Asthma and lower airway disease
The chitinase-like protein YKL-40: A possible biomarker of inflammation and airway remodeling in severe pediatric asthma

https://doi.org/10.1016/j.jaci.2013.03.003Get rights and content

Background

Problematic severe childhood asthma includes a subgroup of patients who are resistant to therapy. The specific mechanisms involved are unknown, and novel biomarkers are required to facilitate treatment and diagnosis of therapy-resistant asthma. The chitinase-like protein YKL-40 has been related to asthma and airway remodeling.

Objectives

To compare serum YKL-40 levels in children with severe, therapy-resistant asthma (n = 34), children with controlled persistent asthma (n = 39), and healthy controls (n = 27), and to investigate correlations with biomarkers of inflammation and airway remodeling.

Methods

The study protocol included questionnaires, measurement of exhaled nitric oxide in exhaled air, blood sampling for inflammatory biomarkers, and high-resolution computed tomography of the lungs to identify bronchial wall thickening (therapy-resistant only). Serum YKL-40 levels were measured by ELISA, and all asthmatic children were genotyped for a CHI3L1 promoter single nucleotide polymorphism (rs4950928).

Results

Serum YKL-40 levels were significantly higher in children with therapy-resistant asthma than in healthy children (19.2 ng/mL vs 13.8 ng/mL, P = .03). Among children with severe, therapy-resistant asthma, YKL-40 levels correlated with fraction of exhaled nitric oxide in exhaled air (r = 0.48, P = .004), blood neutrophils (r = 0.63, P < .001), and bronchial wall thickening on high-resolution computed tomography (r = 0.45, P = .01). Following adjustment for CHI3L1 genotype, significantly greater levels of YKL-40 were found in children with therapy-resistant asthma than in children with controlled asthma.

Conclusions

YKL-40 levels are increased in children with severe, therapy-resistant asthma compared to healthy children, and also compared to children with controlled asthma following correction for genotype.

Section snippets

Methods

In this cross-sectional, explorative case-control study, children aged 6 to 18 years with problematic severe asthma were compared with age-matched peers with controlled asthma. These 2 conditions were defined in accordance with guidelines established by the Global Initiative for Asthma,17 which takes into account the severity of the underlying disease, as indicated by the need for treatment and degree of symptom control achieved.18 Inclusion criteria are presented in Table I. Written informed

Results

Clinical characteristics of the included patients are presented in Table II. Children with therapy-resistant asthma (n = 34) received higher doses of inhaled corticosteroids, had inferior asthma control (P < .001), more airflow obstruction (P = .03), increased bronchial hyperresponsiveness (P = .01), and increased numbers of blood eosinophils (P = .04) and neutrophils (P = .03) compared to children with controlled asthma (n = 39). There were no differences between these 2 groups of children

Discussion

In this cohort of well-characterized school-aged children with asthma, we demonstrate associations between YKL-40 levels, clinical characteristics, and disease severity. We show for the first time that serum YKL-40 level is increased in children with severe, therapy-resistant asthma compared with healthy children. Furthermore, serum levels of YKL-40 significantly correlate with asthma control, airway remodeling measured as bronchial wall thickening by HRCT, and blood neutrophils in children

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    This study was supported by the Freemason Child House Foundation in Stockholm, the Konsul Th. C. Bergh's Foundation, the Swedish Asthma and Allergy Association's Research Foundation, the Centre for Allergy Research at Karolinska Institutet, the Pediatric Research Foundation of Astrid Lindgren Children's Hospital, the Swedish Heart-Lung Foundation, Karolinska Institutet, the Bernard Osher Initiative for Research on Severe Asthma, Stockholm County Council Research Funds, and VINNOVA, Swedish Governmental Agency for Innovation Systems.

    Disclosure of potential conflict of interest: B. Dahlén is a Board member for Actelion DMC; has received one or more grants from or has one or more grants pending with the Swedish Heart-Lung Foundation, the Swedish MRC, and the Swedish Asthma and Allergy Foundation; and has received one or more payments for lecturing from or is on the speakers' bureau for Novartis and for Meda. S. E. Dahlén has been supported by one or more grants from the Swedish MRC, the Swedish Heart-Lung Foundation, and the Stockholm County Council Research Funds; has consultancy arrangements with GSK & AZ Respiratory; and has received one or more payments for lecturing from or is on the speakers' bureau for Nigaard Pharmaceuticals. J. R. Konradsen has received grants from the Freemason Child House Foundation in Stockholm, the Konsul Th. C. Bergh's Foundation, the Swedish Asthma and Allergy Association's Research Foundation, the Centre for Allergy Research at Karolinska Institutet, the Pediatric Research Foundation of Astrid Lindgren Children's Hospital, and the Swedish Heart-Lung Foundation; and has received payment for lecturing from Novartis and Thermo Fisher Scientific. K. C. Lödrup Carlsen has received one or more public grants, has received or has one or more grants pending with the Kloster Foundation, and has received one or more payments for lecturing from or is on the speakers' bureau for GSK. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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