Asthma: a syndrome composed of heterogeneous diseases

doi:10.1016/S1081-1206(10)60826-5

Annals of Allergy, Asthma & Immunology

Volume 101, Issue 1, July 2008, Pages 1-9

https://doi.org/10.1016/S1081-1206(10)60826-5 Get rights and content

Objective

To review the concept that asthma comprises distinct heterogeneous inflammatory disorders characterized by patients showing different phenotypes with distinct genetic components, environmental causes, and immunopathologic signatures.

Data Sources

Ovid MEDLINE and PubMed databases from 1950 to the present time were searched for relevant articles and references regarding the heterogeneity of asthma.

Study Selection

Articles that described the various phenotypes of asthma were used for this review.

Results

Asthma is unlikely to be a single disease but rather a series of complex, overlapping individual diseases or phenotypes, each defined by its unique interaction between genetic and environmental factors. These conditions include syndromes characterized by allergen-exacerbated, nonallergic, and aspirin-exacerbated factors along with syndromes best distinguished by their pathologic findings (eosinophilic, neutrophilic, pauci-granulocytic), response to therapy (corticosteroid resistant), and natural history (remodeling prone). Additional phenotypes will almost certainly be identified as advances in genetics and other profiling methods are made and will be accompanied by the availability of clear biomarkers for distinguishing among them.

Conclusions

Responses to asthma medications vary considerably among patients, likely reflecting, at least in part, the differing sensitivities of the various asthma phenotypes. Selecting the best possible treatment course in individual patients will be aided by clearly identifying the different phenotypes. Physicians need to recognize this when making decisions to adjust treatment to improve asthma control.

Section snippets

INTRODUCTION

Asthma is a syndrome characterized by the presence of chronic inflammation, resulting in airflow obstruction and bronchial hyperresponsiveness that causes wheezing, coughing, and dyspnea.¹ However, asthma is unlikely to be a single disease but rather a series of complex, overlapping individual diseases or phenotypes, each defined by its unique interaction between genetic and environmental factors (Table 1).² Precisely defining each phenotype may allow better understanding of their

ALLERGEN-EXACERBATED (ALLERGIC) ASTHMA

The genetic predisposition for developing IgE-mediated responses to allergens is the strongest risk factor for developing asthma.¹ Most cases of asthma, especially among patients with childhood- or adolescence-onset asthma, are associated with dysregulation of the allergic cascade that drives airway inflammation.³ The incidence of allergy increases with symptom frequency and severity, particularly in children with asthma.⁴ Similarly, allergic sensitization was detected by a positive skin test

NONALLERGIC (INTRINSIC) ASTHMA

Nonallergic asthma—often described as intrinsic asthma—is characterized by more likely onset during adulthood, female predominance, higher degree of severity, and more extensive chronic hyperplastic eosinophilic sinusitis with nasal polyposis.¹⁵ Population-based studies have suggested that nonallergic asthma is associated with prior noninfectious rhinitis and cigarette smoking,16, 17 as well as distinct genetic factors.

The distinct genetic profile of each asthma phenotype is increasingly

ASPIRIN-EXACERBATED RESPIRATORY DISEASE

Aspirin-exacerbated respiratory disease (AERD) is a distinct syndrome characterized by aspirin sensitivity, asthma, chronic hyperplastic eosinophilic sinusitis, nasal polyps, and circulating eosinophilia (Table 2).24, 25 Allergic sensitization is often absent, occurring at a frequency consistent with its prevalence in the population, and does not appear to be a component in the etiology of this disorder. When present, however, allergic sensitization is a comorbid condition that contributes to

PATHOLOGIC PHENOTYPES OF ASTHMA

Several pathologic phenotypes of severe asthma have been proposed, each associated with distinct clinical, inflammatory, and repair processes. These phenotypes include eosinophilic and noneosinophilic forms of asthma (Fig 1), with noneosinophilic asthma further divided into neutrophilic and pauci-granulocytic phenotypes.34, 35

CME Examination

1-6, Borish L, Culp JA. 2008;101:1-9.

CME Test Questions

1.
What percentage of patients whose asthma is not exacerbated by allergens have positive prick skin test results?
- a.
  >60%
- b.
  30% to 60%
- c.
  10% to 30%
- d.
  1% to 10%
- e.
  <1%
2.
Which of the following allergens is not associated with increased asthma morbidity?
- a.
  dust mite
- b.
  cat
- c.
  Alternaria
- d.
  Curvularia spp
- e.
  Timothy
3.
Long-term (approximately 3 month) allergen avoidance is associated with which of the following?
- a.
  loss of airway hyperreactivity to methacholine
- b.
  reduction in allergen specific IgE concentrations
- c.
  decreased reactivity to histamine
- d.

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Twenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent.
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Abi1 mediates airway smooth muscle cell proliferation and airway remodeling via Jak2/STAT3 signaling
2022, iScience
Citation Excerpt :
Asthma is a complex disease whose pathogenesis likely differs among multiple asthma phenotypes (Borish and Culp, 2008; Carr and Bleecker, 2016; Prakash, 2016; Prakash et al., 2017).
Asthma is a complex pulmonary disorder with multiple pathological mechanisms. A key pathological feature of chronic asthma is airway remodeling, which is largely attributed to airway smooth muscle (ASM) hyperplasia that contributes to thickening of the airway wall and further drives asthma pathology. The cellular processes that mediate ASM cell proliferation are not completely elucidated. Using multiple approaches, we demonstrate that the adapter protein Abi1 (Abelson interactor 1) is upregulated in ∼50% of ASM cell cultures derived from patients with asthma. Loss-of-function studies demonstrate that Abi1 regulates the activation of Jak2 (Janus kinase 2) and STAT3 (signal transducers and activators of transcription 3) as well as the proliferation of both nonasthmatic and asthmatic human ASM cell cultures. These findings identify Abi1 as a molecular switch that activates Jak2 kinase and STAT3 in ASM cells and demonstrate that a dysfunctional Abi1-associated pathway contributes to the progression of asthma.

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: Funding Sources: Financial support was provided by National Institutes of Health grants RO1 AI057438 and AI50989. Support for third-party writing assistance for this article was provided by Genentech Inc.

View full text

CME ReviewAsthma: a syndrome composed of heterogeneous diseases

Objective

Data Sources

Study Selection

Results

Conclusions

Section snippets

INTRODUCTION

ALLERGEN-EXACERBATED (ALLERGIC) ASTHMA

NONALLERGIC (INTRINSIC) ASTHMA

ASPIRIN-EXACERBATED RESPIRATORY DISEASE

PATHOLOGIC PHENOTYPES OF ASTHMA

CME Examination

CME Test Questions

Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007

J Allergy Clin Immunol

Asthma: defining of the persistent adult phenotypes

Lancet

Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab)

Pediatrics

Which clinical subgroups within the spectrum of child asthma are attributable to atopy?

Chest

High prevalence of skin test positivity in severe or difficult-to-treat asthma

J Asthma

The role of the mast cell in the pathophysiology of asthma

J Allergy Clin Immunol

The role of immunoglobulin E in allergy and asthma

Am J Respir Crit Care Med

The pro- and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (Fc epsilon RI)

Immunobiology

Anti-TNF-alpha and Th1 cytokine-directed therapies for the treatment of asthma

Curr Opin Allergy Clin Immunol

Indoor allergens and asthma: report of the Third International Workshop

J Allergy Clin Immunol

Antigen avoidance in a mountain environment: influence on basophil releasability in children with allergic asthma

J Allergy Clin Immunol

Reduction of bronchial hyperreactivity during prolonged allergen avoidance

Lancet

Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma

Clin Exp Allergy

Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma

Am J Respir Crit Care Med

Clinical phenotypes of asthma

Curr Opin Pulm Med

Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort

BMJ

Rhinitis increase the risk for adult-onset asthma-a Swedish population-based case-control study (MAP-study)

Respir Med

A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma

Am J Respir Crit Care Med

Collaborative studies on the genetics of asthma-National Heart, Lung and Blood Institute

Clin Exp Allergy

Prevalences of positive skin test responses to 10 common allergens in the US population: results from the third National Health and Nutrition Examination Survey

J Allergy Clin Immunol

Aeroallergen sensitization in healthy children: racial and socioeconomic correlates

J Pediatr

Elevation of total serum immunoglobulin E is associated with asthma in nonallergic individuals

Eur Respir J

IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity

Am J Respir Crit Care Med

Chronic hyperplastic eosinophilic sinusitis as a predictor of aspirin-exacerbated respiratory disease

Ann Allergy Asthma Immunol

Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs

Curr Allergy Asthma Rep

Natural history and clinical features of aspirin-exacerbated respiratory disease

Clin Rev Allergy Immunol

Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma

J Allergy Clin Immunol

CME Review
Asthma: a syndrome composed of heterogeneous diseases