of airway inflammation. The airways narrow as a result of airway smooth muscle contraction, airway edema, airway wall thickening from structural changes, and mucus plugging. Airway hyperresponsiveness is caused by excessive airway smooth muscle contraction, airway wall thickening, and sensory nerve stimulation.
DIAGNOSTIC CRITERIA
The diagnosis of asthma is based on the presence of symptoms consistent with asthma and the presence of variable airflow limitation. Typical asthma symptoms include wheeze, shortness of breath, cough, and chest tightness. These symptoms are not exclusive to asthma; persons with a variety of upper and lower respiratory tract (e.g., inhaled foreign body, vocal cord dysfunction, bronchopulmonary dysplasia, cystic fibrosis, chronic obstructive pulmonary disease) and cardiovascular (e.g., pulmonary emboli, heart failure) medical conditions have the same symptoms. Asthma symptoms and symptom severity are variable. Persons with asthma may be symptom free for short or prolonged periods of time. Symptom intensity varies from mild to severe; symptoms typically worsen at night or early morning, often waking the patient.
TABLE 25.1 Asthma Severity—Chronic Disease Classification (Age 12 Years and Older)
Intermittent
Mild Persistent
Moderate Persistent
Severe Persistent
Severity Components
Step 1
Step 2
Step 3 and Step 4
Step 5 and Step 6
Symptoms
2 or fewer days per week
More than 2 days per week but not daily
Daily
Throughout the day
Nighttime awakenings
2 or fewer nights per month
3 to 4 nights per month
More than 1 night per week but not nightly
Often 7 nights per week
Short-acting beta2-adrenergic agonist use for symptom control
2 or fewer days per week
More than 2 days per week but not more than one time per day
Daily
Several times per day
Interference with normal activity
None
Minor limitation
Some limitation
Extremely limited
Exacerbations requiring systemic corticosteroids
0-1 per year
2 or more per year
2 or more per year
2 or more per year
Lung function
Normal FEV1/FVC:
8-19 y: 85%
20-39 y: 75%
40-59 y: 75%
60-80 y: 70%
Normal FEV1 between exacerbations
FEV1 ≥ 80% predicted
FEV1/FVC normal
FEV1 ≥ 80% predicted
FEV1/FVC normal
FEV1 > 60% but < 80% predicted
FEV1/FVC reduced 5%
FEV1 < 60% predicted
FEV1/FVC reduced > 5%
Severity is determined by the most severe category for any feature.
The physical examination is nonspecific and may be normal. Wheezing may be absent or range from soft end-expiratory wheezing to loud inspiratory and expiratory wheezing; the chest may be silent during a severe exacerbation. Nasal polyps or signs of allergic rhinitis or other atopic medical conditions such as eczema may be present. Persons with a severe asthma exacerbation may present with hunched shoulders, a preference for sitting upright, cyanosis, use of accessory respiratory muscles (abdominal, sternocleidomastoid), elevated or decreased blood pressure, tachycardia or bradycardia, tachypnea or bradypnea, an inability to speak in full sentences, and anxiety.
Spirometry measures lung volumes during a forced maximal exhalation. Airflow limitation is assessed using the forced expiratory volume in the first second (FEV1), the total volume of exhaled air (forced vital capacity, FVC), and the FEV1/FVC ratio. Airflow obstruction is present when the FEV1/FVC is less than 0.70. Bronchoprovocation testing with methacholine or histamine may be performed in patients with suspected asthma who have normal baseline airflow. The current NAEPP guidelines categorize asthma severity in children older than 4 years of age and adults according to nonspirometric and spirometric criteria (Tables 25.1 and 25.2). Children 0 to 4 years of age are classified according to nonspirometric criteria (Table 25.3). A reduced peak expiratory flow (PEF) is consistent with airway obstruction but is not diagnostic of asthma. PEF is commonly used for self-monitoring and assessment of airway obstruction reversibility following inhalation of a short-acting bronchodilator. Spirometry is performed at baseline (prior to starting treatment), after 3 to 6 months of treatment, then repeated annually or more frequently if indicated.
TABLE 25.2 Asthma Severity—Chronic Disease Classification (Children 5-11 Years of Age)
Severity Components
Intermittent
Mild Persistent
Moderate Persistent
Severe Persistent
Symptoms
2 or fewer days per week
More than 2 days per week but not daily
Daily
Throughout the day
Nighttime awakenings
2 or fewer nights per month
3 to 4 nights per month
More than 1 night per week but not nightly
Often 7 times per week
Short-acting beta2-adrenergic agonist use for symptom control
2 or fewer days per week
More than 2 days per week but not daily
Daily
Several times per day
Interference with normal activity
None
Minor limitation
Some limitation
Extremely limited
Exacerbations requiring systemic corticosteroids
0 to 1 per year
2 or more per year
2 or more per year
2 or more per year
Lung function
Normal FEV1 between exacerbations
FEV1 ≥ 80% predicted
FEV1/FVC > 85%
FEV1 ≥ 80% predicted
FEV1/FVC > 80%
FEV1 60%-80% predicted
FEV1/FVC = 75-80%
FEV1 < 60% predicted
FEV1/FVC < 75%
Severity is determined by the most severe category for any feature.
Airflow obstruction reversibility, an important parameter for the diagnosis of asthma, is documented by comparing baseline FEV1 to postbronchodilator FEV1 10 to 15 minutes following the administration of 2 to 4 puffs of a short-acting beta-adrenergic drug. The NAEPP guidelines define airflow obstruction reversibility as an increase in FEV1 of at least 12% and an absolute increase in FEV1 of at least 200 mL (NAEPP, 2007).
TABLE 25.4 Asthma Control Assessment
Well Controlled
Not Well Controlled
Very Poorly Controlled
Symptoms
2 or fewer days per week
More than 2 days per week
Throughout the day
Nighttime awakenings
2 or fewer nights per month
1 to 3 nights per week
4 or more nights per week
Interference with normal activities
None
Some limitations
Extremely limited
Short-acting beta2-adrenergic agonist use for symptom control
Drug therapy is initiated according to the age-specific NAEPP chronic disease recommendations (Tables 25.4, 25.5, 25.6). All persons with asthma, regardless of the severity of asthma, require a short-acting beta2-adrenergic agonist (SABA) bronchodilator for quick relief of acute symptoms. Long-term control medication is added according to the severity of disease. The GINA guidelines recommend reassessing 1 to 3 months after starting treatment and then every 3 to 12 months (GINA, 2015).
TABLE 25.5 Stepwise Approach for Managing Asthma (Children ≥12 Y of Age and Adults)
Step 1 Intermittent
Step 2 Mild Persistent
Step 3 Moderate Persistent
Step 4 Moderate Persistent
Step 5 Severe Persistent
Step 6 Severe Persistent
Preferred: SABA PRN
Preferred:
Low-dose ICS
Alternative:
Cromolyn, LTRA, or theophylline
Preferred:
Low-dose ICS + LABA
OR
Medium-dose ICS
Alternative:
Low-dose ICS + either LTRA, theophylline, or zileuton
Preferred:
Medium-dose ICS + LABA
Alternative:
Medium-dose ICS + either LTRA, theophylline, or zileuton
Preferred:
High-dose ICS + LABA
AND
Consider omalizumab for patients who have allergies
Preferred:
High-dose ICS + LABA + oral CS
AND
Consider omalizumab for patients who have allergies
Patient education and environmental control at each step
Treatment can be stepped down to a less intensive regimen if asthma symptoms have been well controlled for 3 months. Stepping down treatment is done systematically with close monitoring of asthma control. Oral corticosteroids are reduced and then discontinued first. The dose of inhaled corticosteroid (ICS) may then be reduced by 50%. Further reductions in therapy can be made by reducing the dose of the ICS/long-acting bronchodilator regimen to once daily. The long-term control regimen may be stopped if the person with asthma has been free of symptoms for 6 to 12 months and has no risk factors for exacerbations (GINA, 2015).
TABLE 25.6 Stepwise Approach for Managing Asthma (Children 5-11 y of Age)
Step 1 Intermittent
Step 2 Mild Persistent
Step 3 Moderate Persistent
Step 4 Moderate Persistent
Step 5 Severe Persistent
Step 6 Severe Persistent
Preferred:SABA PRN
Preferred:
Low-dose ICS
Alternative:
Cromolyn, LTRA, or theophylline
Preferred:
EITHER:
Low-dose ICS + either LABA, LTRA, or theophylline
OR
Medium-dose ICS
Preferred:
Medium-dose ICS + LABA
Alternative:
Medium-dose ICS + either LTRA or theophylline
Preferred:
High-dose ICS + LABA
Alternative:
High-dose ICS + either LTRA or theophylline
Preferred:
High-dose ICS + LABA + oral systemic CS
Alternative:
High-dose ICS + either LTRA or theophylline + oral systemic corticosteroid
Patient education and environmental control at each step
Treatment is stepped up if persons with asthma are not well controlled despite 2 to 3 months of treatment with long-term control medication. Medication adherence, inhaler drug delivery technique, environmental exposures, and concurrent medications must be assessed and any issues addressed before stepping up to a more intensive medication regimen. Alternate treatment should be stopped and the preferred treatment regimen tried before stepping up therapy.
TABLE 25.7 Stepwise Approach for Managing Asthma (Children 0-4 Years of Age)
Step 1 Intermittent
Step 2 Mild Persistent
Step 3 Moderate Persistent
Step 4 Moderate Persistent
Step 5 Severe Persistent
Step 6 Severe Persistent
Preferred: SABA PRN
Preferred:
Low-dose ICS
Alternative:
Cromolyn or montelukast
Preferred:
Medium-dose ICS
Preferred:
Medium-dose ICS + either LABA or montelukast
Preferred:
High-dose ICS + either LABA or montelukast
Preferred:
High-dose ICS + either LABA or montelukast
AND
Oral systemic CS
Patient education and environmental control at each step
