Chest
Volume 133, Issue 2, February 2008, Pages 420-426
Journal home page for Chest

Original Research
Asthma
Differences in Airway Cytokine Profile in Severe Asthma Compared to Moderate Asthma

https://doi.org/10.1378/chest.07-1881Get rights and content

Background

Some studies of severe asthma suggest that persistence or alteration in the pattern of inflammation may be associated with the severity of the disease. Whether there are differences in the expression of the principal cytokines and chemokines relevant to eosinophilic and neutrophilic inflammation in the airway tissues of severe compared to moderate asthmatics has not been determined. The aim of this study was to compare the patterns of expression of representative T-helper (Th) type 1 (interferon [IFN]-γ) and Th-2 cytokines (interleukin [IL]-4, IL-5) and the neutrophil- and eosinophil-associated chemokines (IL-8 and eotaxin) in the airway tissues of patients with severe and moderate asthma.

Methods

Subjects with severe asthma (n = 24) and a comparison moderate asthma group (n = 26) were assessed using spirometry, induced sputum, exhaled nitric oxide, and bronchial biopsy. The expression of proteins of interest in the epithelium and subepithelium of the airway wall was examined by immunocytochemistry.

Results

Subjects with severe asthma were more symptomatic, had a lower FEV1, and had more sputum neutrophilia (p = 0.007) and eosinophilia (p = 0.001). Exhaled nitric oxide was similar between groups. IL-8 and IFN-γ expression were increased and IL-4 expression was decreased in severe asthma compared to moderate disease (p < 0.001 for each comparison). Eotaxin and IL-5 expression did not differ between the groups.

Conclusion

Patients with severe asthma have increases in neutrophils and eosinophils in the sputum, and differ in airway cytokine/chemokine expression from moderate asthmatics. Excess neutrophilia may be explained by increased expression of IL-8, but differences in eosinophilia do not appear to be associated with IL-5 and eotaxin expression.

Section snippets

Study Subjects

Physicians at two tertiary care centers were asked to identify patients with severe asthma who met the following criteria proposed by the ATS workshop on refractory asthma.10 For severe asthma, subjects were required to have received treatment with daily oral steroids for > 50% of the previous 12 months or to have been prescribed high-dose inhaled-steroid equivalent to > 880 μg/d of fluticasone, (ex-actuator) with at least one other add-on therapy (long acting β-agonist, leukotriene receptor

Clinical Characteristics

Characteristics of the 26 subjects with severe asthma and 24 subjects with moderate or treatment responsive asthma are provided in Table 1 . Subjects were of similar age, and there was a trend toward a higher proportion of women in the severe group. Four subjects in each group had smoked > 10 pack-years, and a similar proportion was obese as judged by a body mass index (BMI) ≥ 30 kg/m2. Among those in whom the age of onset could be determined, 18 of 21 subjects in the moderate group and 20 of

Discussion

We studied subjects with severe poorly controlled asthma, compliant with medication, and compared them to patients whose disease was moderate and managed successfully with regular inhaled steroids in conjunction with long-acting β-agonists in many instances. Despite high doses of inhaled or supplemental doses of oral corticosteroids, the patients with severe asthma had more airway inflammation as reflected in sputum eosinophilia and neutrophilia. Furthermore, these subjects expressed a

References (41)

  • BarnesPJ et al.

    Difficult asthma

    Eur Respir J

    (1998)
  • BenayounL et al.

    Airway structural alterations selectively associated with severe asthma

    Am J Respir Crit Care Med

    (2003)
  • WenzelSE et al.

    Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids

    Am J Respir Crit Care Med

    (1997)
  • NaseerT et al.

    Expression of IL-12 and IL-13 mRNA in asthma and their modulation in response to steroid therapy

    Am J Respir Crit Care Med

    (1997)
  • LeungDY

    Steroid-resistant asthma

    West J Med

    (1995)
  • HaukPJ et al.

    Increased glucocorticoid receptor β expression converts mouse hybridoma cells to a corticosteroid-insensitive phenotype

    Am J Respir Cell Mol Biol

    (2002)
  • American Thoracic Society

    Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions

    Am J Respir Crit Care Med

    (2000)
  • JuniperEF et al.

    Development and validation of a questionnaire to measure asthma control

    Eur Respir J

    (1999)
  • American Thoracic Society

    Standardization of spirometry, 1994 update

    Am J Respir Crit Care Med

    (1995)
  • American Thoracic Society. Recommendations for standardized procedures for the on-line and off-line measurement of...
  • Cited by (190)

    • T-cell responses in asthma exacerbations

      2022, Annals of Allergy, Asthma and Immunology
    • Management Strategies to Reduce Exacerbations in non-T2 Asthma

      2021, Journal of Allergy and Clinical Immunology: In Practice
      Citation Excerpt :

      Numerous studies have implicated a role for ongoing T1 inflammation in asthma, including identification of increased levels of T1 cytokines such as TNF-α26 and IFN-γ27 in bronchoalveolar lavage fluid of some patients with asthma. Studies of populations with severe asthma have identified higher expression of IFNG and numbers of IFN-γ+ cells in bronchoalveolar lavage samples28 and discovered increased numbers of IFN-γ+ staining cells in airway biopsies.29 Transcriptomic analyses have also identified increased expression of multiple transcripts involved in T1 inflammation.30-32

    • Pathology of Asthma

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    View all citing articles on Scopus

    Dr. Ernst and Dr. Martin have received an unrestricted grant from GlaxoSmithKline that was in part used to support this project.

    None of the other authors have any conflicts of interest to declare.

    This study and the Difficult Asthma Program are supported by the Richard and Edith Strauss Canada Foundation and an unrestricted grant from GlaxoSmithKline, Canada. Joanne Shannon was the recipient of the Ann Woolcock Memorial Fellowship financed by GlaxoSmithKline, Canada.

    View full text