Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough

doi:10.1016/j.jaci.2004.11.049

Journal of Allergy and Clinical Immunology

Volume 115, Issue 4, April 2005, Pages 728-736

https://doi.org/10.1016/j.jaci.2004.11.049 Get rights and content

Background

Cough is a frequent symptom in children, but the differentiation of asthmatic cough from cough of other origins can be difficult. Chemokines recruit T lymphocytes to inflamed tissues, and the corresponding chemokine receptors are differentially expressed on T_H1 and T_H2 cells.

Objective

We sought to determine whether levels of T_H1/T_H2-related chemokines and their receptors differ in bronchoalveolar lavage fluid (BALF) from 12 children with allergic asthma, 15 nonatopic children with chronic cough, and 10 children without airway disease.

Methods

The T_H1-related (IFN-γ–inducible protein of 10 kd [IP-10], IFN-γ–inducible T cell α chemoattractant [ITAC], monokine induced by IFN-γ [Mig], and IFN-γ) and T_H2-related (thymus- and activation-regulated chemokine [TARC], macrophage-derived chemokine [MDC], IL-5, and IL-4) chemokines and cytokines were quantified in BALF by ELISA and a particle-based multiplex array. Percentages of pulmonary lymphocytes expressing CXCR3⁺ and CCR5⁺ (T_H1) and CCR4⁺ and CCR3⁺ (T_H2) chemokine receptors were determined in BALF by flow cytometry.

Results

Pulmonary CCR4⁺CD4⁺ cells and levels of TARC and MDC were significantly increased in asthmatic children versus children with chronic cough or without airway disease. In asthmatic children CCR4⁺CD4⁺ cells correlated positively with levels of TARC, MDC, and serum IgE levels and negatively with FEV₁. In contrast, CXCR3⁺CD8⁺ cells and levels of ITAC were significantly increased in children with non-atopic chronic cough compared with the other groups. In children with chronic cough, CXCR3⁺CD8⁺ cells correlated with levels of ITAC and IFN-γ.

Conclusion

Pulmonary CCR4⁺CD4⁺ and CXCR3⁺CD8⁺ cells and their ligands TARC, MDC, and ITAC clearly differentiate asthmatic children from nonatopic children with chronic cough. The analysis of these markers could facilitate the diagnostic discrimination of asthma versus other reasons for chronic cough in children.

Section snippets

Patients

Children and adolescents requiring fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) at the Department of Pulmonology and Allergology of the University Children's Hospital of Munich from 1999 through 2004 were considered for inclusion in this study. The study population was set up retrospectively by an independent investigator (M.G.) who was blinded to the experimental results. Patients were selected if allergic asthma or chronic cough could be diagnosed according to the criteria

Patients

Thirty-seven children (21 male, 16 female patients; median age, 8.3 years; age range, 5.2-17.3 years) were selected for this study (Table I). Twelve children fulfilled the criteria for allergic asthma. These children were atopic, as shown by positive skin prick test results, increased total serum IgE levels, and specific serum IgE levels. According to the National Institutes of Health classification,²³ all asthmatic children had moderate-to-severe persistent asthma with symptoms for at least 3

Discussion

The present work demonstrates that TARC and MDC levels in BALF were increased in asthmatic children, whereas ITAC and, to a lesser degree, IFN-γ levels were increased in nonatopic, nonasthmatic children with chronic cough. These findings were accompanied by increased frequencies of BALF CCR4⁺CD4⁺ T cells in children with asthma, whereas CXCR3⁺CD8⁺ lymphocytes were significantly more frequent in children with chronic cough compared with children in the asthmatic or control groups. Significant

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LTRAs must theoretically be effective against cough of asthmatic subjects through its “anti-asthma” effects, while evidence supporting direct antitussive effects of cys-LTs on “cough receptors” is scarce. An important clinical question is that whether LTRAs involve non-specific antitussive effects. While a definite answer is not available yet, this possibility seems unlikely at the moment, although some secondary anti-inflammatory properties have been reported for montelukast. This issue needs to be clarified by future research to avoid overuse of this expensive class of medication.

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: Supported by grants from the Else-Kröner-Fresenius Stiftung, the Friedrich-Baur-Stiftung, and the University and Science Program of the Ludwig-Maximilians-University (HWP).

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Asthma diagnosis and treatmentPulmonary chemokines and their receptors differentiate children with asthma and chronic cough

Background

Objective

Methods

Results

Conclusion

Section snippets

Patients

Patients

Discussion

Pediatr Clin North Am

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Pathol

J Allergy Clin Immunol

Cough variant asthma in children

JAMA

Chemokines and disease

Nat Immunol

Rules of chemokine receptor association with T cell polarization in vivo

J Clin Invest

Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s

J Exp Med

CCR5 is characteristic of Th1 lymphocytes

Nature

Assessment of chemokine receptor expression by human Th1 and Th2 cells in vitro and in vivo

J Leukoc Biol

Chemokine receptor expression on T cells in blood and cerebrospinal fluid at relapse and remission of multiple sclerosis: imbalance of Th1/Th2-associated chemokine signaling

J Neuroimmunol

The biology of chemokines and their receptors

Ann Rev Immunol

Asthma diagnosis and treatment
Pulmonary chemokines and their receptors differentiate children with asthma and chronic cough