Pulmonary Medicine

Asthma (include occupational asthma): Pathogenesis and Epidemiology

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What every physician needs to know:

Asthma is common disease in both adults and children. It ranks as the second leading cause of hospital admission for children. Accurate determination of the prevalence of asthma is difficult, however, because clinicians and researchers employ many definitions of the disorder. Presentations of asthma are variable, and an understanding of asthma pathophysiology is incomplete. Furthermore, significant individual variability exists with regard to genetic predisposition, co-morbid conditions, and triggering exposures.

Despite significant recent advances, a unified understanding of the physiology, histology, and immunology of asthma remains elusive, in part because of the lack of a clear correlation among symptoms, triggers, and treatment efficacy. Consequently, no definitive test exists to confirm the diagnosis of asthma or to guide the selection of treatment. Notably, several characteristics of asthma are common to many phenotypes, including airway inflammation, airway hyper-responsiveness, and reversible airflow obstruction.

Classification:

Definition of Asthma

The many definitions of asthma all have in common the finding of a pathologic decline in lung function, which involves bronchial hyperreactivity (BHR) and at least a component of partially reversible airway obstruction. With BHR, bronchospasm is easily initiated in response to various triggers and is likely the result of underlying chronic airway inflammation. Unfortunately, in children, BHR is difficult to assess; in adults, factors other than asthma, such as chronic bronchitis, may cause BHR.

According to the National Heart, Lung and Blood Institute (NHLBI) Expert Report 3 (EPR3) - Guidelines for the Diagnosis and Management of Asthma, asthma is defined as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role: in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Reversibility of airflow limitation may be incomplete in some patients with asthma."

This definition is relatively nonspecific and likely includes other diseases. However, the definition is useful in identifying patients for whom a particular management strategy is likely to be effective. Given this definition, asthma may present in a variety of ways that vary by age, severity, co-morbidities, triggering stimuli, and ability to detect BHR.

Asthma in Children

Asthma in young children may be difficult to diagnose with certainty because of difficulty in determining quantitative measures of BHR. In addition, symptoms may be transient, occurring only during upper respiratory tract infections. In children over the age of five, spirometry may performed effectively and obstruction detected; in younger children, pulmonary function testing is usually not possible or is inaccurate. Many young children who have symptoms characteristic of asthma, including wheezing and coughing (especially at night), may not have chronic airway inflammation.

The diagnosis of asthma becomes more likely when respiratory symptoms are recurrent or associated with an extrinsic trigger, such as cold air, exercise or activity, or allergens or irritants. Many children have wheezing associated with viral illnesses. Some will develop asthma as older children or adults, but many do not. In fact, two-thirds of children labeled as “transient wheezers” early in life no longer have symptoms by the time they are ten.

Asthma in Adults

In adults, symptoms of asthma include dyspnea, chest tightness, cough, and wheezing. However, just as in children, not all symptoms may be present in an individual patient. Assessment of BHR in adults is much easier than it is in children, and BHR is often the basis on which the diagnosis of asthma is made. However accurate testing requires properly performed spirometry, including a good effort by the patient. Pulmonary function testing reveals a decreased ratio of Forced Expiratory Volume in one second (FEV1) to Forced Vital Capacity (FVC). An FEV1/FVC ratio less than 80 percent is considered an “obstructive” pattern. An improvement in FEV1 of at least 12 percent, accompanied by a minimum increment in FEV1 of 200 mL following bronchodilator administration, is also highly suggestive of asthma.

In adults, other diseases, such as COPD, are characterized by reduced FEV1/FVC and bronchodilator responsiveness. However, in COPD the improvement in airflow obstruction following bronchodilator is smaller and less complete than in asthma. Other diseases may mimic or co-exist with asthma. Allergic Bronchopulmonary Aspergillosis (ABPA), aspirin-exacerbated respiratory disease (AERD), and vocal cord dysfunction (VCD), among others, must be considered. Methacholine challenge testing (MCT) has been used to assess BHR. However, MCT is normal in some patients with asthma and may be abnormal in some who do not have asthma.

Are you sure your patient has asthma? What should you expect to find?

See chapter, Asthma: Clinical Manifestations and Management .

Beware: there are other diseases that can mimic asthma:

See chapter, Asthma: Clinical Manifestations and Management.

How and/or why did the patient develop asthma?

Overall Prevalence of Asthma

In 2009, the National Center for Health Statistics of the Centers for Disease Control estimated the prevalence of asthma in the United States at 17.5 million (7.1%) adults and 7.1 million (9.6%) children. More than half had asthma that was sufficiently severe or poorly uncontrolled to cause an asthma attack within the previous year. These patients made 17 million visits to doctors' offices and emergency rooms and accounted for over 456,000 hospitalizations. Despite advances in diagnosis and treatment, asthma remains a serious disease that is responsible for more than three thousand deaths annually (1.1 per 100,000 total population).

From 1980 to 1997, asthma prevalence in the United States increased significantly, from 4 percent to 6 percent. Changes in the National Health Interview Survey in 1997 make direct comparison of more recent and historical data impossible, but asthma prevalence since 2001 also has increased (Figure 1). However, the rate of asthma attacks, which may be a more important measure, has remained constant, suggesting either recent improvements in asthma management or inclusion of less severe phenotypes.

Figure 1.

US Asthma Prevalence

Asthma Prevalence by Age and Gender

Asthma prevalence is unevenly distributed across gender, age, geography, and income level. In children, asthma is significantly more common among boys (Figure 2). In early adolescence, the prevalence is equal between the sexes, and asthma becomes more common in women throughout most of adulthood. The overall prevalence of asthma decreases with age in males, but it may increase in females, peaking in the late teenage years. It reaches a plateau by age 25 years for both genders. In older adulthood, women are less likely than men to have asthma. However, the prevalence of asthma in men and women is equal by age 85.

Figure 2.

Age Specific Asthma Prevalence

Asthma Prevalence by Racial and Ethnic Group, Geography, and Income

Asthma prevalence varies significantly by ethnic group. In the United States, asthma affects 8.2 percent of non-Hispanic whites, 11.1 percent of non-Hispanics blacks, and 6.3 percent of Hispanics. Among Hispanics, the prevalence varies widely, with 16.6 percent of Puerto Ricans affected compared with only 4.9 percent of those of Mexican heritage (Figure 3). The reasons for these difference are not clear.

Figure 3.

Prevalence of Asthma by Subgroup

The prevalence of asthma in the Northeast and Midwest is slightly higher than in the South or West. Urban dwellers have a slightly lower prevalence of asthma than do those in rural areas. These differences are much smaller, however, than those observed among various ethnic groups. Finally, asthma prevalence also correlates with income level, decreasing dramatically as income increases above the poverty line.

Consequences of Asthma

Asthma results in considerable morbidity and utilization of health care resources. In 2009, asthma-related outpatient physician visits totaled 7.8 million for adults and 7.5 million for children. In the same year, 1.1 million adults and 0.6 million children had asthma-related emergency room visits, and asthma-related hospitalizations exceeded 299,000 for adults and 157,000 for children. Although black and white asthmatic patients generate the same relative numbers of ambulatory visits for asthma, black patients are more than three times as likely to visit the emergency room and nearly twice as likely to be hospitalized as white patients. Finally, of the 3447 asthma deaths reported in 2007, 185 were children. Asthma-related mortality is higher among blacks than among other ethnic groups (Figure 4).

Figure 4.

Asthma Mortality by Race/Ethnicity

In addition to generating significant health care expenses, asthma accounts for substantial costs in lost productivity. Asthma is responsible for 10.5 million missed school days, as nearly 60 percent of children with asthma miss at least one day of school annually. In addition, 5.5 percent of asthmatic children have a long-term reduction in activity level compared with other children of the same age.

Employed adults with asthma miss more than 14 million work days annually, as nearly 34 percent of adult asthmatics miss at least one day of work annually. An additional 22 million days of household work or other work are lost annually among asthmatics who are not employed outside the home. Estimates suggest that asthma-related costs were more than $56 billion in 2007, or about $3300 per asthmatic.

Natural History of Asthma

In the majority of cases, asthma begins during childhood. Because objective measures of airway dysfunction are difficult to obtain in young children, a major focus for diagnosis is detection of clinically apparent wheezing. During the first three years of life, half of children have wheezing associated with a viral upper respiratory infection. Some of these infants likely have small airways that predispose them to wheezing in the presence of even small amounts of airway inflammation or mucus production.

This finding may be even more prevalent in children who are born prematurely, who have underdeveloped lungs. While the majority of these children recover without subsequent asthma symptoms, a significant number continue to have asthma-associated symptoms through adolescence and beyond. Some will appear to “outgrow” their asthma, only to have a recurrence of symptoms as an adult.

Unlike children, adults diagnosed with asthma rarely have complete remission of their disorder. Some of these adults may have had symptoms of asthma and atopy as children. Adult-onset asthma is common and may be atopic or non-atopic in origin. The disorder may be intrinsic or related to occupational or other exposures. Although adult-onset asthma appears not to decrease life expectancy and not to worsen significantly over time, the risk of asthma-related death increases with age and may be underreported. Asthma is a source of significant morbidity and may be life-threatening, especially when it is present with other comorbidities, such as cardiac disease and severe food or medication allergies.

Which individuals are at greatest risk of developing asthma?

Important socioeconomic risks for development of asthma include:

  • Childhood

  • Black race

  • Lower income

Important medical risks for development of asthma include:

  • Allergic diatheses

  • Family history of asthma or allergies

  • Eosinophilic disorders

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The pathophysiology of asthma is characterized by airway inflammation. Pathological examination of the lungs may identify cellular and other components of airway inflammation.

What is Airway Inflammation?

Airway inflammation is thought to be a major underlying cause of asthma. However, details of the inflammatory process are a source of considerable controversy. Furthermore, mechanisms other than inflammation may be important since not all asthma responds to glucocorticoids or anti-IgE therapy. A variety of cells from various portions of the immune system are present in airway biopsies obtained from asthmatics.

Whether asthma is primarily a disease of innate immunity involving cells like eosinophils and neutrophils or primarily an abnormal adaptive immune response driven by lymphocytes remains unclear. Regardless of its cause, chronic inflammation leads to the classic sequelae of tissue damage and fibrosis, as evident in thickening of the lamina reticularis and smooth muscle hypertrophy. Chronic inflammation also promotes bronchial hyper-responsiveness, which is the hallmark of asthma.

Role of Eosinophils

Eosinophils are characteristically associated with both allergic disease and asthma. Biopsies from most patients with asthma demonstrate eosinophils, but the degree of eosinophilic infiltration correlates with disease severity. Furthermore, eosinophils produce large quantities of biologically active compounds (Table 1) that modulate immune function and impact other tissues, including nerves and endothelial cells. Although eosinophils are often present in asthmatic airways, eosinophil-driven inflammation does not mediate pathogenesis of the disorder in all asthma phenotypes.

Table 1.

Role of Cell Products in Asthma

Role of Neutrophils

Neutrophils appear to play an important role in asthma pathogenesis for some subtypes of the disease. Neutrophils are present in higher numbers in patients who have more severe disease, such as steroid-dependent asthma or fatal asthma. Like eosinophils, neutrophils generate a host of biologically active compounds that promote further inflammation and tissue damage (Table 1). However, it remains unclear whether neutrophils are directly responsible for asthma symptoms or are simply recruited to areas of pre-existing inflammation.

Role of Macrophages

Macrophages are important regulatory cells of the innate immune response. In response to stimulation, macrophages may enhance inflammation both directly and by recruiting other immune cells. Macrophages also produce anti-inflammatory cytokines, such as IL-10, and can re-orient the immune response by secreting IL-12, thereby promoting TH1, rather than allergic TH2, responses. In addition, macrophages and dendritic cells are potent antigen-presenting cells that activate adaptive immune responses and direct the nature of that response by secreting TH1- or TH2-promoting cytokines. Macrophages may also constitute a link between asthma and infections like respiratory syncitial virus (RSV).

Role of Mast Cells

Mast cells are important mediators of allergic disease, and they also play a role in host defense. Mast cells produce compounds, such as histamine, that cause allergic disease, and they drive allergic inflammation through production of cytokines and proteases. The classic trigger for mast cell activation is cross-linking of IgE on the cell surface; however, other non-specific triggers also induce mast cell activation.

Mast cells are key mediators of allergic disease and of allergy-associated asthma phenotypes. Consistent with this notion is the observation that administration of anti-IgE monoclonal antibody (omalizumab) effectively reduces symptoms for some patients with asthma. However, the response is variable, which underscores the fact that no single inflammatory pathway is responsible for all forms of asthma or all manifestations of the disorder.

Role of Lymphocytes

Lymphocytes, particularly CD4+ helper T cells, direct immune system activation. Although asthma is sometimes considered an atopic disease with many allergic asthma phenotypes, TH2 skewing is neither necessary nor sufficient for development of asthma. Certainly, some patients have a TH2 imbalance that involves T-cell-produced IL-4, -5, and -13, leading to eosinophil infiltration and local IgE class-switching by B cells.

However, IFNγ-induced promotion of TH1 responses does not decrease asthma severity, and IFNγ itself has been found to be elevated in some patients during asthma flares. Recently described TH9 cells are also upregulated in asthma and seem to be involved in allergic inflammation, although further research is needed to determine their significance in asthma. Absence or dysfunction of regulatory T cells may also play a role in asthma pathogenesis through failure to promote tolerance to inhaled agents, including allergens.

Role of Epithelial Cells

Epithelial cells contribute to the structure of the airways and provide a barrier to inhaled particles and other agents. In addition, airway epithelial cells are highly responsive to their environment and may influence local inflammation. In response to endogenous signals, as well as through interactions with immune cells, endothelial cells alter the expression of adhesion molecules on their surfaces and production of biologically active molecules, including cytokines and proinflammatory mediators (Table 1). These molecules act to recruit inflammatory cells to sites of epithelial cell damage, thus directly promoting inflammation. Some also have local effects, causing increased proliferation of endothelial cells and surrounding connective tissue, resulting in airway remodeling.

Acting in concert, the aforementioned collection of cells produces chronic airway inflammation. The relative contribution of each cell component may differ greatly among patients, perhaps accounting for the variability in symptoms and response to treatment. Furthermore, the relative contributions of these cells may vary within any one patient, depending on environmental exposures, infection, and other co-morbid conditions that account for asthma flares and difficulty in disease control. Regardless of the underlying cause, chronic airway inflammation leads to tissue damage.

Epithelial damage and repair processes, as reflected in increased epidermal growth factor receptor (EGFR) levels, correlate with asthma severity. Whether impaired epithelial repair processes drive the chronic inflammation or dysregulated inflammation results in chronic tissue damage remains unclear.

What imaging studies will be helpful in making or excluding the diagnosis of asthma?

See chapter, Asthma: Clinical Manifestations and Management.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of asthma?

Pulmonary function testing, including provocative lung testing, is a non-invasive way of assessing airway hyper-responsiveness.

What is Airway Hyper-responsiveness?

The bronchial smooth muscle in asthma is more likely in this condition to constrict in response to stimuli compared with normal airways. Such heightened responsiveness can be demonstrated by performing provocative lung testing, such as methacholine challenge testing (MCT). Inhalation of methacholine, a cholinergic agonist, produces more bronchoconstriction in response to a given dose in asthmatics than in individuals without asthma. This heightened responsiveness is expressed in a pulmonary function laboratory report as the "PC 20," the concentration of inhaled provocative agent that causes a 20 percent reduction in FEV1. Just as exogenously administered chemical agents may cause bronchoconstriction, other stimuli, such as cold air, particulates, allergens, and physical stimuli like exercise, may also induce contraction of bronchial smooth muscle.

Airway Hyper-responsiveness in Asthma

The individual response to bronchospasm-inducing stimuli varies widely. Most asthmatics demonstrate some degree of increased tendency for bronchospasm, but the range of responses among individuals without asthma is broad, and there is overlap between hyper-responsive non-asthmatics and minimally responsive asthmatics. Consequently, a clear cut-off that defines asthma on provocation challenge does not exist. A “positive” challenge is not required and is not used regularly for establishing the diagnosis. However, the extent of airway hyper-responsiveness does appear to correlate with severity of symptoms.

Cause of Airway Hyper-responsiveness

Airway inflammation is believed to underlie bronchial hyper-responsiveness. The number of inflammatory cells (including eosinophils, neutrophils, and T cells) recovered from bronchoalveolar lavage fluid from asthmatics who undergo bronchoscopy correlates with airway hyper-responsiveness. Adequate treatment with an inhaled corticosteroid decreases hyper-responsiveness, presumably by reducing cellular infiltration and resulting inflammation. However, what remain unknown are what effect inflammation has on airway smooth muscle cells and the underlying connective tissues responsible for the hyper-responsiveness, and whether the hyper-responsiveness is a direct effect of the inflammation or a consequence of long-term, chronic injury.

The Role of Airway Hyper-responsiveness in Asthma Symptoms

Airway hyper-responsiveness leads to airway obstruction, the pathophysiologic hallmark of asthma. Airway obstruction in asthma is largely a reversible process, with essentially normal airway lumen size in between asthma exacerbations. Notably, however, some degree of irreversible airway narrowing may occur over time as a result of airway remodeling, as described previously. Other factors, such as mucus plug formation, may also affect lumen patency.

Treatment of airway inflammation with oral or inhaled corticosteroids is aimed at reducing airway inflammation and mitigating airway remodeling, airway hyper-responsiveness, and mucus production. In contrast, use of inhaled beta-agonists like and other such agents targets a reduction in smooth muscle contraction. Although important in treating acute symptoms, the latter group of medications is short-acting and does not address the underlying cause of asthma symptoms.

Finally, other agents target specific pathways involved in inflammation; examples include leukotriene antagonists (e.g., montelukast, zafirlukast, and zileuton), antihistamines, and anti-IgE monoclonal antibody (e.g., omalizumab). Since each of the principal pathogenetic pathways plays a variable role in asthma pathogenesis among patients, the clinical benefit of the various classes of medications varies.

What diagnostic procedures will be helpful in making or excluding the diagnosis of asthma?

One consequence of chronic airway inflammation in asthma is so-called "airway remodeling," the histologic and cellular characteristics of which can be seen in specimens obtained through fiberoptic bronchoscopy. Although not routinely used for clinical purposes in diagnosing or managing asthma, bronchoscopy conducted in a research setting may provide valuable insight into the underlying mechanisms of disease pathogenesis.

Epithelial Damage

The bronchial epithelium consists of pseudostratified, ciliated, columnar cells that sit atop a lining of basal cells that are tightly adherent to the underlying basement membrane. Desquamation of the superficial columnar cells occurs in asthma in response to exposure to allergens or other irritants. Over time, these cells are replaced by simple, stratified, non-ciliated epithelial cells.

The damage is largely caused by products of inflammation (described above); however, evidence exists that airway epithelial cells in asthmatics are more susceptible to damage from inflammatory mediators, inhaled agents, and viral infection than are those in other people. Damage to the epithelium is also caused or enhanced by underlying tissue changes, including thickening and edema of the underlying submucosal tissue, a process that may not depend on the presence of chronic inflammation.

Submucosal Remodeling

Submucosal airway remodeling in asthma includes thickening of the lamina reticularis that underlies the basement membrane, deposition of collagen, and smooth muscle hypertrophy. The result is an increase in bronchial wall thickness that can be more than twice normal; the degree of thickening may or may not correlate with disease severity. The damage is also mediated by inflammatory cells, including those that reside normally in the tissue, such as macrophages, dendritic cells, and mast cells, as well as those recruited from the circulation, such as neutrophils, eosinophils, and lymphocytes.

Local mediators of this process include myofibroblasts, which, when activated by inflammatory signals, proliferate and increase collagen synthesis. The inflammatory signals include transforming growth factor beta (TGFβ), endothelial growth factor (EGF), tumor necrosis factor (TNF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and possibly vascular endothelial growth factor (VEGF).

Smooth Muscle Hypertrophy

Smooth muscle hypertrophy occurs throughout the airways of asthmatics. Much like the increase in subepithelial connective tissue cells, smooth muscle cell hypertrophy responds to chronic inflammation and repair signals, such as EGF. Repeated, aberrant smooth muscle contraction may also lead to an increase in muscle mass over time.

Consequences of Airway Remodeling

The driving force behind airway remodeling in asthma remains unclear. Some suggest that it is caused by chronic inflammation, while others suggest that the inflammatory processes simply occur in parallel with the airway remodeling that arises from disordered cellular regeneration and repair. Regardless of the cause, thickening of the airways combined with increased smooth muscle contraction leads to airway narrowing and obstruction of airflow. Even small increases in airway thickness may result in significant increases in airway resistance.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of asthma?

Although asthma is characterized by a familial predisposition, the disorder is polygenic and is associated with complex inheritance patterns that are strongly influenced by gene-environment interactions.

Genetics Versus Environmental Influences in Asthma

Genetic predisposition to asthma may outweigh environmental effects. Individuals from families with a history of asthma frequently develop the disorder despite markedly differing environmental exposures. Furthermore, no set of environmental exposures alone is routinely linked to development of asthma. As previously discussed, asthma is a disease with many phenotypes and is characterized by variability in severity and triggers. Application of the candidate gene approach and genome-wide association studies has resulted in identification of several genes and chromosome regions that appear to correlate with development of asthma.

Gene Associations in Asthma

Currently, more than 1800 studies that report on asthma and genetics are listed in the Genetic Association Database maintained by the NIH (http://geneticassociationb.nih.gov/). However, the majority of findings in the reports have not yet been replicated or proven to have clinical significance. While many of the genes associated with asthma are involved in immune system function, others are important for maintenance of connective tissues (e.g., matrix metalloproteinases and metallopeptidases), metabolic control, or other functions.

No single gene has been convincingly identified as being causally related to asthma in a large percentage of patients. Rather, asthma is thought to be a complex disease that results from the contributions of many genes. Epigenetic changes may also play a role. Histone modifications have been associated with bronchial hyperresponsiveness and corticosteroid resistance in asthma.

If you decide the patient has asthma, how should the patient be managed?

See chapter, Asthma: Clinical Manifestations and Management.

What is the prognosis for patients managed in the recommended ways?

See chapter, Asthma: Clinical Manifestations and Management.

What other considerations exist for patients with asthma?

See chapter, Asthma: Clinical Manifestations and Management.

What’s the evidence?

Akuthota, P, Xenakis, JJ, Weller, PF. "Eosinophils: offenders or general bystanders in allergic airway disease and pulmonary immunity". J Innate Immun. vol. 3. 2011. pp. 113-9.

Reviews evidence from animal models and human clinical trials that supports the importance of eosinophils in the pathogenesis of allergic airway disease.

Borish, L, Culp, JA. "Asthma: a syndrome composed of heterogeneous diseases". Ann Allergy Asthma Immunol. vol. 101. 2008. pp. 1-8.

Describes many of the phenotypes of asthma and discusses how they differ.

Busse, WW. "The relationship of airway hyperresponsiveness and airway inflammation: airway hyperresponsiveness in asthma: its measurement and clinical significance". Chest. vol. 138. 2010. pp. 4S-10S.

Part of a series of articles that discuss the cause, importance, and measurement of airway hyperresponsiveness in asthma.

http://www.hcup-us.ahrq.gov/kidoverview.jsp.

http://www.cdc.gov/nchs/fastats/asthma.htm.

http://www.cdc.gov/nchs/VitalStats.htm.

The CDC compiles data on medical resource usage, outcomes, and epidemiology for many diseases, including asthma.

Domingo, C, Moreno, A, Mirapeix, R. "Rationale for the use of immunomodulatory therapies in the Global Initiative for Asthma (GINA) step V asthma other than oral glucocorticosteroids". Intern Med J.. vol. 41. 2011. pp. 525-36.

Review of omalizumab and other immune-modulating treatments for asthma.

"Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma". National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. 2007 August 28, 2007.

EPR3, the consensus statement written by experts who care for patients with asthma, outlines the current state of knowledge for the epidemiology, pathophysiology, diagnosis, and treatment of asthma.

Fahy, JV. "Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies". Proc Am Thorac Soc. vol. 6. 2009. pp. 256-9.

Examines the role and interaction between eosinophils and neutrophils in asthma.

Holgate, ST, Roberts, G, Arshad, HS, Howarth, PH, Davies, DE. "The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis". Proc Am Thorac Soc. vol. 6. 2009. pp. 655-9.

Evidence presented suggests that the airway epithelium in asthma is abnormal and contributes to the development of asthma and asthma symptoms.

Lloyd, CM, Hessel, EM. "Functions of T cells in asthma: more than just T(H)2 cells". Nat Rev Immunol. vol. 10. 2010. pp. 838-48.

Discusses the roles of different T cell subsets in the allergic lung and therapies that may target them.

March, ME, Sleiman, PM, Hakonarson, H. "The genetics of asthma and allergic disorders". Discov Med. vol. 11. 2011. pp. 35-45.

Summary of the genome wide association studies in asthma and the functional themes and characteristics that underlie asthma revealed through genetic and genomic research.

Moiseeva, EP, Bradding, P. "Mast cells in lung inflammation". Adv Exp Med Biol. vol. 716. 2011. pp. 235-69.

Discusses the contribution of mast cells and their products to the pathophysiology of lung diseases.

North, ML, Ellis, AK. "The role of epigenetics in the developmental origins of allergic disease". Ann Allergy Asthma Immunol. vol. 106. 2011. pp. 355-61.

A review of the current research findings in the field of epigenetics pertaining to the developmental origins of allergic disease.

Stern, DA, Morgan, WJ, Halonen, M, Wright, AL, Martinez, FD. "Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study". Lancet. vol. 372. 2008. pp. 1058-64.

Describes the natural history of children who wheeze and discusses the risk of developing asthma long-term.

Suarez, CJ, Parker, NJ, Finn, PW. "Innate immune mechanism in allergic asthma". Curr Allergy Asthma Rep. vol. 8. 2008. pp. 451-9.

A review of the role of innate immune cells and molecules in modifying allergic immuneresponses.

Westergren-Thorsson, G, Larsen, K, Nihlberg, K. "Pathological airway remodelling in inflammation". Clin Respir J. vol. Suppl 1. 2010. pp. 1-8.

Review of airway remodeling with a focus on the underlying cells and molecular mechanisms.

Zeki, AA, Kenyon, NJ, Yoneda, K, Louie, S. "The adult asthmatic". Clin Rev Allergy Immunol 2011.

Reviews the progression of asthma into adulthood, including host and environmental factors.
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