Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts - 27/09/17
Doi : 10.1016/j.jaci.2016.08.046
Alexander J. Hose, MA, MPH a, ⁎ 
, Martin Depner, PhD a, Sabina Illi, PhD a, Susanne Lau, MD, PhD b, Thomas Keil, MD, MScPH c, d, Ulrich Wahn, MD b, Oliver Fuchs, MD, PhD e, f, g, Petra Ina Pfefferle, PhD, DrPH h, Elisabeth Schmaußer-Hechfellner, BSc a, Jon Genuneit, MD i, Roger Lauener, MD j, k, Anne M. Karvonen, PhD l, Caroline Roduit, MD j, m, Jean-Charles Dalphin, MD, PhD n, Josef Riedler, MD o, Juha Pekkanen, MD, PhD l, p, Erika von Mutius, MD e, Markus J. Ege, MD e
the
, Martin Depner, PhD a, Sabina Illi, PhD a, Susanne Lau, MD, PhD b, Thomas Keil, MD, MScPH c, d, Ulrich Wahn, MD b, Oliver Fuchs, MD, PhD e, f, g, Petra Ina Pfefferle, PhD, DrPH h, Elisabeth Schmaußer-Hechfellner, BSc a, Jon Genuneit, MD i, Roger Lauener, MD j, k, Anne M. Karvonen, PhD l, Caroline Roduit, MD j, m, Jean-Charles Dalphin, MD, PhD n, Josef Riedler, MD o, Juha Pekkanen, MD, PhD l, p, Erika von Mutius, MD e, Markus J. Ege, MD ethe
MAS∗
Carl Peter Bauer q, Johannes Forster r, Fred Zepp s, Volker Wahn t, Antje Schuster u, Renate L. Bergmann v, Karl E. Bergmann v, Andreas Reich w, Linus Grabenhenrich w
q Department of Pediatrics, Technical University of Munich, Munich, Germany
r Department of Paediatrics, St Josefs Hospital, Freiburg, Germany
s Centre for Paediatric and Adolescent Medicine, University Medical Centre Mainz, Mainz, Germany
t University Children's Hospital, Charité, Berlin, Germany
u Department of Paediatrics, University Medical Centre Düsseldorf, Düsseldorf, Germany
v Department of Obstetrics, Charité-Universitätsmedizin Berlin, Berlin, Germany
w Institute of Social Medicine, Epidemiology and Health Economics, Charité-Universitätsmedizin Berlin, Berlin, Germany
PASTURE study groups‡
Bianca Schaub e, Georg J. Loss a, x, Harald Renz y, Michael Kabesch x, aa, Marjut Roponen bb, Anne Hyvärinen l, Pekka Tiittanen l, Sami Remes cc, Charlotte Braun-Fahrländer dd, ee, Remo Frei j, ff, Vincent Kaulek n, Marie-Laure Dalphin gg, Gert Doekes hh, Nicole Blümer ii, Urs Frey g
a Dr von Hauner Children's Hospital, LMU Munich, Munich, Germany
e Dr von Hauner Children's Hospital, LMU Munich, and the Comprehensive Pneumology Center, Munich (CPC-M), Germany (Member of the German Center for Lung Research [DZL]), Munich, Germany
l Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland
j Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
n Department of Respiratory Disease, University of Besançon, UMR/CNRS6249 Chrono-environment, University Hospital, Besançon, France
g University Children's Hospital (UKBB), University of Basel, Basel, Switzerland
x Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, Calif
y Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg (Member of the German Center for Lung Research), Marburg, Germany
z KUNO Children's University Hospital Regensburg, Department of Pediatric Pneumology and Allergy Campus St Hedwig, Regensburg, Germany
aa Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, Hannover, Germany
bb Department of Environmental Science, Inhalation Toxicology Laboratory, University of Eastern Finland, Kuopio, Finland
cc Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland
dd Swiss Tropical and Public Health Institute, Basel, Switzerland
ee University of Basel, Basel, Switzerland
ff Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
gg Department of Pediatrics, University of Besançon, University Hospital, Besançon, France
hh Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands
ii Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
a Dr von Hauner Children's Hospital, LMU Munich, Munich, Germany
b Department for Pediatric Pneumology and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
c Institute of Social Medicine, Epidemiology and Health Economics, Charité-Universitätsmedizin Berlin, Berlin, Germany
d Institute for Clinical Epidemiology and Biometry, University of Wuerzburg, Wuerzburg, Germany
e Dr von Hauner Children's Hospital, LMU Munich, and the Comprehensive Pneumology Center, Munich (CPC-M), Germany (Member of the German Center for Lung Research [DZL]), Munich, Germany
f Division of Respiratory Medicine, Department of Pediatrics, Inselspital, University of Bern, Bern, Switzerland
g University Children's Hospital (UKBB), University of Basel, Basel, Switzerland
h Comprehensive Biomaterial Bank Marburg CBBM, Fachbereich Medizin der Philipps Universität Marburg, Zentrum für Tumor und Immunbiologie ZTI Marburg (Member of the German Center for Lung Research), Marburg, Germany
i Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
j Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland
k Children's Hospital of Eastern Switzerland, St Gallen, Switzerland
l Department of Health Protection, National Institute for Health and Welfare, Kuopio, Finland
m Children's Hospital, University of Zürich, Zürich, Switzerland
n Department of Respiratory Disease, University of Besançon, UMR/CNRS6249 Chrono-environment, University Hospital, Besançon, France
o Children's Hospital Schwarzach, and the Teaching Hospital of Paracelsus Medical Private University Salzburg, Salzburg, Austria
p Department of Public Health, University of Helsinki, Helsinki, Finland
∗Corresponding author: Alexander J. Hose, MA, MPH, Dr von Hauner Children's Hospital, Ludwig-Maximilians-Universität of Munich, Lindwurmstr 4, D-80337 Munich, Germany.Dr von Hauner Children's HospitalLudwig-Maximilians-Universität of MunichLindwurmstr 4MunichD-80337Germany
Abstract |
Background |
Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear.
Objective |
We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE).
Methods |
Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort.
Results |
The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk.
Conclusions |
LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Atopy, IgE, sensitization, asthma, lung function, cytokines, severe atopy, atopic diseases, latent class analysis, unsupervised clustering, path analysis, epidemiology
Abbreviations used : CAP, LC, LCA, MAS, PASTURE, sIgE
Plan
| The Multizentrische Allergiestudie (MAS) study was funded by grants from the German Federal Ministry of Education and Research (BMBF; reference nos. 07015633, 07 ALE 27, 01EE9405/5, and 01EE9406) and the German Research Foundation (DFG; reference no. KE 1462/2-1). The funders had no role in the design, management, data collection, analysis, or interpretation of the data or in the writing of the manuscript or the decision to submit for publication. For PASTURE, work was supported by the European Commission (research grants QLK4-CT-2001-00250, FOOD-CT-2006-31708, and KBBE-2007-2-2-06), the European Research Council (Grant 250268), and the German Federal Ministry of Education and Research (BMBF; project German Center for Lung Research [DZL]). The funding sources did not influence the study design; the collection, analysis, and interpretation of data; the writing of the manuscript; and the decision to submit the paper for publication. The corresponding author had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. |
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| Disclosure of potential conflict of interest: M. Depner's organization has received grants (or has grants pending) from the European Research Council and the German Research Foundation. S. Lau has received grants from the German Research Foundation (DFG), Symbiopharm, Allergopharma, and the German Ministry of Agriculture and has consultant arrangements with Merck Drug Monitoring Committee. In regards to the work under consideration for publication, T. Keil's institution has received a grant from BMBF & DFG (Public money for follow-up of the population-based birth cohort Multizentrische Allergiestudie [MAS]), and in regard to other related financial activities, they also have received money from by EU FP7 (MeDALL, iFAAM) for birth cohort data harmonization and analyses of allergic diseases including food allergy. O. Fuchs has received a grant from the European Respiratory Society (ERS) and Long-Term Research Fellowship (no. 675; during work relevant for this publication); O. Fuchs also received a grant from the Training Scholarship by the Austrian, German and Swiss Paediatric Respiratory Society (GPP; during work relevant for this publication). J. Genuneit's institution has received a grant from the European Commission (QLK4-CT-2001-00250, FOOD-CT-2006-31708, and KBBE-2007-2-2-06). In regard to the work under consideration for publication, R. Lauener's institution has received a grant from the Kühne Foundation (EU-grant) and received support for travel to meetings for study or for other purposes (Kühne Foundation), and in regard to other disclosures, R. Lauener's institution does receive grant from the Kühne Foundation; in addition, R. Lauener also has received payment for lectures (including service on speakers bureaus) from Meda, Menarini, Astra-Zeneca, Novartis, Vivor, and Pfizer (all unrelated to the topic of this manuscript). A. M. Karvonen has received a grant from the Academy of Finland (Grant no: 287675); A. M. Karvonen institution has received a grant from the Academy of Finland (grant no. 139021), the Juho Vainio Foundation, Sohlberg Foundation, and VTR. J.-C. Dalphin has received a grant from Novartis Pharma; has received personal fees from Novartis Pharma, Chiesi, Intermune, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim; and has received nonfinancial support from Novartis, GlaxoSmithKline, AstraZeneca, Intermune, Chiesi, Boehringer Ingelheim, and Stallergenes. J. Pekkanen has received a grant from the European Union, the Academy of Finland, and minor grants from Finnish foundations supporting medical research (the Juho Vainio Foundation, the Päivikki and Sakari Sohlberg Foundation, and Finnish cultural foundation). E. von Mutius receives grant funding from the European Research Council and European Commission, serves as a consultant for System Analytic, and serves as an expert testimony for European Research council, University of Tampere, GBS RE HEFCE; E. von Mutius received payments for lectures from Mundipharma, HAL Allergie GmbH, American Thoracic Society, Abbvie Deutschland GmbH & Co. KG, medUpdate GmbH, Okosoziales Forum Oberosterreich, Novartis Pharma, and OM Pharma. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2016
American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 139 - N° 6
P. 1935 - juin 2017 Retour au numéro
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