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Asthma

Author: Michael J Morris, MD; Chief Editor: Zab Mosenifar, MD more...

Updated: Jul 27, 2011

Background

Asthma is a common chronic disease worldwide and affects approximately 24 million persons in the UnitedStates. It is the most common chronic disease in childhood, affecting an estimated 7 million children, and it is acommon cause of hospitalization for children in the United States.

The pathophysiology of asthma is complex and involves airway inflammation, intermittent airflow obstruction, andbronchial 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 bronchialreactivity. 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 numerousexogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airway smooth muscleand indirect stimulation by pharmacologically active substances from mediator-secreting cells such as mast cellsor nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generally correlates with theclinical severity of asthma.

Spirometry with postbronchodilator response should be obtained as the primary test to establish the asthmadiagnosis. Pulse oximetry measurement is desirable in all patients with acute asthma to exclude hypoxemia. Thechest radiograph remains the initial imaging evaluation in most individuals with symptoms of asthma, but in mostpatients with asthma, chest radiography findings are normal or may indicate hyperinflation. Exercise spirometry isthe 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 andits severity. The severity of asthma is classified as intermittent, mild persistent, moderate persistent, or severepersistent. 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 inhaledcorticosteroids, inhaled cromolyn (Intal) or nedocromil (Tilade), long-acting bronchodilators, theophylline (Theo-24,Theochron, Uniphyl), leukotriene modifiers, and anti-IgE antibodies. Relief medications include short-actingbronchodilators, systemic corticosteroids, and ipratropium (Atrovent). With severe exacerbations, indications forhospitalization 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 bronchitermed the respiratory bronchioles and alveolar ducts. While the first 2 types function mostly as anatomic deadspace, they also contribute to airway resistance. The smallest non-gas-exchanging airways, the terminalbronchioles, 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 atransport apparatusBasement membraneA smooth-muscle matrix extending to the alveolar entrancesPredominantly fibrocartilaginous or fibroelastic-supporting connective tissue.

Cellular elements include mast cells, which are involved in the complex control of releasing histamine and othermediators. Basophils, eosinophils, neutrophils, and macrophages also are responsible for extensive mediatorrelease in the early and late stages of bronchial asthma. Stretch and irritant receptors reside in the airways, as docholinergic motor nerves, which innervate the smooth muscle and glandular units. In bronchial asthma, smoothmuscle contraction in an airway is greater than that expected for its size if it were functioning normally, and thiscontraction 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[4] :

The critical role of inflammation has been further substantiated, but evidence is emerging for considerablevariability in the pattern of inflammation, thus indicating phenotypic differences that may influence treatmentresponsesOf the environmental factors, allergic reactions remain important. Evidence also suggests a key andexpanding role for viral respiratory infections in these processesThe onset of asthma for most patients begins early in life, with the pattern of disease persistencedetermined by early, recognizable risk factors including atopic disease, recurrent wheezing, and a parentalhistory of asthmaCurrent asthma treatment with anti-inflammatory therapy does not appear to prevent progression of theunderlying disease severity

The pathophysiology of asthma is complex and involves the following components:

Airway inflammationIntermittent airflow obstructionBronchial hyperresponsiveness

Airway inflammation

The mechanism of inflammation in asthma may be acute, subacute, or chronic, and the presence of airway edemaand mucus secretion also contributes to airflow obstruction and bronchial reactivity. Varying degrees ofmononuclear cell and eosinophil infiltration, mucus hypersecretion, desquamation of the epithelium, smooth

muscle hyperplasia, and airway remodeling are present.[1] See the image below.

Asthma treatment. Asthma causes and symptoms. Antigen presentation by the dendritic cell w ith the lymphocyte and cytokine response

leading to airw ay 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 airwayinflammation 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 adhesionmolecules (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 tonumerous exogenous and endogenous stimuli. The mechanisms involved include direct stimulation of airwaysmooth muscle and indirect stimulation by pharmacologically active substances from mediator-secreting cellssuch as mast cells or nonmyelinated sensory neurons. The degree of airway hyperresponsiveness generallycorrelates 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 andincreased prostaglandin D2 levels were identified as important predictors of severe asthma as compared with othersteroid-treated subjects with asthma.

Chronic inflammation of the airways is associated with increased bronchial hyperresponsiveness, which leads tobronchospasm 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 maybe 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 Thlymphocytes. 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 thatthe 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 relationshipto 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 ofimmunoglobulin E-dependent mediator release upon exposure to aeroallergens and is the primary component ofthe early asthmatic response. Airway edema occurs 6-24 hours following an allergen challenge and is referred toas the late asthmatic response. Chronic mucous plug formation consists of an exudate of serum proteins and celldebris 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 changeslead to a decreased ability to expel air and may result in hyperinflation. The resulting overdistention helps maintainairway patency, thereby improving expiratory flow; however, it also alters pulmonary mechanics and increases thework of breathing.

Bronchial hyperresponsiveness

Hyperinflation compensates for the airflow obstruction, but this compensation is limited when the tidal volumeapproaches the volume of the pulmonary dead space; the result is alveolar hypoventilation. Uneven changes inairflow resistance, the resulting uneven distribution of air, and alterations in circulation from increased intra-alveolarpressure due to hyperinflation all lead to ventilation-perfusion mismatch. Vasoconstriction due to alveolar hypoxiaalso contributes to this mismatch. Vasoconstriction is also considered an adaptive response toventilation/perfusion mismatch.

In the early stages, when ventilation-perfusion mismatch results in hypoxia, hypercarbia is prevented by the readydiffusion of carbon dioxide across alveolar capillary membranes. Thus, patients with asthma who are in the earlystages of an acute episode have hypoxemia in the absence of carbon dioxide retention. Hyperventilation triggeredby 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-perfusionmismatch, carbon dioxide retention occurs. In the early stages of an acute episode, respiratory alkalosis resultsfrom hyperventilation. Later, the increased work of breathing, increased oxygen consumption, and increasedcardiac output result in metabolic acidosis. Respiratory failure leads to respiratory acidosis.

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; cockroachallergens; and fungi)

allergens; and fungi)

Viral respiratory tract infectionsExercise, hyperventilationGastroesophageal reflux diseaseChronic sinusitis or rhinitisAspirin or nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, sulfite sensitivityUse of beta-adrenergic receptor blockers (including ophthalmic preparations)

Obesity[9]

Environmental pollutants, tobacco smokeOccupational exposureIrritants (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 stressPerinatal factors (prematurity and increased maternal age; maternal smoking and prenatal exposure totobacco 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 patientsexperience 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 othernonsteroidal 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 asthmasymptoms with acetaminophen use.

Primary treatment is avoidance of these medications, but leukotriene antagonists have shown promise intreatment, 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 significantlyincrease 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 occupationalagents have been associated with asthma. High-risk jobs include farming, painting, janitorial work, and plasticsmanufacturing. 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. AnACCP consensus statement defines work-related asthmas as including occupational asthma (ie, asthma inducedby 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-mediatedasthma has a latency of months to years after exposure. Non-immune-mediated asthma, or irritant-inducedasthma (reactive airway dysfunction syndrome), has no latency period and may occur within 24 hours after anaccidental exposure to high concentrations of respiratory irritants. Pay careful attention to the patient'soccupational history. Those with a history of asthma who report worsening of symptoms during the week andimprovement during the weekends should be evaluated for occupational exposure. Peak-flow monitoring duringwork (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 childrenwith 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 childhoodpneumonia 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] Treatmentwith 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 factorfor asthma symptoms. Either acute infectious sinus disease or chronic inflammation may contribute to worseningairway 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 acondition in which exercise or vigorous physical activity triggers acute bronchospasm in persons with heightenedairway reactivity. It is observed primarily in persons who have asthma (exercise-induced bronchospasm inasthmatic persons) but can also be found in patients with normal resting spirometry findings with atopy, allergicrhinitis, or cystic fibrosis and even in healthy persons, many of whom are elite athletes (exercise-inducedbronchospasm 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 lossfrom the airway, heat loss from the airway, or a combination of both. The upper airway is designed to keep inspiredair at 100% humidity and body temperature at 37°C (98.6°F). The nose is unable to condition the increasedamount of air required for exercise, particularly in athletes who breathe through their mouths. The abnormal heatand water fluxes in the bronchial tree result in bronchoconstriction, occurring within minutes of completingexercise. Results from bronchoalveolar lavage studies have not demonstrated an increase in inflammatorymediators. These patients generally develop a refractory period, during which a second exercise challenge doesnot 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 airEnvironmental pollutants (eg, sulfur, ozone)level of bronchial hyperreactivityChronicity of asthma and symptomatic controlDuration and intensity of exerciseAllergen exposure in atopic individualsCoexisting respiratory infection

The assessment and diagnosis of exercise-induced bronchospasm is made more often in children and youngadults than in older adults and is related to high levels of physical activity. Exercise-induced bronchospasm can beobserved 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 thepathophysiology of asthma. Polymorphisms in the gene that encodes platelet-activating factor hydrolase, anintrinsic 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 (Mycobacteriumtuberculosis, measles, or hepatitis A); rural living; exposure to other children (eg, presence of older siblings andearly 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 geneticbackground of the child, with a cytokine imbalance toward Th2, sets the stage to promote the production ofimmunoglobulin E (IgE) antibody to key environmental antigens (eg, dust mites, cockroaches, Alternaria, andpossibly cats). Therefore, a gene-by-environment interaction occurs in which the susceptible host is exposed toenvironmental 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 Th2generation 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 inchildren. Specifically, these findings described a statistically significant association between asthma andabnormal lipid and glucose metabolism beyond body mass association.

Epidemiology

Asthma affects 5-10% of the population or an estimated 23.4 million persons, including 7 million children.[13] Theoverall prevalence rate of exercise-induced bronchospasm is 3-10% of the general population if persons who do nothave asthma or allergy are excluded, but the rate increases to 12-15% of the general population if patients withunderlying asthma are included. Asthma affects an estimated 300 million individuals worldwide. Annually, theWorld 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 ofthe 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 industrializedcountries 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-onsetcases diagnosed in persons older than 40 years occur in females. Boys are more likely than girls to experience adecrease 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 18years. Approximately half of all children diagnosed with asthma have a decrease or disappearance of symptoms

by early adulthood.[30]

Prognosis

International asthma mortality is reported as high as 0.86 deaths per 100,000 persons in some countries. USasthma mortality rates in 2006 were reported at 1.2 deaths per 100,000 persons. Mortality is primarily related tolung function, with an 8-fold increase in patients in the lowest quartile, but mortality has also been linked withasthma management failure, especially in young persons. Other factors that impact mortality include age olderthan 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 bylate 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 canlead to chronic symptoms and a significant irreversible component to their disease. Many patients who developasthma 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.[34]

The key points of education include the following:

Patient education should be integrated into every aspect of asthma careAll members of the healthcare team, including nurses, pharmacists, and respiratory therapists, shouldprovide 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 andshould 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-managementbehaviors 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 ofasthma 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 patienteducation articles Asthma, Asthma FAQs, Asthma in Children, and Understanding Asthma Medications.

Contributor Information and DisclosuresAuthorMichael J Morris, MD Clinical Assistant Professor, Pulmonary Disease/Critical Care Service, Department ofMedicine, Brooke Army Medical Center; Associate Program Director, Internal Medicine Residency, SanAntonio Uniformed Services Health Education Consortium

Michael J Morris, MD is a member of the following medical societies: American Association for RespiratoryCare, American College of Chest Physicians, American College of Physicians, American Thoracic Society, andAssociation of Military Surgeons of the US

Disclosure: Nothing to disclose.

Coauthor(s)Gregory J Argyros Col, MD Director, Education, Training, and Research, J7/Joint Task Force, NationalCapital Region Medical; Professor of Medicine, Uniformed Services University of the Health Sciences

Gregory J Argyros Col, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanCollege of Chest Physicians, American College of Physicians-American Society of Internal Medicine, and

American Thoracic Society


Stephen G Batuello, MD Consulting Staff, Colorado ENT Specialists

Stephen G Batuello, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Physician Executives, American Medical Association, andColorado Medical Society


Edward Bessman, MD Chairman, Department of Emergency Medicine, John Hopkins Bayview MedicalCenter; Assistant Professor, Department of Emergency Medicine, Johns Hopkins University School of Medicine

Edward Bessman, MD is a member of the following medical societies: American Academy of EmergencyMedicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine


Paul Blackburn, DO, FACOEP, FACEP Attending Physician, Department of Emergency Medicine, MaricopaMedical Center

Paul Blackburn, DO, FACOEP, FACEP is a member of the following medical societies: American College ofEmergency Physicians, American College of Osteopathic Emergency Physicians, American MedicalAssociation, and Arizona Medical Association


Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine,Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western ReserveUniversity School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha,American Academy of Emergency Medicine, American College of Chest Physicians, American College ofEmergency Physicians, American College of Physicians, American Heart Association, American ThoracicSociety, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences, andSociety for Academic Emergency Medicine


Praveen Buddiga, MD Physician, Allergy, Asthma and Immunology, Baz Allergy, Asthma and Sinus Center,Fresno, California

Praveen Buddiga, MD, is a member of the following medical societies: American Academy of Allergy Asthmaand Immunology and American College of Allergy, Asthma and Immunology

Disclosure: Meda Honoraria Speaking and teaching; Teva Honoraria Speaking and teaching; AstraZenecaHonoraria Speaking and teaching

Robert K Bush, MD Professor of Medicine (CHS, Emeritus), University of Wisconsin School of Medicine andPublic Health; Chief of Allergy (retired), William S Middleton Veterans Affairs Hospital

Robert K Bush, MD is a member of the following medical societies: American Academy of Allergy Asthma andImmunology and American College of Physicians

Disclosure: University of WI- Madison Emeritus- Reitred; Wm S. Middleton VA Hospital Retired Retired; TevaPharmaceuticals IRA Holding None; Associate Editor Journal Allergy Clinical Immunology Honoraria None

Michael R Bye, MD Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia UniversityCollege of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan StanleyChildren's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, AmericanCollege of Chest Physicians, and American Thoracic Society


Charles Callahan, DO Professor, Deputy Chief of Clinical Services, Walter Reed Army Medical Center

Charles Callahan, DO is a member of the following medical societies: American Academy of Pediatrics,American College of Chest Physicians, American College of Osteopathic Pediatricians, American ThoracicSociety, Association of Military Surgeons of the US, and Christian Medical & Dental Society


Peter G Canaday, MD Private Practice, Consultant Radiologist, Dakota Dunes, SD

Peter G Canaday, MD is a member of the following medical societies: American College of Chest Physicians,American College of Radiology, American Medical Association, American Roentgen Ray Society, NebraskaMedical Association, Radiological Society of North America, Society of Breast Imaging, and Society ofThoracic Radiology


G Patricia Cantwell, MD, FCCM Professor of Clinical Pediatrics, University of Miami, Leonard M MillerSchool of Medicine; Chief, Division of Pediatric Critical Care Medicine, Medical Manager, Urban Search &Rescue, South Florida TF-2, Medical Director, Holtz Children's Hospital Palliative Care Team, Medical Director,Tilli Kids – Pediatric Initiative of Hospice Care of SE Florida, Director, Pediatric Critical Care Transport, HoltzChildren's Hospital/Jackson Memorial Hospital

G Patricia Cantwell, MD, FCCM is a member of the following medical societies: American Academy of Hospiceand Palliative Medicine, American Academy of Pediatrics, American Heart Association, American TraumaSociety, National Association of EMS Physicians, Society of Critical Care Medicine, and Wilderness MedicalSociety


Lanny Garth Close, MD Chair, Professor, Department of Otolaryngology-Head and Neck Surgery, ColumbiaUniversity College of Physicians and Surgeons

Lanny Garth Close, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanAcademy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and NeckSurgery, American College of Physicians, American Laryngological Association, American Society for Headand Neck Surgery, and New York Academy of Medicine


Cheryl D Courtlandt, MD Faculty, Department of Pediatrics, University of North Carolina at Chapel Hill Schoolof Medicine; Medical Director, Pediatric Asthma Program, Attending Physician, Department of Pediatrics,Levine Children's Hospital, Carolinas Medical Center

Cheryl D Courtlandt, MD is a member of the following medical societies: Ambulatory Pediatric Association,American Academy of Pediatrics, and National Medical Association


Stephen C Dreskin, MD, PhD Professor of Medicine, Departments of Internal Medicine, Director of Allergy,Asthma, and Immunology Practice, University of Colorado Health Sciences Center

Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of AllergyAsthma and Immunology, American Association for the Advancement of Science, American Association ofImmunologists, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and JointCouncil of Allergy, Asthma and Immunology

Disclosure: Genentech Consulting fee Consulting; American Health Insurance Plans Consulting fee Consulting;Johns Hopkins School of Public Health Consulting fee Consulting; Array BioPharma Consulting fee Consulting

Pamela L Dyne, MD Professor of Clinical Medicine/Emergency Medicine, University of California, LosAngeles, David Geffen School of Medicine; Attending Physician, Department of Emergency Medicine, OliveView-UCLA Medical Center

Pamela L Dyne, MD is a member of the following medical societies: American Academy of EmergencyMedicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine


Barry J Evans, MD Assistant Professor of Pediatrics, Temple University Medical School; Director of PediatricCritical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's MedicalCenter

Barry J Evans, MD is a member of the following medical societies: American Academy of Pediatrics, AmericanCollege of Chest Physicians, American Thoracic Society, and Society of Critical Care Medicine


Michael R Filbin, MD Clinical Instructor, Department of Emergency Medicine, Massachusetts GeneralHospital

Michael R Filbin, MD is a member of the following medical societies: American College of EmergencyPhysicians, Massachusetts Medical Society, and Society for Academic Emergency Medicine


Joseph P Garry, MD, FACSM, FAAFP Associate Professor, Sports Medicine Faculty, Department of Familyand Community Medicine, University of Minnesota Medical School

Joseph P Garry, MD, FACSM, FAAFP is a member of the following medical societies: American Academy ofFamily Physicians, American College of Sports Medicine, American Heart Association, American MedicalSociety for Sports Medicine, and North American Primary Care Research Group


Murray Grossan, MD Consulting Staff, Tower Ear, Nose and Throat

Murray Grossan, MD is a member of the following medical societies: American Medical Association, AmericanTinnitus Association, California Medical Association, and Los Angeles County Medical Association

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Payel Gupta, MD Department of Allergy and Immunology, ENT Faculty Practice

Payel Gupta, MD is a member of the following medical societies: American College of Physicians


William F Kelly III, MD Assistant Professor of Medicine, Uniformed Services University of the HealthSciences; Staff Physician, Division of Pulmonary/Critical Care Medicine, Department of Medicine, Walter ReedArmy Medical Center

William F Kelly III, MD is a member of the following medical societies: Alpha Omega Alpha, American Collegeof Chest Physicians, and American College of Physicians


Rick Kulkarni, MD Attending Physician, Department of Emergency Medicine, Cambridge Health Alliance,Division of Emergency Medicine, Harvard Medical School

Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy ofEmergency Medicine, American College of Emergency Physicians, American Medical Association, AmericanMedical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

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Eugene C Lin, MD Consulting Radiologist, Virginia Mason Medical Center; Clinical Assistant Professor ofRadiology, University of Washington School of Medicine

Eugene C Lin, MD is a member of the following medical societies: American College of Nuclear Medicine,American College of Radiology, Radiological Society of North America, and Society of Nuclear Medicine


Markus Little, MD Resident Physician, Department of Emergency Medicine, State University of New YorkDownstate Medical Center


Jeffrey A Miller, MD Associate Adjunct Professor of Clinical Radiology, University of Medicine and Dentistryof New Jersey; Faculty, Department of Radiology, Veterans Affairs of New Jersey Health Care System

Jeffrey A Miller, MD is a member of the following medical societies: American Roentgen Ray Society, Societyfor Health Services Research in Radiology, and Society of Thoracic Radiology


Daniel R Neuspiel, MD, MPH, FAAP Director of Ambulatory Pediatrics, Levine Children's Hospital, CarolinasMedical Center; Adjunct Clinical Professor of Pediatrics, University of North Carolina School of Medicine

Daniel R Neuspiel, MD, MPH, FAAP is a member of the following medical societies: American Academy ofPediatrics, American College of Physician Executives, American Public Health Association, New YorkAcademy of Medicine, and Phi Beta Kappa


John D Newell Jr, MD Professor of Radiology, Head, Division of Radiology, National Jewish Health;Professor, Department of Radiology, University of Colorado School of Medicine

John D Newell Jr, MD is a member of the following medical societies: American College of Chest Physicians,American College of Radiology, American Roentgen Ray Society, American Thoracic Society, Association ofUniversity Radiologists, Radiological Society of North America, and Society of Thoracic Radiology

Disclosure: Siemens Medical Grant/research funds Consulting; Vida Corporation Ownership interest Boardmembership; TeraRecon Grant/research funds Consulting; eMedicine Honoraria Consulting; Humana PressHonoraria Other

John J Oppenheimer, MD Clinical Associate Professor, Department of Medicine, University of Medicine andDentistry of New Jersey; Director of Clinical Research, Pulmonary and Allergy Associates, PA

John J Oppenheimer, MD is a member of the following medical societies: American Academy of AllergyAsthma and Immunology and American College of Allergy, Asthma and Immunology

Disclosure: AZ Consulting fee Consulting; AZ Grant/research funds Independent contractor; Glaxo Consultingfee Consulting; Glaxo Grant/research funds Independent contractor; Merck Consulting fee Consulting; MerckGrant/research funds Independent contractor; SRXA Consulting

Stephen Rosenfeld, MD Professor Emeritus, Department of Medicine, Allergy, Immunology andRheumatology Unit, University of Rochester School of Medicine and Dentistry

Stephen Rosenfeld, MD is a member of the following medical societies: American Academy of Allergy Asthmaand Immunology, American Association of Immunologists, American Federation for Clinical Research, ClinicalImmunology Society, and Medical Society of the State of New York

Immunology Society, and Medical Society of the State of New York


Constantine K Saadeh, MD President, Allergy ARTS, LLP; Principal Investigator, Amarillo Center for ClinicalResearch, Ltd

Constantine K Saadeh, MD is a member of the following medical societies: American Academy of AllergyAsthma and Immunology, American College of Rheumatology, American Medical Association, SouthernMedical Association, and Texas Medical Association


Anthony J Saglimbeni, MD President, South Bay Sports and Preventive Medicine Associates; PrivatePractice; Team Internist, San Francisco Giants; Team Internist, West Valley College; Team Physician,Bellarmine College Prep; Team Physician, Presentation High School; Team Physician, Santa Clara University;Consultant, University of San Francisco, Academy of Art University, Skyline College, Foothill College, De AnzaCollege

Anthony J Saglimbeni, MD, is a member of the following medical societies: California Medical Association andSanta Clara County Medical Association


Assaad J Sayah, MD Chief, Department of Emergency Medicine, Cambridge Health Alliance

Assaad J Sayah, MD is a member of the following medical societies: National Association of EMS Physicians


Thomas Scanlin, MD Chief, Division of Pulmonary Medicine and Cystic Fibrosis Center, Department ofPediatrics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School

Thomas Scanlin, MD is a member of the following medical societies: American Association for theAdvancement of Science, American Society for Biochemistry and Molecular Biology, American ThoracicSociety, Society for Pediatric Research, and Society for Pediatric Research


Adam J Schwarz, MD Consulting Staff, Critical Care Division, Pediatric Subspecialty Faculty, Children'sHospital of Orange County

Adam J Schwarz, MD is a member of the following medical societies: American Academy of Pediatrics and PhiBeta Kappa


Girish D Sharma, MD Associate Professor of Pediatrics, Rush Medical College; Director, Section of PediatricPulmonology and Rush Cystic Fibrosis Center, Rush University Medical Center

Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics,American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland


Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine,Research Director, State University of New York College of Medicine; Consulting Staff, Department ofEmergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians andSociety for Academic Emergency Medicine


William W Storms, MD Clinical Professor, University of Colorado Health Sciences Center; Private Practice,The William Storms Allergy Clinic, Colorado Springs, Colorado

Disclosure: Amgen Grant/research funds None; AstraZeneca Honoraria Consulting; AstraZeneca HonorariaSpeaking and teaching; Consumer Reports/Consumer Union Honoraria Consulting; Genentech Grant/researchfunds None; Genentech Honoraria Consulting; Genentech Speaking and teaching; Meda Grant/research fundsNone; Meda Honoraria Consulting; Meda Honoraria Speaking and teaching

Russell D White, MD Professor of Medicine, Professor of Orthopedic Surgery, Director of Sports MedicineFellowship Program, Medical Director, Sports Medicine Center, Head Team Physician, University of Missouri-Kansas City Intercollegiate Athletic Program, Department of Community and Family Medicine, University ofMissouri-Kansas City School of Medicine, Truman Medical Center-Lakewood

Russell D White, MD is a member of the following medical societies: Alpha Omega Alpha, American Academyof Family Physicians, American Association of Clinical Endocrinologists, American College of Sports Medicine,American Diabetes Association, and American Medical Society for Sports Medicine


Craig C Young, MD Professor, Departments of Orthopedic Surgery and Community and Family Medicine,Medical Director of Sports Medicine, Director of Primary Care Sports Medicine Fellowship, Medical College ofWisconsin

Craig C Young, MD is a member of the following medical societies: American Academy of Family Physicians,American College of Sports Medicine, American Medical Society for Sports Medicine, and Phi Beta Kappa


Mark Zwanger, MD, MBA Assistant Professor, Department of Emergency Medicine, Jefferson MedicalCollege of Thomas Jefferson University

Mark Zwanger, MD, MBA is a member of the following medical societies: American Academy of EmergencyMedicine, American College of Emergency Physicians, and American Medical Association


Specialty Editor BoardMichael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine;Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthmaand Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthmaand Immunology, American Association of Immunologists, American College of Allergy, Asthma andImmunology, American Society for Clinical Investigation, American Thoracic Society, and Association ofAmerican Physicians

Disclosure: Alcon Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting;Schering/Merck Consulting fee Consulting; Teva Consulting fee Consulting; Meda Honoraria Speaking andteaching; Ista Consulting

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Robert E O'Connor, MD, MPH Professor and Chair, Department of Emergency Medicine, University of VirginiaHealth System

Robert E O'Connor, MD, MPH is a member of the following medical societies: American Academy ofEmergency Medicine, American College of Emergency Physicians, American College of Physician Executives,American Heart Association, American Medical Association, Medical Society of Delaware, NationalAssociation of EMS Physicians, Society for Academic Emergency Medicine, and Wilderness Medical Society


Arlen D Meyers, MD, MBA Professor, Department of Otolaryngology-Head and Neck Surgery, University ofColorado School of Medicine

Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plasticand Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, and AmericanHead and Neck Society

Disclosure: Covidien Corp Consulting fee Consulting; US Tobacco Corporation Unrestricted gift Unknown; AxisThree Corporation Ownership interest Consulting; Omni Biosciences Ownership interest Consulting; SentegraOwnership interest Board membership; Syndicom Ownership interest Consulting; Oxlo Consulting; MedvoyOwnership interest Management position; Cerescan Imaging Honoraria Consulting; GYRUS ACMI HonorariaConsulting

Chief EditorZab Mosenifar, MD Director, Division of Pulmonary and Critical Care Medicine, Director, Women's GuildPulmonary Disease Institute, Professor and Executive Vice Chair, Department of Medicine, Cedars SinaiMedical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD is a member of the following medical societies: American College of Chest Physicians,American College of Physicians, American Federation for Medical Research, and American Thoracic Society


AcknowledgmentsThe authors and editors of eMedicine gratefully acknowledge the contributions of previous authors MichaelGoldman, MD, Jan Malacara, PA-C, Rohit K Katial, MD, A Antoine Kazzi, MD, Araz Marachelian, MD, andJannette Collins, MD, MEd, FCCP, to the development and writing of the source articles.

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