Allergic and Environmental Asthma
Asthma is a clinical syndrome characterized by episodic reversible airway obstruction, increased bronchial reactivity, and airway inflammation. Asthma results from complex interactions among inflammatory cells, their mediators, airway epithelium and smooth muscle, and the nervous system. In genetically susceptible individuals, these interactions can lead the patient with asthma to symptoms of breathlessness, wheezing, cough, and chest tightness.
Risk factors for asthma include a family history of allergic disease, the presence of allergen-specific immunoglobulin E (IgE), viral respiratory illnesses, exposure to aeroallergens, cigarette smoke, obesity, and lower socioeconomic status.
Environmental exposure in sensitized individuals is a major inducer of airway inflammation, which is a hallmark finding in the asthmatic lung. Although triggers induce inflammation through different pathways, the resulting effects all lead to increased bronchial reactivity.
The importance of allergy in asthma has been well established. Exposure to dust mites within the first year of life is associated with later development of asthma and, possibly, atopy. Mite and cockroach antigens are common, and exposure and sensitization has been shown to increase asthma morbidity. Allergies trigger asthma attacks in 60-90% of children and in 50% of adults. Approximately 75-85% of patients with asthma have positive (immediate) skin test results. In children, this sensitization is associated with disease activity.
Although most people with asthma have aeroallergen-induced symptoms, some individuals manifest symptoms with nonallergic triggers. About 3-10% of people with asthma are sensitive to nonsteroidal antiinflammatory drugs (NSAIDs). Approximately 5-10% of people with asthma have occupation- or industry-induced airway disease. Many individuals develop symptoms after viral respiratory tract infections.
Allergen avoidance and other environmental control efforts are feasible and effective. Symptoms, pulmonary function test findings, and airway hyperreactivity (AHR) improve with avoidance of environmental allergens. Removing even one of many allergens can result in clinical improvement. However, patients frequently are not compliant with such measures.
The allergic response in the airway is the result of a complex interaction of mast cells, eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. Inhalation-challenge studies with allergens reveal an early allergic response (EAR), which occurs within minutes and peaks at 20 minutes following inhalation of the allergen. Clinically, the manifestations of the EAR in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are the result of mast cell–derived mediators. Four to ten hours later, a late allergic response may occur, which is characterized by infiltration of inflammatory cells into the airway and is most likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils.
Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper T cells can be induced by cytokines to develop into TH 1 (ie, by interferon-gamma, interleukin [IL]–2) or TH 2 (ie, by IL-4, IL-5, IL-9, IL-13). Regulatory T cells (Treg) appear to play an important role in TH 2 cell response to allergens. Allergens drive the cytokine pattern toward TH 2, which promotes B-cell IgE production and eosinophil recruitment. Subsequently, IgE binds to the high-affinity receptor for IgE, Fc-epsilon-RI, on the surface of mast cells and basophils; with subsequent exposure to the allergen, the IgE is cross-linked. This leads to degranulation of the mast cell and basophil. Preformed mast cell mediators, such as histamine and proteases, are released, leading to the EAR.
Newly formed mediators such as leukotriene C4 and prostaglandin D2 also contribute to the EAR. Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha [TNF-α]) are released from mast cells and are generated de novo after mast cell activation. These cytokines contribute to the late allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into the airway, causing epithelial denudation and exposure of nerve endings. The lymphocytes that are attracted to the airway continue to promote the inflammatory response by secreting cytokines and chemokines, which further potentiate the cellular infiltration into the airway.
The ongoing inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of mucous glands, thickening of basement membranes, and continuing cellular infiltration. These long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis and irreversible airway obstruction in some, but not most, patients.
Prevalence is difficult to determine because definitions and survey methods vary, but the prevalence of asthma appears to be on the rise. Asthma has a prevalence of 10.9%, affecting more than 22 million people, including more than 6 million children.1,2
Global Initiative for Asthma (GINA) researchers note an increase in prevalence, morbidity, mortality, and economic burden over the past 40 years, especially in children.1 Asthma affects more than 300 million people worldwide, and some reports suggest asthma prevalence is increasing by 50% every decade.1 The highest recorded prevalences outside North America are in the United Kingdom (>15%), New Zealand (15.1%), and Australia (14.7%).3
- In the United States, mortality has increased, especially in children who live in inner-city areas, despite advances in disease understanding and therapy. The number of deaths annually decreased from 5067 (1960-1962) to a low of 1870 (1975-1978) and then increased to 5429 (1993-1995). Worldwide, approximately 180,000 deaths annually are attributed to asthma; most deaths occur in those older than 45 years.
- In the United States, asthma is annually responsible for 1.5 million emergency department (ED) visits; 500,000 hospital admissions (third leading preventable cause); and 100 million days of restricted activity. Medical expenses as well as lost work and productivity cost an estimated .7 billion in 1998. In Western countries, the financial burden on patients ranges from 0 to ,300 per patient year, increasing with more severe disease.
- Increased morbidity is multifactorial; morbidity may be increased by increased exposure to indoor allergens, less exposure to viral infections early in life, more environmental pollution, overuse of short-acting beta-2 agonists, underuse of anti-inflammatory medications, and limited access to or education about health care.
- Worldwide, economic costs for asthma are more than costs for tuberculosis and AIDS combined. Cost is associated with disease severity;4 more than half of all expenditures are attributed to the 10-20% of patients with the most severe disease.
- Genetic differences may alter susceptibility to asthma as well as responsiveness to asthma medications.2Significant genetic variation exists between and within racial and ethnic groups, but the issue is confounded by important coexisting economic, cultural, and environmental differences, including geography (place of birth).5 Associations have been suggested between polymorphisms in the B2-adrenergic receptor (ADRB2) and reduced responsiveness and increased adverse effects with long-acting beta-agonist bronchodilators. More recent studies suggest this is not the case.6
- Females, ethnic minorities, people with a low annual family income (<,000/y in the United States), and persons with poor access to or education about health care have worse outcomes than other individuals.
- Hospitalization and death rates are 50% higher for African American adults than white adults and 150% higher in children.
- Asthma is rare in Eskimos.
- Boys have been shown to be at greater risk for asthma than girls. In children younger than 14 years, the prevalence is twice as high in boys than in girls.
- The difference narrows with age, and women aged 40 years have a greater prevalence than men of the same age.
- Disease onset can occur in people of any age, but children often present when younger than 6 years. Asthma is one of the most common chronic diseases of childhood.
- Many young children “outgrow” asthma, especially boys who have no personal or family history of atopy. However, clinical experience shows that many teenagers who become asthma-free may experience asthma again in their 20s and 30s. Perinatal exposure to allergens or passive smoke has been postulated to make outgrowing asthma less likely.
The classic history consists of wheeze, cough, and dyspnea. The predictive value of any single parameter is approximately 30% but is much higher when parameters are combined. Chest discomfort (eg, pain, tightness, congestion, inability to take a full breath) is also common. Some patients may have cough without other symptoms. Refractory chest colds may also suggest the diagnosis.
- Record the following:
- Age of onset
- Frequency and severity of daytime and nocturnal symptoms
- Symptom triggers, such as exercise, animals, irritants (smoke), and occupation (worse on workdays)
- Seasonal and geographic variation, including presence of symptoms indoors and outdoors
- Limits on activity, lost work or school days, and quality of life
- Number of emergency department and urgent clinic visits, hospital admissions, intensive care unit (ICU) stays, and need for mechanical ventilation
- Past treatments, including oral and inhaled steroids, frequency of rescue inhaler use, immunotherapy, and environmental avoidance
- Family history of asthma
- Personal or family history of atopy, allergy, rhinitis (including nonallergic rhinitis), or sinusitis
- Gastroesophageal reflux symptoms
- Food allergy
- Growth (children)
- Atopic dermatitis
- All patients should be asked about or should undergo assessment regarding exacerbation of symptoms, as follows:
- Perennial symptoms - Pet in the home (especially in the bedroom, bed, or both), school, day care, or work environment; moisture, dampness, and humidifier use; mold and musty odors in any part of the home; cockroaches in the home; worsening of symptoms after vacuuming rugs (typical of dust mite allergen)
- Seasonal symptoms (may extend beyond one season in temperate or tropical climates) - Early spring (trees), late spring and summer (grasses), summer and fall (dry molds), and fall (weeds)
- Personal or secondary tobacco smoke exposure in or out of the home
- Gas-burning stoves, fireplaces, or heaters used in home
- Sprays or chemical agents at work, home, or with hobbies
- Symptoms only at one place (ie, at work during week with no symptoms on weekends)
- School or business associates with similar problems
- Symptoms after eating (dried, canned, or processed food)
- Medications such as beta-blockers (including eye drops), aspirin, or other NSAIDs
Physical examination findings are often normal.
- Head and neck: Nasal mucosal swelling, discharge, polyps, or sinus percussion tenderness may suggest associated allergic rhinitis or sinusitis. Wheezing heard only or mostly over the neck may suggest vocal cord dysfunction (VCD) or other laryngeal abnormality, though VCD can be present without a localizing wheeze. Increased jugular venous distension may point to an alternative explanation, such as heart failure, for the patient’s dyspnea and wheezing. Similarly, palpation of cervical or supraclavicular adenopathy would suggest malignancy, sarcoidosis, or infection.
- Cardiac: Findings are normal. Patients with status asthmaticus may have a pulsus paradoxus greater than 10 mm Hg. A murmur, S3 gallop, or rub suggests a cardiac problem and not asthma.
- Respiratory: During an acute asthma exacerbation, lung examination findings may include wheezing, rhonchi, hyperinflation, or prolonged expiratory phase. With severe disease, lung auscultation may reveal absent breath sounds (indicating poor air movement) or signs of respiratory distress and failure (eg, nasal flaring, grunting, accessory muscle use, cyanosis). Focal wheezing may indicate foreign body or other airway obstruction such as a tumor.
- Skin: Check the patient for atopic dermatitis.
- Extremities: Digital clubbing should not be present. Edema should also not be present. If edema is found, this suggests right- or left-sided heart failure.
The etiology of asthma is likely multifactorial. Genetic factors may control individual predispositions to asthma. Genetics may also be associated with responses to medications. Variation in the beta-adrenergic receptor gene of the Arg-Arg type has been associated with adverse responses to inhaled short-acting beta-agonist inhalers. Genetics alone cannot account for the significant increases in prevalence, as genetic factors take several generations to develop, and asthma and atopy are not always co-inherited. Several environmental or lifestyle factors have been implicated.
- The hygiene hypothesis proposes that cleaner environments have led to less immunological stress, reducing the development of an asthma-protective TH 1 cytokine phenotype.
- Measles infection, BCG vaccine administration, hepatitis A seropositivity, and other stimuli that increase production of interferon-gamma and IL-12 may inhibit the TH 2 allergic response.
- In selected series, vaccinations, fewer childhood infections, liberal use of antibiotics, more processed food in diets, smaller families, and less exposure to day care environments have been associated with increased atopy and asthma. This is exemplified in western versus eastern Germany; asthma, atopy, and AHR are more prevalent in western Germany, while bronchitis is more common in eastern Germany.
- One theory to explain the increased prevalence of allergic disease is that with fewer infectious stimuli in the environment, the in utero TH 2 allergic cytokine state never switches to the TH 1 state.
- Causes or triggers of asthma can be divided as follows:
- Allergic: Aeroallergens can include seasonal pollen, mold spores, dust mites, animal allergens, and food (especially in children). Monosodium glutamate does not appear to be an allergen.7
- Nonallergic: These may include smoke, odors, cold air and weather, chemicals, medications (eg, aspirin, other NSAIDs, beta-blockers), exercise, hormonal changes (eg, pregnancy, menstrual cycle), and bisulfite food additives.
Other Problems to Be Considered
Children and young adults
Vocal cord dysfunction
Congenital cardiac anomalies
Primary ciliary dyskinesia
Exercise-induced supraventricular tachycardia
Vocal cord dysfunction
Post-infectious reactive airways disease (usually lasts less than 6 months)
Congestive heart failure
Chronic eosinophilic pneumonia
Endobronchial tumor or other obstructing lesion
Churg-Strauss syndrome (allergic angiitis and granulomatosis)
Allergic bronchopulmonary aspergillosis
Reactive airways dysfunction syndrome: This is a distinct entity caused by exposure to a single, large, inhaled agent leading to asthma symptoms within 24 hours and lasting 3 months or longer.
- The most important tests are pulmonary function tests (see Other Tests).
- Skin testing is one of the most useful ways to determine specific allergen sensitivity. Skin tests or in-vitro tests for allergen-specific IgE such as radioallergosorbent tests (RAST), fluorescent allergosorbent tests (FAST), or CAP tests are necessary for informed advice to patients about allergen avoidance techniques, and for planning allergen immunotherapy regimens. Skin tests have the advantage of being immediately available and visible to patients, which may reinforce to patients the need for environmental control and, possibly, immunotherapy (see Other Tests).
- The serum IgE level is elevated only approximately half the time in patients with allergic disease. Obtaining an IgE level is not indicated in most patients with asthma, although levels greater than 1000 ng/mL (1 IU= 2.4 ng) may suggest an alternate diagnosis, such as allergic bronchopulmonary aspergillosis (confounding illness such as atopic dermatitis may also result in high IgE levels).
- Sputum and serum eosinophilia tests are not routinely performed or required for diagnosis, although some authors have found that they are useful for guiding therapy. Decrease in sputum eosinophilia may suggest asthma control or responsiveness to inhaled steroids. Note that a finding of greater than 1000 eosinophils per microliter of peripheral blood can indicate parasitic infestation, drug allergies, or eosinophilic pulmonary disorders such as allergic bronchopulmonary aspergillosis or Churg-Strauss syndrome.
- Exhaled nitric oxide levels correlate with eosinophilic airway inflammation and are reduced by corticosteroid therapy. These levels may also help predict the onset of exacerbations. Exhaled breath condensate and exhaled breath temperature are also novel biomarkers that have been studied. Cost and availability of monitors need to improve before this modality can become routine in general practice in medical offices or home use.
- In older patients, an elevated serum brain natriuretic peptide (BNP) level may help suggest heart failure as a primary or contributing cause of dyspnea and wheezing.
- Chest radiographs: These are taken only if pneumonia, large airway lesions, or heart failure is suggested; if symptoms are atypical or refractory to therapy; if the patient has unilateral or focal wheezing; or if the patient has new adult-onset asthma symptoms.
- Modified or limited sinus CT scans: Consider CT scans of the sinuses if chronic sinusitis is suggested. About 65% of people with severe asthma have concomitant sinusitis.
- Chest CT scans: These are indicated in select patients to help exclude interstitial lung disease, bronchiectasis, bronchiolitis, or infection.
- Echocardiograms: These are performed if congestive heart failure is suggested based on history and physical examination findings.
- Symptom improvement with asthma therapy is suggestive but not diagnostic of asthma. Symptoms alone do not necessarily reflect asthma severity. Infants may be treated empirically. In patients older than 5 years, objectively demonstrating reversible airflow obstruction with pulmonary function tests, if possible, is essential.
- Obstruction is defined as a ratio less than 70% of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC). FEV1 is normally greater than 80% of values predicted by age. Young patients with a supranormal FVC can sometimes have a reduced FEV1 -to-FVC ratio without having obstructive lung disease.
- Reversibility can be shown by administering a short-acting beta-2 agonist inhaler with a resultant 12% and more than 200-mL improvement in FEV1 or FVC.8 If no response, 2-3 weeks of oral or inhaled corticosteroids (20 mg twice daily for the average patient) may be required to demonstrate an improvement in airflow. Note that airflow obstruction in some patients with chronic obstructive pulmonary disease may be partially reversible.
- Relative annual risk of exacerbations may be related to FEV1.
- A 15% drop in FEV1 after 6 minutes of running or other exercise can be diagnostic of exercise-induced bronchospasm.
- A 20% variation in the peak expiratory flow rate (PEFR) between high and low values is highly suggestive of asthma, but formal pulmonary function testing (as above) is recommended because the PEFR is extremely effort-dependent.
- An asthma specialist can perform bronchoprovocation testing with exercise, histamine, methacholine, or eucapnic voluntary hyperventilation. The results from these tests have a very high negative predictive value and are useful for excluding the diagnosis of asthma. The most common challenge is with increasing doses of inhaled methacholine. A 20% decline in FEV1 with a methacholine concentration of 8 mg/mL or less is considered a positive (abnormal) test result. This testing should be avoided during pregnancy because of the risk of precipitating an asthma attack and because methacholine is a class C drug.
- Skin testing should be performed to help detect the presence of allergen-specific IgE against environmental triggers that are suggested based on the patient's history.
- Testing is recommended for antigens to which the patient is exposed rather than testing with a standard panel.
- Skin test findings have a fairly high false positive rate but a very good negative predictive value. Thus, a positive test result does not mean that a patient is currently being exposed to an allergen or that he or she will react to it in a natural exposure. A negative test result generally rules out the possibility that an allergen is having an impact on the patient’s asthma.9 Antihistamine medications and tricyclic antidepressants (TCAs) interfere with allergy skin testing; short courses of oral glucocorticoids at moderate doses do not.
- Testing should not be performed during an asthma exacerbation, and the testing site should be equipped for the treatment of rare life-threatening reactions.
- Skin testing is performed with controls (eg, histamine and saline) to avoid false-positive (dermatographism) or false-negative results.
- Identification of allergen triggers can assist in formulating an environmental control strategy, titration of therapy (ie, seasonal exacerbation), or an immunotherapy regimen.
- RAST testing may be used in place of skin testing if dermatologic disease is generalized, antihistamine or TCA use cannot be suspended (these do not interfere with RAST results), or skin testing is relatively contraindicated. However, skin testing is more specific, more sensitive, and usually less expensive than RAST testing.
- 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.
- A trial of allergen avoidance may be diagnostic and therapeutic, but because it is difficult or impossible to avoid most allergens completely, failure to improve with an attempt at allergen avoidance cannot rule out allergy to those allergens.
- If restrictive or other lung disease is suggested by history, physical examination, or pulmonary function testing findings, additional data must be obtained, including complete lung volumes, respiratory muscle strength, diffusion capacity, and a high-resolution CT scan.
- Perform a barium swallow, endoscopy, or 24-hour pH probe (the Bravo study is now possible in selected centers) to help diagnose gastroesophageal reflux disease (GERD) if a patient’s condition is refractory to asthma therapy. Empiric medical therapy is often tried without performing these tests, especially if a patient has symptoms of GERD. In cases of GERD, a prolonged trial may be necessary. The median time to improvement of GERD-induced cough has been reported as 3 months.10
- Measure oxygenation (ie, with pulse oximetry or arterial blood gas testing) in selected patients.
- Perform sweat chloride testing for cystic fibrosis or immunoglobulin level testing for immunodeficiency if these conditions are suggested.
- Staining nasal secretions with Hansel stain is sometimes used to assess for nasal eosinophilia, which is suggestive of allergy; however, the sensitivity and specificity of this stain are low.
- Direct and indirect laryngoscopies are indicated if vocal cord dysfunction (VCD) or another laryngeal abnormality is suggested. A flow-volume curve on pulmonary function test may demonstrate extrathoracic obstruction, supporting the diagnosis of VCD.
- Cardiac stress testing, cardiopulmonary exercise testing, or both may be indicated if the etiology of dyspnea cannot be determined.
The diagnosis of asthma is not made histologically. However, autopsy and bronchoscopic biopsy findings include mucus plugging, inflammatory cell infiltrates and debris, vascular permeability, mucosal edema, and epithelial exfoliation. Remodeling, consisting of hypertrophy of smooth muscle, squamous and goblet cell metaplasia, mucous gland hypertrophy, and basement membrane thickening due to collagen and other matrix protein deposition, may be present.
Sputum analysis results show creola bodies (ie, bronchial regenerative cells with nuclear atypia), Charcot-Leyden crystals (ie, residual product of eosinophils), and Curschmann spirals (ie, concentric layers of mucous and debris).
The National Asthma Education and Prevention Program, Expert Panel Report 3 from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health has a new focus on defining severity in terms of both impairment and risk; monitoring asthma control and not just assessing severity; simplifying treatment recommendations by age and the management of exacerbations; and promoting a multifaceted approach to patient education, environmental controls, and management of comorbidities.2 Some of their recommendations are reproduced below. For complete details and for guidelines for children aged ≤11 years, see the full NHLBI EP-3report.
See also Medication for detailed information on medications, and see Patient Education for additional resources for health care professionals.
In asthma staging for adults (including youths ≥12 y), note that severity should be assigned to the most severe category in which any feature occurs.
- Daytime symptoms 2 or fewer times per week
- Nighttime awakenings 2 or fewer times per month
- Use of short-acting beta-agonist for symptom control (not including taking preventively prior to exercise) 2 or fewer times per week
- No interference in normal activity
- Lung function normal between exacerbations, FEV1 >80% predicted, FEV1/FVC ratio normal (85% for ages 8-19 y, 80% for 20-39 y, 75% for 40-59 y, 70% for 60-80 y)
- Exacerbations requiring oral systemic corticosteroids once per year at most
- Recommended therapy is Step 1 - Short-acting beta-agonists as needed
- Mild persistent
- Daytime symptoms more than twice per week, but not daily
- Nighttime awakenings 3-4 times per month
- Use of short-acting beta-agonist for symptom control (not including taking preventively prior to exercise) more than 2 times per week but not daily and not more than once on any one day
- Minor limitation in normal activity
- FEV1 >80%