Your Family Physician

Introduction

Background

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.

Pathophysiology

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 T_H 1 (ie, by interferon-gamma, interleukin [IL]–2) or T_H 2 (ie, by IL-4, IL-5, IL-9, IL-13). Regulatory T cells (Treg) appear to play an important role in T_H 2 cell response to allergens. Allergens drive the cytokine pattern toward T_H 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.

Frequency

United States

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

International

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

Mortality/Morbidity

• 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 $12.7 billion in 1998. In Western countries, the financial burden on patients ranges from $300 to $1,300 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.

Race

• Genetic differences may alter susceptibility to asthma as well as responsiveness to asthma medications.² Significant 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 (<$20,000/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.

Sex

• 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.

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.

Clinical

History

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:
  • Allergic
    • 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)
  • Environmental
    • 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

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.

Causes

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 T_H 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 T_H 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 T_H 2 allergic cytokine state never switches to the T_H 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.

Source : http://emedicine.medscape.com/article/137501-overview