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. 2021 Apr;204(1):152-164.
doi: 10.1111/cei.13550. Epub 2020 Dec 15.

Cytokine levels in children and adults with wheezing and asthma show specific patterns of variability over time

M Weckmann #  1   2 , D Thiele #  2   3 , L Liboschik  1   2 , T Bahmer  2   4   5 , M Pech  1   2 , A-M Dittrich  6   7 , O Fuchs  1   2   8 , C Happle  6   7 , B Schaub  9   10 , I Ricklefs  1   2 , K F Rabe  2   4 , E von Mutius  9   10 , G Hansen  6   7 , I R König  2   3 , M V Kopp  1   2   8 ; ALLIANCE Study Group
Collaborators, Affiliations

Cytokine levels in children and adults with wheezing and asthma show specific patterns of variability over time

M Weckmann et al. Clin Exp Immunol. 2021 Apr.

Abstract

Levels of cytokines are used for in-depth characterization of patients with asthma; however, the variability over time might be a critical confounder. To analyze the course of serum cytokines in children, adolescents and adults with asthma and in healthy controls and to propose statistical methods to control for seasonal effects. Of 532 screened subjects, 514 (91·5%) were included in the All Age Asthma Cohort (ALLIANCE). The cohort included 279 children with either recurrent wheezing bronchitis (more than two episodes) or doctor-diagnosed asthma, 75 healthy controls, 150 adult asthmatics and 31 adult healthy controls. Blood samples were collected and 25 μl serum was used for analysis with the Bio-Plex Pr human cytokine 27-Plex assay. Mean age, body mass index and gender in the three groups of wheezers, asthmatic children and adult asthmatics were comparable to healthy controls. Wheezers (34·5%), asthmatic children (78·7%) and adult asthmatics (62·8%) were significantly more often sensitized compared to controls (4·5, 22 and 22·6%, respectively). Considering the entire cohort, interleukin (IL)-1ra, IL-4, IL-9, IL-17, macrophage inflammatory protein (MIP)-1- α and tumor necrosis factor (TNF)- α showed seasonal variability, whereas IL-1β, IL-7, IL-8, IL-13, eotaxin, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, MIP-1 β and platelet-derived growth factor (PDGF)-BB did not. Significant differences between wheezers/asthmatics and healthy controls were observed for IL-17 and PDGF-BB, which remained stable after adjustment for the seasonality of IL-17. Seasonality has a significant impact on serum cytokine levels in patients with asthma. Because endotyping has achieved clinical importance to guide individualized patient-tailored therapy, it is important to account for seasonal effects.

Keywords: adults; asthma; cytokines; season: variability; wheeze: children.

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Conflict of interest statement

A. M. D., I. K., M. P., I. R., D. T., C. H. and L. L. declare no conflicts of interest. B. S. reports grants from DFG, BMBF and EU outside the submitted work. T. B. reports grants from BMBF: unrestricted research grant for the German Center for Lung Research (DZL), during the conduct of the study; personal fees from AstraZeneca, personal fees from GlaxoSmithKline, personal fees from Novartis, Roche and Chiesi, outside the submitted work. O. F. reports personal fees from Vertex Germany, Menarini Switzerland, Novartis Switzerland, ALK Abello Switzerland, Vifor Switzerland, Milupa Nutricia Switzerland, Stallergenes Greer Switzerland, Bencard Switzerland, Medical Tribune Switzerland, aha! Swiss Allergy Centre and the German Society of Paediatric Allergology, outside the submitted work. G. H. reports personal fees from Novartis, Sanofi, during the conduct of the study. M. V. K. reports grants from Federal Ministry of Research and Education (BMBF) during the conduct of the study, personal fees from ALK‐Abello, Allergopharma, Boehringer‐Ingelheim, Chiesi, Glaxo, Infectopharm, Meda, Sanofi‐Aventis, Leti Pharma, Novartis and Vertex, outside the submitted work. E. v. M. reports grants from German Federal Ministry of Education and Research during the conduct of the study, personal fees from Pharmaventures, OM Pharma S. A., Springer‐Verlag GmbH, Elsevier GmbH and Elsevier Ltd, Peptinnovate Ltd, Turun Yliopisto, Tampereen Yliopisto, Helsingin Yliopisto, European Respiratory Society, Deutsche Pharmazeutische Gesellschaft e. V., Massachusetts Medical Society, Chinese University of Hongkong, European Commission, Böhringer Ingelheim International GmbH, Universiteit Utrecht, Faculteit Diergeneeskunde, Universität Salzburg, Georg Thieme Verlag and Japanese Society of Pediatric Allergy and Clinical Immunology (JSPACI), outside the submitted work; in addition, E. v. M. has a patent LU101064 (Barn dust extract for the prevention and treatment of diseases pending), a patent EP2361632 (Specific environmental bacteria for the protection from and/or the treatment of allergic, chronic inflammatory and/or autoimmune disorders) with royalties paid to ProtectImmun GmbH and a patent publication number EP 1411977 (composition containing bacterial antigens used for the prophylaxis and the treatment of allergic diseases); licensed to ProtectImmun GmbH, a patent publication number EP1637147 (Stable dust extract for allergy protection licensed to ProtectImmun GmbH) and a patent publication number EP 1964570 (Pharmaceutical compound to protect against allergies and inflammatory diseases) licensed to ProtectImmun GmbH. K. F. R. reports grants and personal fees from Boehringer and Astra Zeneca and personal fees from Novartis, Sanofi, Regeneron, Roche and Chiesi Pharmaceuticals outside the submitted work. M. W. reports grants from Federal Ministry for Education and Research (BMBF), University of Lübeck and German Academic Exchange Service during the conduct of the study.

Figures

Fig. 1
Fig. 1
All age asthma study population.
Fig. 2
Fig. 2
Log‐transformed cytokine levels of the pediatric (green) and adult part (red) of the cohort. Boxes show the median, 25th and 75th percentiles; bars indicate the range. Numbers in the right column indicate number of values below the lower limit of quantification(LOQ) /values above the upper LOQ and total samples in children and adults.
Fig. 3
Fig. 3
Exemplary presentation of the monthly course of cytokine levels. The cosinor model revealed a seasonal variability, i.e. for the cytokines interleukin (IL)‐4 and IL‐17. No differences were observed between asthmatics and controls for IL‐4, while IL‐17 was significantly lower in wheezers/asthmatics. Boxes show the median, 25th and 75th percentiles; bars indicate the range.
See this image and copyright information in PMC

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