Asthma 

Asthma is a common chronic disease worldwide and affects approximately 24 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.^{[1, 2]}

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, inhaled cromolyn (Intal) or nedocromil (Tilade), long-acting bronchodilators, theophylline (Theo-24, Theochron, Uniphyl), leukotriene modifiers, and anti-IgE 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.

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.^[3]

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.

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^[4] :

• 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.^[1] See the image below.

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.

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.^[8]

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.

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^[9]
• 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.^[10]

A study by Beasley et al demonstrated some epidemiological evidence that exposure to acetaminophen is associated with an increased risk of asthma.^[11] 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.

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.^[12] 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.^[12]

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).^[13]

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.^[13]

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.^[14] 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.^[15]

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.^[16] 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.^[17]

Exercise-induced asthma

Exercise-induced asthma (EIA), or exercise-induced bronchospasm (EIB), is an asthma variant defined as a condition in which exercise or vigorous physical activity triggers acute bronchospasm in persons with heightened airway reactivity. It is observed primarily in persons who have asthma (exercise-induced bronchospasm 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 athletes (exercise-induced bronchospasm in athletes). Exercise-induced bronchospasm is often a neglected diagnosis, and the underlying asthma may be silent in as many as 50% of patients, except during exercise.^{[18, 19]}

The pathogenesis of exercise-induced bronchospasm 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 bronchospasm symptoms (in both people 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 bronchospasm is made more often in children and young adults than in older adults and is related to high levels of physical activity. Exercise-induced bronchospasm 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.^[20]

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, recent studies suggest the possibility that the loss of normal immune balance arises from a cytokine dysregulation in which Th1 activity in asthma is diminished.^[21]

In addition, some studies highlight the importance of genotypes in children's susceptibility to asthma and response to specific antiasthma medications.^{[22, 23, 24, 25]}

Obesity

A study by Cottrell et al explored the relationship between asthma, obesity, and abnormal lipid and glucose metabolism.^[26] 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.

Asthma affects 5-10% of the population or an estimated 23.4 million persons, including 7 million children.^[13] 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.^[27]

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.^[28]

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.^[29] 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.^[30]

International asthma mortality is reported as high as 0.86 deaths per 100,000 persons in some countries. US asthma mortality rates in 2006 were reported at 1.2 deaths 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.^[31]

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 1.81 million people (47.8% of them aged 18 y or younger) require treatment in an emergency department.^[32] For 2010, the annual expenditures for health and lost productivity due to asthma are projected to be $20.7 billion.^[33]

Nearly one half of children diagnosed with asthma 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 (ie, 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.

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.^[34]

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.^{[35, 36, 37]}
• 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).^[38]

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.^[39]

The 2009 Veterans Administration/Department of Defense (VA/DoD) clinical practice guideline for management of asthma in children and adults concurs with EPR-3 in recommending self-management education for both the patient and caregiver as part of the treatment program.^[40]

For excellent patient education resources, visit eMedicine's Asthma Center. Also, see eMedicine's patient education articles Asthma, Asthma FAQs, Asthma in Children, and Understanding Asthma Medications.