Rhinitis, sinusitis, and upper airway disease
Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of biomarkers

https://doi.org/10.1016/j.jaci.2015.12.1324Get rights and content

Background

Current phenotyping of chronic rhinosinusitis (CRS) into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) might not adequately reflect the pathophysiologic diversity within patients with CRS.

Objective

We sought to identify inflammatory endotypes of CRS. Therefore we aimed to cluster patients with CRS based solely on immune markers in a phenotype-free approach. Secondarily, we aimed to match clusters to phenotypes.

Methods

In this multicenter case-control study patients with CRS and control subjects underwent surgery, and tissue was analyzed for IL-5, IFN-γ, IL-17A, TNF-α, IL-22, IL-1β, IL-6, IL-8, eosinophilic cationic protein, myeloperoxidase, TGF-β1, IgE, Staphylococcus aureus enterotoxin–specific IgE, and albumin. We used partition-based clustering.

Results

Clustering of 173 cases resulted in 10 clusters, of which 4 clusters with low or undetectable IL-5, eosinophilic cationic protein, IgE, and albumin concentrations, and 6 clusters with high concentrations of those markers. The group of IL-5–negative clusters, 3 clusters clinically resembled a predominant chronic rhinosinusitis without nasal polyps (CRSsNP) phenotype without increased asthma prevalence, and 1 cluster had a TH17 profile and had mixed CRSsNP/CRSwNP. The IL-5–positive clusters were divided into a group with moderate IL-5 concentrations, a mixed CRSsNP/CRSwNP and increased asthma phenotype, and a group with high IL-5 levels, an almost exclusive nasal polyp phenotype with strongly increased asthma prevalence. In the latter group, 2 clusters demonstrated the highest concentrations of IgE and asthma prevalence, with all samples expressing Staphylococcus aureus enterotoxin–specific IgE.

Conclusion

Distinct CRS clusters with diverse inflammatory mechanisms largely correlated with phenotypes and further differentiated them and provided a more accurate description of the inflammatory mechanisms involved than phenotype information only.

Section snippets

Study design

The study was designed as a multicenter case-control study carried out by the GA2LEN Sinusitis Cohort group (principal investigator, C. Bachert) in the framework of the European FP6 research initiative. The ear, nose, and throat departments in tertiary referral academic hospitals of Ghent, Leuven, Amsterdam, Barcelona, London, Berlin, Helsinki, Lodz, Malmö, and Stockholm participated in this study. This study was approved by the ethics committees of all individual institutions involved in data

Results

Of the 226 cases and 106 control subjects who underwent surgery, 173 cases and 89 control subjects had an adequate amount of tissue collected to carry out all intended analyses. Demographic, phenotype, and cytokine data of cases and control subjects are tabulated in Table II; demographic data of the sample included were not different from those of the total cohort. Cases had a significantly higher age and a higher prevalence of smoking history and asthma. Cases had significantly higher

Discussion

We present inflammatory endotypes of CRS based on a cluster analysis of biomarkers; secondarily, we correlate these results to clinical characteristics (phenotypes). In this cohort of European subjects who underwent surgery for CRS, we observed considerable data variability, so that multiple homogeneous subgroups (clusters) could be differentiated. This observation indicates that CRS is not a homogeneous inflammatory disease and that endotypes are present with a wide diversity of inflammatory

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    Supported by the Sixth European Union Framework Program for Research (contract no. FOOD-CT-2004-506378) and Fonds Wetenschappelijk Onderzoek Vlaanderen, International Coordination Action (no. G.0854.09).

    Disclosure of potential conflict of interest: P. Tomassen has received research support from the Sixth European Union Framework Program for Research and Fonds Wetenschappelijk Onderzoek Vlaanderen. C. Van Drunen has received research support from the European Union FP6 (GA2LEN Network of Excellence), European Union (BM4SIT), GlaxoSmithKline, ALK-Abelló, and Allergopharma. J. Mullol is on the boards for Uriach, Meda, Johnson & Johnson, FAES, Crucell, and ALK-Abelló; has received research support from GlaxoSmithKline, Iriach, FAES, and Meda; and has received lecture fees from Uriah, Hartington Pharmaceuticals, Novartis, FAES, Menarini, MSD, and Pierre-Fabre. E. Toskala has received consultancy fees from Merck as an Advisory Board member. G. Scadding has received consultancy fees from ALK-Abelló, Meda, and GlaxoSmithKline; has received research support from GlaxoSmithKline; and has received lecture fees from ALK-Abelló and Meda. V. Lund has received research support from GlaxoSmithKline and Optinose; has received lecture fees from MSD; and receives royalties as Editor of Cummings Otorhinolaryngology, Elsevier. W. Fokkens has received research support from Meda and has received payment for developing educational presentation (webcast on treatment of rhinitis for general practitioners). The rest of the authors declare that they have no relevant conflicts of interest.

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