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1. Prediction of overall survival in patients with locally advanced pancreatic cancer using longitudinal diffusion-weighted MRI

Author

Anne L. H. Bisgaard, Carsten Brink, Tine Schytte, Rana Bahij, Mathilde Weisz Ejlsmark, Uffe Bernchou, Anders S. Bertelsen, Per Pfeiffer, and Faisal Mahmood

Subjects
diffusion-weighted MRI, biomarker, pancreatic cancer, apparent diffusion coefficient, overall survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background and purposeBiomarkers for prediction of outcome in patients with pancreatic cancer are wanted in order to personalize the treatment. This study investigated the value of longitudinal diffusion-weighted magnetic resonance imaging (DWI) for prediction of overall survival (OS) in patients with locally advanced pancreatic cancer (LAPC) treated with stereotactic body radiotherapy (SBRT).Materials and methodsThe study included 45 patients with LAPC who received 5 fractions of 10 Gy on a 1.5T MRI-Linac. DWI was acquired prior to irradiation at each fraction. The analysis included baseline values and time-trends of the apparent diffusion coefficient (ADC) and DWI parameters obtained using a decomposition method. A multivariable Cox proportional hazards model for OS was made using best-subset selection, using cross-validation based on Bootstrap.ResultsThe median OS from the first day of SBRT was 15.5 months (95% CI: 13.2-20.6), and the median potential follow-up time was 19.8 months. The best-performing multivariable model for OS included two decomposition-based DWI parameters: one baseline and one time-trend parameter. The C-Harrell index describing the model’s discriminating power was 0.754. High baseline ADC values were associated with reduced OS, whereas no association between the ADC time-trend and OS was observed.ConclusionDecomposition-based DWI parameters indicated value in the prediction of OS in LAPC. A DWI time-trend parameter was included in the best-performing model, indicating a potential benefit of acquiring longitudinal DWI during the SBRT course. These findings support both baseline and longitudinal DWI as candidate prognostic biomarkers, which may become tools for personalization of the treatment of patients with LAPC.

Published
2024
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2. Longitudinal trajectories of anxiety, depression, and bipolar disorder in inflammatory bowel disease: a population-based cohort studyResearch in context

Author

Tania H. Bisgaard, Gry Poulsen, Kristine H. Allin, Laurie Keefer, Ashwin N. Ananthakrishnan, and Tine Jess

Subjects
Inflammatory bowel disease, IBD, Gut-brain axis, Depression, Anxiety, Bipolar disorder, Medicine (General), R5-920
Abstract

Summary: Background: Inflammatory bowel disease (IBD) is associated with psychiatric diseases, but it is unclear to what degree patients with IBD are affected over their lifetime. We aimed to longitudinally investigate the risk of anxiety, depression, and bipolar disorder before and after IBD diagnosis to understand the full burden of these diseases in patients with IBD. Methods: In this population based cohort study, we identified 22,103 patients diagnosed with IBD between January 1, 2003 and December 31, 2013 in the Danish National registers and 110,515 matched reference individuals from the general population. We calculated yearly prevalence of hospital contacts for anxiety, depression, and bipolar disorder and dispensed prescriptions for antidepressants from five years before to ten years after IBD diagnosis. We used logistic regression to calculate prevalence odds ratios (OR) for each outcome prior to IBD diagnosis, and Cox regression to calculate hazard ratios (HR) of new outcomes after IBD diagnosis. Findings: During >150,000 person years follow-up, patients with IBD had higher risk of anxiety (OR 1.4; 95% confidence interval (CI) 1.2–1.7) and depression (OR 1.4; 95% CI 1.3–1.6) starting at least five years before and continuing until at least ten years after IBD diagnosis (HR 1.3; 95% CI 1.1–1.5 for anxiety and HR 1.5; 95% CI 1.4–1.7 for depression). The risk was particularly high around IBD diagnosis and in patients diagnosed with IBD after the age of 40 years. We found no association between IBD and bipolar disorder. Interpretation: This population-based study suggests that anxiety and depression are clinically significant comorbidities of IBD both before and after IBD diagnosis, which warrant thorough evaluation and management, particularly around the time of IBD diagnosis. Funding: The Danish National Research Foundation [DNRF148], the Lundbeck Foundation [R313-2019-857], and Aage og Johanne Louis-Hansens Fond [9688-3374 TJS].

Published
2023
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3. Depression and anxiety in inflammatory bowel disease: epidemiology, mechanisms and treatment

Author

Tania H. Bisgaard, Kristine H. Allin, Laurie Keefer, Ashwin N. Ananthakrishnan, and Tine Jess

Subjects
Hepatology, Gastroenterology
Abstract

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity.

Published
2022
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7. Identification of oropharyngeal microbiome-driven asthma and wheezing clusters in children

Author

M I Abdel-Aziz, J Thorsen, S Hashimoto, S J H Vijverberg, A H Neerincx, P Brinkman, W V Aalderen, J Stokholm, M Roggenbuck-Wedemeyer, N H Vissing, M S Mortensen, A D Brejnrod, L J Fleming, C S Murray, S J Fowler, U Frey, A Bush, F Singer, G Hedlin, B Nordlund, D E Shaw, K F Chung, I M Adcock, R Djukanovic, C Auffray, A T Bansal, A R Sousa, S S Wagers, B L Chawes, K Bønnelykke, S J Sørensen, A D Kraneveld, P J Sterk, G Roberts, H Bisgaard, and A H Maitland-Van Der Zee

Published
2022

13. Effect of prenatal bisphenol A exposure on child obesity through epigenetic influence on the insulin-like growth factor 2 receptor(IGF2R)gene

Author

Kyung Shin Lee, Bung Nyun Kim, Youn-Hee Lim, Jinwoo Cho, H. Bisgaard, Yun-Chul Hong, K. Bønnelykke, Young Ah Lee, S. Park, Johanna Inhyang Kim, Yoon Jung Choi, and Choong Ho Shin

Subjects
endocrine system, medicine.medical_specialty, Bisphenol A, urogenital system, business.industry, Insulin-like growth factor 2 receptor, IGF2R gene, medicine.disease, Obesity, chemistry.chemical_compound, Endocrinology, chemistry, In utero, Internal medicine, General Earth and Planetary Sciences, Medicine, Child obesity, Epigenetics, business, reproductive and urinary physiology, hormones, hormone substitutes, and hormone antagonists, General Environmental Science
Abstract

BACKGROUND: Epigenetic mechanisms have been suggested to play a role in the link between in utero exposure to bisphenol A (BPA) and pediatric obesity; however, there is little evidence regarding th...

Published
2020
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14. Urinary Leukotriene E 4 and Prostaglandin D 2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study

Author

Johan Kolmert, Cristina Gómez, David Balgoma, Marcus Sjödin, Johan Bood, Jon R. Konradsen, Magnus Ericsson, John-Olof Thörngren, Anna James, Maria Mikus, Ana R. Sousa, John H. Riley, Stewart Bates, Per S. Bakke, Ioannis Pandis, Massimo Caruso, Pascal Chanez, Stephen J. Fowler, Thomas Geiser, Peter Howarth, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Annelie Behndig, Dominick E. Shaw, Richard G. Knowles, Cécile T. J. Holweg, Åsa M. Wheelock, Barbro Dahlén, Björn Nordlund, Kjell Alving, Gunilla Hedlin, Kian Fan Chung, Ian M. Adcock, Peter J. Sterk, Ratko Djukanovic, Sven-Erik Dahlén, Craig E. Wheelock, H. Ahmed, C. Auffray, A. T. Bansal, E. H. Bel, J. Bigler, B. Billing, F. Baribaud, H. Bisgaard, M. J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, A. Chaiboonchoe, C. H. Compton, J. Corfield, D. Cunoosamy, A. D’Amico, B. De Meulder, V. J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L. J. Fleming, E. Formaggio, U. Frey, M. Gahlemann, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, P. W. Hekking, T. Higenbottam, J. M. Hohlfeld, A. J. Knox, N. Lazarinis, D. Lefaudeux, M. J. Loza, R. Lutter, A. Manta, S. Masefield, J. G. Matthews, A. Mazein, A. Meiser, R. J. M. Middelveld, M. Miralpeix, N. Mores, C. S. Murray, J. Musial, D. Myles, L. Pahus, S. Pavlidis, A. Postle, P. Powel, G. Praticò, M. PuigValls, N. Rao, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J. P. R. Schofield, W. Seibold, A. Selby, R. Sigmund, F. Singer, P. J. Skipp, M. Smicker, K. Sun, B. Thornton, M. Uddin, W. M. van Aalderen, M. van Geest, J. Vestbo, N. H. Vissing, A. H. Wagener, S. S. Wagers, Z. Weiszhart, S. J. Wilson, J. Östling, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Male, Severe asthma, Metabolite, type 2 inflammation, Respiratory Medicine and Allergy, [SDV]Life Sciences [q-bio], Physiology, Omalizumab, Critical Care and Intensive Care Medicine, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Child, ComputingMilieux_MISCELLANEOUS, mass spectrometry, Lungmedicin och allergi, 2. Zero hunger, Leukotriene E4, Prostaglandin D2, Type 2 inflammation, Middle Aged, respiratory system, 3. Good health, medicine.anatomical_structure, Prednisolone, Female, lipids (amino acids, peptides, and proteins), medicine.drug, Pulmonary and Respiratory Medicine, Adult, severe asthma, Settore BIO/14 - FARMACOLOGIA, Urinary system, U-BIOPRED, Asthma and Allergy, 03 medical and health sciences, Correspondence, medicine, Humans, Asthma, Inflammation, Mass spectrometry, business.industry, Original Articles, Eosinophil, medicine.disease, respiratory tract diseases, urinary eicosanoid metabolites, 030228 respiratory system, chemistry, Diabetes Mellitus, Type 2, Exhaled nitric oxide, Prostaglandins, Urinary eicosanoid metabolites, business, Biomarkers
Abstract

Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE 2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE 2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE 4 and the PGD 2 metabolite 2,3-dinor-11β-PGF 2α. High concentrations of LTE 4 and PGD 2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Published
2020
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15. Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation

Author

Zala Jevnikar, Jörgen Östling, Elisabeth Ax, Jenny Calvén, Kristofer Thörn, Elisabeth Israelsson, Lisa Öberg, Akul Singhania, Laurie C.K. Lau, Susan J. Wilson, Jonathan A. Ward, Anoop Chauhan, Ana R. Sousa, Bertrand De Meulder, Matthew J. Loza, Frédéric Baribaud, Peter J. Sterk, Kian Fan Chung, Kai Sun, Yike Guo, Ian M. Adcock, Debbie Payne, Barbro Dahlen, Pascal Chanez, Dominick E. Shaw, Norbert Krug, Jens M. Hohlfeld, Thomas Sandström, Ratko Djukanovic, Anna James, Timothy S.C. Hinks, Peter H. Howarth, Outi Vaarala, Marleen van Geest, Henric Olsson, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, F.K. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, V. Goss, Y. Guo, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, A.J. James, R. Knowles, A.J. Knox, N. Krug, D. Lefaudeux, M.J. Loza, A. Manta, J.G. Matthews, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, P. Montuschi, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, A. Postle, P. Powel, G. Praticò, N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, J.P.R. Schofield, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson, Publica, HUS Children and Adolescents, Commission of the European Communities, Pulmonology, AII - Inflammatory diseases, and Paediatric Pulmonology

Subjects
Male, 0301 basic medicine, MMP3, Allergy, MATRIX METALLOPROTEINASES, Respiratory Medicine and Allergy, Eepithelial integrity, airway inflammation, Systemic inflammation, DISEASE, Cohort Studies, transcriptomics, 0302 clinical medicine, Receptors, Immunology and Allergy, Lung, Macrophage inflammatory protein, Cells, Cultured, Lungmedicin och allergi, remodeling, Toll-like receptor, Cultured, CHITINASE-LIKE PROTEIN, 3. Good health, Phenotype, TARGET, medicine.anatomical_structure, 1107 Immunology, Airway Remodeling, eosinophils, medicine.symptom, Life Sciences & Biomedicine, hierarchical clustering, Signal Transduction, Adult, Settore BIO/14 - FARMACOLOGIA, Immunology, lung epithelium, 03 medical and health sciences, HYPERRESPONSIVENESS, Respiratory Hypersensitivity, medicine, Humans, Hierarchical Clustering, Inflammation, Science & Technology, Innate immune system, exacerbation frequency, Interleukin-6, business.industry, Sputum, Epithelial Cells, Gene signature, Receptors, Interleukin-6, DYSFUNCTION, Asthma, respiratory tract diseases, Eosinophils, Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes study group, Cross-Sectional Studies, SEVERITY, 030104 developmental biology, Gene Expression Regulation, 030228 respiratory system, INTERLEUKIN-6 RECEPTOR, BARRIER FUNCTION, 3121 General medicine, internal medicine and other clinical medicine, CELLS, epithelial integrity, IL-6 signaling, Exacerbation frequency, Transcriptome, business, Biomarkers
Abstract

BackgroundAlthough several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear.ObjectiveWe sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients.MethodsAn IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS–specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens.ResultsActivation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS–high asthma with increased epithelial expression of IL-6TS–inducible genes in the absence of systemic inflammation. The IL-6TS–high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β.ConclusionsLocal lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.

Published
2019
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16. IL-17-high asthma with features of a psoriasis immunophenotype

Author

Jörgen Östling, Marleen van Geest, James P.R. Schofield, Zala Jevnikar, Susan Wilson, Jonathan Ward, Rene Lutter, Dominick E. Shaw, Per S. Bakke, Massimo Caruso, Sven-Erik Dahlen, Stephen J. Fowler, Ildikó Horváth, Norbert Krug, Paolo Montuschi, Marek Sanak, Thomas Sandström, Kai Sun, Ioannis Pandis, Charles Auffray, Ana R. Sousa, Yike Guo, Ian M. Adcock, Peter Howarth, Kian Fan Chung, Jeanette Bigler, Peter J. Sterk, Paul J. Skipp, Ratko Djukanović, Outi Vaarala, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, K.F. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, Y. Guo, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, P. Howarth, A.J. James, R. Knowles, A.J. Knox, N. Krug, D. Lefaudeux, M.J. Loza, R. Lutter, A. Manta, S. Masefield, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, P. Montuschi, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, P. Powell, G. Praticò, M. Puig N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson, Antonios Aliprantis, David Allen, Kjell Alving, P. Badorrek, David Balgoma, S. Ballereau, Clair Barber, Manohara Kanangana Batuwitage, A. Bautmans, A. Bedding, A.F. Behndig, Jorge Beleta, A. Berglind, A. Berton, Grazyna Bochenek, Armin Braun, D. Campagna, Leon Carayannopoulos, C. Casaulta, Romanas Chaleckis, B. Dahlén, imothy Davison, Jorge De Alba, Inge De Lepeleire, Tamara Dekker, Ingrid Delin, P. Dennison, Annemiek Dijkhuis, Paul Dodson, Aleksandra Draper, K. Dyson, Jessica Edwards, L. El Hadjam, Rosalia Emma, Magnus Ericsson, C. Faulenbach, Breda Flood, G. Galffy, Hector Gallart, D. Garissi, J. Gent, M. Gerhardsson de Verdier, D. Gibeon, Cristina Gomez, Kerry Gove, Neil Gozzard, E. Guillmant-Farry, E. Henriksson, Lorraine Hewitt, U. Hoda, Richard Hu, Sile Hu, X. Hu, E. Jeyasingham, K. Johnson, N. Jullian, Juliette Kamphuis, Erika J. Kennington, Dyson Kerry, G. Kerry, M. Klüglich, Hugo Knobel, Johan Kolmert, J.R. Konradsen, Maxim Kots, Kosmas Kretsos, L. Krueger, Scott Kuo, Maciej Kupczyk, Bart Lambrecht, A.-S. Lantz, Christopher Larminie, L.X. Larsson, P. Latzin, N. Lazarinis, N. Lemonnier, Saeeda Lone-Latif, L.A. Lowe, Alexander Manta, Lisa Marouzet, Jane Martin, Caroline Mathon, L. McEvoy, Sally Meah, A. Menzies-Gow, Leanne Metcalf, Maria Mikus, Philip Monk, Shama Naz, K. Nething, Ben Nicholas, U. Nihlén, Peter Nilsson, R. Niven, B. Nordlund, S. Nsubuga, Antonio Pacino, Susanna Palkonen, J. Pellet, Giorgio Pennazza, Anne Petrén, Sandy Pink, C. Pison, Anthony Postle, Malayka Rahman-Amin, Lara Ravanetti, Emma Ray, Stacey Reinke, Leanne Reynolds, K. Riemann, Martine Robberechts, J.P. Rocha, C. Rossios, Kirsty Russell, Michael Rutgers, G. Santini, Marco Santoninco, M. Saqi, Corinna Schoelch, S. Scott, N. Sehgal, Marcus Sjödin, Barbara Smids, Caroline Smith, Jessica Smith, Katherine M. Smith, P. Söderman, A. Sogbessan, F. Spycher, Doroteya Staykova, S. Stephan, J. Stokholm, K. Strandberg, M. Sunther, M. Szentkereszty, L. Tamasi, K. Tariq, John-Olof Thörngren, Jonathan Thorsen, S. Valente, Marianne van de Pol, C.M. van Drunen, Jonathan Van Eyll, Jenny Versnel, Anton Vink, C. von Garnier, A. Vyas, Frans Wald, Samantha Walker, Kristiane Wetzel, Coen Wiegman, Siân Williams, Xian Yang, Elizabeth Yeyasingham, W. Yu Amgen, W. Zetterquist, Z. Zolkipli, A.H. Zwinderman, Publica, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Pulmonology, AII - Inflammatory diseases, Experimental Immunology, Ear, Nose and Throat, Epidemiology and Data Science, APH - Methodology, and Commission of the European Communities

Subjects
0301 basic medicine, Male, URINARY-EXCRETION, Allergy, Neutrophils, Inflammatory bowel disease, Cohort Studies, DOUBLE-BLIND, 0302 clinical medicine, Immunology and Allergy, POPULATION, Interleukin-13, Interleukin-17, psoriasis, BRODALUMAB, Up-Regulation, IL-17, Phenotype, 1107 Immunology, Biomarker (medicine), Female, Interleukin 17, medicine.symptom, Life Sciences & Biomedicine, ENDOTYPES, Signal Transduction, EXPRESSION, Adult, Settore BIO/14 - FARMACOLOGIA, Immunology, PHENOTYPES, Bronchi, 03 medical and health sciences, INFLAMMATION, Psoriasis, medicine, Humans, Interleukin 8, Asthma, U-BIOPRED Study Group, Science & Technology, business.industry, Gene Expression Profiling, biomarkers, Epithelial Cells, asthma, bronchial brushings, medicine.disease, bronchial biopsies, Neutrophilia, 030104 developmental biology, 030228 respiratory system, EXACERBATION, CELLS, Sputum, business, Transcriptome, Biomarkers
Abstract

Background The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. Objective We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Methods Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes. Results Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. Conclusion The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

Published
2019
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17. Pathway discovery using transcriptomic profiles in adult-onset severe asthma

Author

Pieter-Paul Hekking, Matt J. Loza, Stelios Pavlidis, Bertrand de Meulder, Diane Lefaudeux, Fred Baribaud, Charles Auffray, Ariane H. Wagener, Paul Brinkman, Rene Lutter, Aruna T. Bansal, Ana R. Sousa, Steve A. Bates, Yannis Pandis, Louise J. Fleming, Dominique E. Shaw, Stephen J. Fowler, Y. Guo, Andrea Meiser, Kai Sun, Julie Corfield, Peter H. Howarth, Elisabeth H. Bel, Ian M. Adcock, Kian Fan Chung, Ratko Djukanovic, Peter J. Sterk, I.M. Adcock, H. Ahmed, C. Auffray, P. Bakke, A.T. Bansal, F. Baribaud, S. Bates, E.H. Bel, J. Bigler, H. Bisgaard, M.J. Boedigheimer, K. Bønnelykke, J. Brandsma, P. Brinkman, E. Bucchioni, D. Burg, A. Bush, M. Caruso, A. Chaiboonchoe, P. Chanez, F.K. Chung, C.H. Compton, J. Corfield, A. D'Amico, S.E. Dahlen, B. De Meulder, R. Djukanovic, V.J. Erpenbeck, D. Erzen, K. Fichtner, N. Fitch, L.J. Fleming, E. Formaggio, S.J. Fowler, U. Frey, M. Gahlemann, T. Geiser, S. Hashimoto, J. Haughney, G. Hedlin, P.W. Hekking, T. Higenbottam, J.M. Hohlfeld, C. Holweg, I. Horváth, P. Howarth, A.J. James, R. Knowles, N. Krug, D. Lefaudeux, M.J. Loza, R. Lutter, A. Manta, S. Masefield, J.G. Matthews, A. Mazein, A. Meiser, R.J.M. Middelveld, M. Miralpeix, N. Mores, C.S. Murray, J. Musial, D. Myles, L. Pahus, I. Pandis, S. Pavlidis, P. Powel, G. Praticò, M Puig Valls, N. Rao, J. Riley, A. Roberts, G. Roberts, A. Rowe, T. Sandström, W. Seibold, A. Selby, D.E. Shaw, R. Sigmund, F. Singer, P.J. Skipp, A.R. Sousa, P.J. Sterk, K. Sun, B. Thornton, W.M. van Aalderen, M. van Geest, J. Vestbo, N.H. Vissing, A.H. Wagener, S.S. Wagers, Z. Weiszhart, C.E. Wheelock, S.J. Wilson, Publica, Pulmonology, AII - Inflammatory diseases, Graduate School, AII - Amsterdam institute for Infection and Immunity, ARD - Amsterdam Reproduction and Development, Medical Research Council (MRC), and Pediatric surgery

Subjects
0301 basic medicine, Male, Allergy, Severe asthma, ILC3, mast cells, Disease, Eosinophil, Severity of Illness Index, transcriptomics, 0302 clinical medicine, Eosinophilic, Immunology and Allergy, Medicine, Age of Onset, Oligonucleotide Array Sequence Analysis, mechanisms, Innate lymphoid cell, Adult-onset asthma, eosinophils, gene set variation analysis, phenotyping, severe asthma, Middle Aged, Phenotype, Asthma Control Questionnaire, 1107 Immunology, Female, medicine.symptom, Adult, Genetic Markers, Immunology, mechanism, macromolecular substances, Lung injury, 03 medical and health sciences, Humans, adult-onset asthma, Asthma, U-BIOPRED Study Group, business.industry, Gene Expression Profiling, medicine.disease, respiratory tract diseases, 030104 developmental biology, Cross-Sectional Studies, 030228 respiratory system, Sputum, business, Transcriptome, mast cell
Abstract

Background: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous samples. Objective: We sought to identify gene profiles associated with adult-onset severe asthma. Methods: This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (

Published
2018
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18. Genome-wide association and longitudinal analyses reveal genetic loci linking pubertal height growth, pubertal timing and childhood adiposity

Author

D. L. Cousminer, D. J. Berry, N. J. Timpson, W. Ang, E. Thiering, E. M. Byrne, H. R. Taal, V. Huikari, J. P. Bradfield, M. Kerkhof, M. M. Groen Blokhuis, E. Kreiner Moller, M. Marinelli, C. Holst, J. T. Leinonen, J. R. B. Perry, I. Surakka, O. Pietilainen, J. Kettunen, V. Anttila, M. Kaakinen, U. Sovio, A. Pouta, S. Das, V. Lagou, C. Power, I. Prokopenko, D. M. Evans, J. P. Kemp, B. St Pourcain, S. Ring, A. Palotie, E. Kajantie, C. Osmond, T. Lehtimaki, J. S. Viikari, M. Kahonen, N. M. Warrington, S. J. Lye, L. J. Palmer, C. M. T. Tiesler, C. Flexeder, G. W. Montgomery, S. E. Medland, A. Hofman, H. Hakonarson, M. Guxens, M. Bartels, V. Salomaa, J. M. Murabito, J. Kaprio, T. I. A. Sorensen, F. Ballester, H. Bisgaard, D. I. Boomsma, G. H. Koppelman, S. F. A. Grant, V. W. V. Jaddoe, N. G. Martin, J. Heinrich, C. E. Pennell, O. T. Raitakari, J. G. Eriksson, G. D. Smith, E. Hypponen, M. R. Jarvelin, M. I. McCarthy, S. Ripatti, E. Widen, Adair LS, Ang W, Atalay M, van Beijsterveldt T, Bergen N, Benke K, Berry DJ, Boomsma DI, Bradfield JP, Charoen P, Coin L, Cooper C, Cousminer DL, Das S, Davis OS, Dedoussis GV, Elliott P, Estivill X, Evans DM, Feenstra B, Flexeder C, Frayling T, Freathy RM, Gaillard R, Geller F, Gillman M, Grant SF, Groen Blokhuis M, Goh LK, Guxens M, Hakonarson H, Hattersley AT, Haworth CM, Hadley D, Hedebrand J, Heinrich J, Hinney A, Hirschhorn JN, Hocher B, Holloway JW, Holst C, Hottenga JJ, Horikoshi M, Huikari V, Hypponen E, Iñiguez C, Jaddoe VW, Jarvelin MR, Kaakinen M, Kilpeläinen TO, Kirin M, Kowgier M, Lakka HM, Lakka TA, Lange LA, Lawlor DA, Lehtimäki T, Lewin A, Lindgren C, Lindi V, Maggi R, Marsh J, McCarthy MI, Melbye M, Middeldorp C, Millwood I, Mohlke KL, Mook Kanamori DO, Murray JC, Nivard M, Nohr EA, Ntalla I, Oken E, Ong KK, O'Reilly PF, Palmer LJ, Panoutsopoulou K, Pararajasingham J, Pearson ER, Pennell CE, Power C, Price TS, Prokopenko I, Raitakari OT, Rodriguez A, Salem RM, Saw SM, Scherag A, Sebert S, Siitonen N, Simell O, Sørensen TI, Sovio U, Pourcain BS, Strachan DP, Sunyer J, Taal HR, Teo YY, Thiering E, Tiesler C, Timpson NJ, Uitterlinden AG, Valcárcel B, Warrington NM, White S, Widén E, Willemsen G, Wilson JF, Yaghootkar H, Zeggini E, Elks CE, Perry JR, Sulem P, Chasman DI, Franceschini N, He C, Lunetta KL, Visser JA, Byrne EM, Gudbjartsson DF, Esko T, Koller DL, Kutalik Z, Lin P, Mangino M, Marongiu M, McArdle PF, Smith AV, Stolk L, van Wingerden SH, Zhao JH, Albrecht E, Corre T, Ingelsson E, Hayward C, Magnusson PK, Smith EN, Ulivi S, Warrington M, Zgaga L, Alavere H, Amin N, Aspelund T, Bandinelli S, Barroso I, Berenson GS, Bergmann S, Blackburn H, Boerwinkle E, Buring JE, Busonero F, Campbell H, Chanock SJ, Chen W, Cornelis MC, Couper D, Coviello AD, de Faire U, de Geus EJ, Deloukas P, Döring A, Davey Smith G, Easton DF, Eiriksdottir G, Emilsson V, Eriksson J, Ferrucci L, Folsom AR, Foroud T, Garcia M, GASPARINI, PAOLO, Gieger C, Gudnason V, Hall P, Hankinson SE, Ferreli L, Heath AC, Hernandez DG, Hofman A, Hu FB, Illig T, Järvelin MR, Johnson AD, Karasik D, Khaw KT, Kiel DP, Kolcic I, Kraft P, Launer LJ, Laven JS, Li S, Liu J, Levy D, Martin NG, McArdle WL, Mooser V, Murray SS, Nalls MA, Navarro P, Nelis M, Ness AR, Northstone K, Oostra BA, Peacock M, Palotie A, Paré G, Parker AN, Pedersen NL, Peltonen L, Pharoah P, Polasek O, Plump AS, Pouta A, Porcu E, Rafnar T, Rice JP, Ring SM, Rivadeneira F, Rudan I, Sala C, Salomaa V, Sanna S, Schlessinger D, Schork NJ, Scuteri A, Segrè AV, Shuldiner AR, Soranzo N, Srinivasan SR, Tammesoo ML, Tikkanen E, Toniolo D, Tsui K, Tryggvadottir L, Tyrer J, Uda M, van Dam RM, van Meurs JB, Vollenweider P, Waeber G, Wareham NJ, Waterworth DM, Weedon MN, Wichmann HE, Wright AF, Young L, Zhai G, Zhuang WV, Bierut LJ, Boyd HA, Crisponi L, Demerath EW, van Duijn CM, Econs MJ, Harris TB, Hunter DJ, Loos RJ, Metspalu A, Montgomery GW, Ridker PM, Spector TD, Streeten EA, Stefansson K, Thorsteinsdottir U, Widen E, Murabito JM, Murray A., D'ADAMO, ADAMO PIO, Cousminer, Diana L, Berry, Diane J, Timpson, Nicholas J, Ang, Wei, Hyppönen, Elina, Widen, Elisabéth, ReproGen Consortium, Early Growth Genetics (EGG) Consortium, Pediatrics, Epidemiology, Internal Medicine, D. L., Cousminer, D. J., Berry, N. J., Timpson, W., Ang, E., Thiering, E. M., Byrne, H. R., Taal, V., Huikari, J. P., Bradfield, M., Kerkhof, M. M., Groen Blokhui, E., Kreiner Moller, M., Marinelli, C., Holst, J. T., Leinonen, J. R. B., Perry, I., Surakka, O., Pietilainen, J., Kettunen, V., Anttila, M., Kaakinen, U., Sovio, A., Pouta, S., Da, V., Lagou, C., Power, I., Prokopenko, D. M., Evan, J. P., Kemp, B., St Pourcain, S., Ring, A., Palotie, E., Kajantie, C., Osmond, T., Lehtimaki, J. S., Viikari, M., Kahonen, N. M., Warrington, S. J., Lye, L. J., Palmer, C. M. T., Tiesler, C., Flexeder, G. W., Montgomery, S. E., Medland, A., Hofman, H., Hakonarson, M., Guxen, M., Bartel, V., Salomaa, J. M., Murabito, J., Kaprio, T. I. A., Sorensen, F., Ballester, H., Bisgaard, D. I., Boomsma, G. H., Koppelman, S. F. A., Grant, V. W. V., Jaddoe, N. G., Martin, J., Heinrich, C. E., Pennell, O. T., Raitakari, J. G., Eriksson, G. D., Smith, E., Hypponen, M. R., Jarvelin, M. I., Mccarthy, S., Ripatti, E., Widen, Adair, L, Ang, W, Atalay, M, van Beijsterveldt, T, Bergen, N, Benke, K, Berry, Dj, Boomsma, Di, Bradfield, Jp, Charoen, P, Coin, L, Cooper, C, Cousminer, Dl, Das, S, Davis, O, Dedoussis, Gv, Elliott, P, Estivill, X, Evans, Dm, Feenstra, B, Flexeder, C, Frayling, T, Freathy, Rm, Gaillard, R, Geller, F, Gillman, M, Grant, Sf, Groen Blokhuis, M, Goh, Lk, Guxens, M, Hakonarson, H, Hattersley, At, Haworth, Cm, Hadley, D, Hedebrand, J, Heinrich, J, Hinney, A, Hirschhorn, Jn, Hocher, B, Holloway, Jw, Holst, C, Hottenga, Jj, Horikoshi, M, Huikari, V, Hypponen, E, Iñiguez, C, Jaddoe, Vw, Jarvelin, Mr, Kaakinen, M, Kilpeläinen, To, Kirin, M, Kowgier, M, Lakka, Hm, Lakka, Ta, Lange, La, Lawlor, Da, Lehtimäki, T, Lewin, A, Lindgren, C, Lindi, V, Maggi, R, Marsh, J, Mccarthy, Mi, Melbye, M, Middeldorp, C, Millwood, I, Mohlke, Kl, Mook Kanamori, Do, Murray, Jc, Nivard, M, Nohr, Ea, Ntalla, I, Oken, E, Ong, Kk, O'Reilly, Pf, Palmer, Lj, Panoutsopoulou, K, Pararajasingham, J, Pearson, Er, Pennell, Ce, Power, C, Price, T, Prokopenko, I, Raitakari, Ot, Rodriguez, A, Salem, Rm, Saw, Sm, Scherag, A, Sebert, S, Siitonen, N, Simell, O, Sørensen, Ti, Sovio, U, Pourcain, B, Strachan, Dp, Sunyer, J, Taal, Hr, Teo, Yy, Thiering, E, Tiesler, C, Timpson, Nj, Uitterlinden, Ag, Valcárcel, B, Warrington, Nm, White, S, Widén, E, Willemsen, G, Wilson, Jf, Yaghootkar, H, Zeggini, E, Elks, Ce, Perry, Jr, Sulem, P, Chasman, Di, Franceschini, N, He, C, Lunetta, Kl, Visser, Ja, Byrne, Em, Gudbjartsson, Df, Esko, T, Koller, Dl, Kutalik, Z, Lin, P, Mangino, M, Marongiu, M, Mcardle, Pf, Smith, Av, Stolk, L, van Wingerden, Sh, Zhao, Jh, Albrecht, E, Corre, T, Ingelsson, E, Hayward, C, Magnusson, Pk, Smith, En, Ulivi, S, Warrington, M, Zgaga, L, Alavere, H, Amin, N, Aspelund, T, Bandinelli, S, Barroso, I, Berenson, G, Bergmann, S, Blackburn, H, Boerwinkle, E, Buring, Je, Busonero, F, Campbell, H, Chanock, Sj, Chen, W, Cornelis, Mc, Couper, D, Coviello, Ad, D'Adamo, ADAMO PIO, de Faire, U, de Geus, Ej, Deloukas, P, Döring, A, Davey Smith, G, Easton, Df, Eiriksdottir, G, Emilsson, V, Eriksson, J, Ferrucci, L, Folsom, Ar, Foroud, T, Garcia, M, Gasparini, Paolo, Gieger, C, Gudnason, V, Hall, P, Hankinson, Se, Ferreli, L, Heath, Ac, Hernandez, Dg, Hofman, A, Hu, Fb, Illig, T, Järvelin, Mr, Johnson, Ad, Karasik, D, Khaw, Kt, Kiel, Dp, Kolcic, I, Kraft, P, Launer, Lj, Laven, J, Li, S, Liu, J, Levy, D, Martin, Ng, Mcardle, Wl, Mooser, V, Murray, S, Nalls, Ma, Navarro, P, Nelis, M, Ness, Ar, Northstone, K, Oostra, Ba, Peacock, M, Palotie, A, Paré, G, Parker, An, Pedersen, Nl, Peltonen, L, Pharoah, P, Polasek, O, Plump, A, Pouta, A, Porcu, E, Rafnar, T, Rice, Jp, Ring, Sm, Rivadeneira, F, Rudan, I, Sala, C, Salomaa, V, Sanna, S, Schlessinger, D, Schork, Nj, Scuteri, A, Segrè, Av, Shuldiner, Ar, Soranzo, N, Srinivasan, Sr, Tammesoo, Ml, Tikkanen, E, Toniolo, D, Tsui, K, Tryggvadottir, L, Tyrer, J, Uda, M, van Dam, Rm, van Meurs, Jb, Vollenweider, P, Waeber, G, Wareham, Nj, Waterworth, Dm, Weedon, Mn, Wichmann, He, Wright, Af, Young, L, Zhai, G, Zhuang, Wv, Bierut, Lj, Boyd, Ha, Crisponi, L, Demerath, Ew, van Duijn, Cm, Econs, Mj, Harris, Tb, Hunter, Dj, Loos, Rj, Metspalu, A, Montgomery, Gw, Ridker, Pm, Spector, Td, Streeten, Ea, Stefansson, K, Thorsteinsdottir, U, Widen, E, Murabito, Jm, Murray, A., Hedebrand, Johannes (Beitragende*r), Hinney, Anke (Beitragende*r), Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, Neuroscience Campus Amsterdam - Brain Imaging Technology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, Faculteit Medische Wetenschappen/UMCG, Groningen Research Institute of Pharmacy, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, Netherlands Twin Register (NTR), Genetic Linkage, Medizin, Gene Expression, Genome-wide association study, VARIANTS, Body Mass Index, 0302 clinical medicine, genetic linkage, Transforming Growth Factor beta, Neoplasms, molecular biology, genetics, Child, Genetics (clinical), Adiposity, 2. Zero hunger, 0303 health sciences, adiposity, Mitogen-Activated Protein Kinase 3, Association Studies Articles, Age Factors, ACHONDROPLASIA, General Medicine, Genome-Wide Association Study, pubertal height growth, pubertal timing, Phenotype, OBESITY, Menarche, body height, Female, Signal Transduction, medicine.medical_specialty, age factors, CHROMOSOME 16P11.2, Adolescent, BIRTH, Quantitative Trait Loci, 030209 endocrinology & metabolism, Context (language use), Biology, Childhood obesity, MENARCHE, Young Adult, 03 medical and health sciences, AGE, SDG 3 - Good Health and Well-being, Prepuberty, Internal medicine, Genetics, medicine, Humans, Molecular Biology, 030304 developmental biology, Sign, FACTOR RECEPTOR-3, MUTATIONS, Puberty, ta3121, medicine.disease, Obesity, Body Height, Genetic architecture, Endocrinology, POPULATION COHORT, gene expression, Body mass index, Follow-Up Studies
Abstract

The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. Although little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty and cancer progression, pointing to shared underlying mechanisms. To discover genetic loci influencing pubertal height and growth and to place them in context of overall growth and maturation, we performed genome-wide association meta-analyses in 18 737 European samples utilizing longitudinally collected height measurements. We found significant associations (P

Published
2013
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19. Measurement of exhaled nitric oxide in children, 2001: E. Baraldi and J.C. de Jongste on behalf of the Task Force

Author

null Members of the Task Force, E. Baraldi, J.C. de Jongste, B. Gaston, K. Alving, P.J. Barnes, H. Bisgaard, A. Bush, C. Gaultier, H. Grasemann, J.F. Hunt, N. Kissoon, G.L. Piacentini, F. Ratjen, P. Silkoff, and S. Stick

Subjects
Pulmonary and Respiratory Medicine, Respiratory Medicine, medicine.medical_specialty, Age groups, business.industry, Task force, Lung disease, Exhaled nitric oxide, Medicine, business, Intensive care medicine, Exhaled air, Lung function
Abstract

Measurement of fractional exhaled nitric oxide in exhaled air is an exciting innovative technique that gives new insights in to the pathophysiology of lung disease and asthma in particular, with many potential clinical applications. Careful standardisation of measurement techniques will facilitate the use of this new measurement in paediatric respiratory medicine; this Task Force was set up for this purpose. Methodologies, for use in all age groups, are already available and there are abundant questions relating to interpretation and application of fractional exhaled nitric oxide waiting to be addressed. Noninvasiveness and instantaneous results potentially make it a suitable monitoring instrument for use in children. Exhaled nitric oxide measurement has definitely found its way into clinical research in paediatric respiratory medicine. Evidence for clinically-useful applications is accumulating, and the merits of this new technique must now be demonstrated in larger studies, using standardised methodology in an appropriate setting.

Published
2002
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22. Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study

Author

J P, Thyssen, K, Ross-Hansen, J D, Johansen, C, Zachariae, B C, Carlsen, A, Linneberg, H, Bisgaard, C G, Carson, N H, Nielsen, M, Meldgaard, P B, Szecsi, S, Stender, and T, Menné

Subjects
Adult, Male, Heterozygote, Adolescent, Genotype, Hand Dermatoses, Filaggrin Proteins, Middle Aged, Dermatitis, Atopic, Young Adult, Cross-Sectional Studies, Intermediate Filament Proteins, Mutation, Humans, Female, Aged, Skin Tests
Abstract

Filaggrin metabolites act as osmolytes and are important for skin hydration. Carriers of filaggrin loss-of-function mutations have a higher prevalence of atopic dermatitis and dry skin. There is also evidence to suggest that filaggrin mutations increase the risk of hand eczema in atopic individuals. In our clinic, we have observed a distinct phenotype of hand eczema in patients with filaggrin mutation carrier status, characterized by fissured dermatitis on the dorsal aspect of the hands and with only sparse involvement of the palms including fine scaling.To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population.Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested.In an adjusted logistic regression analysis, filaggrin mutation status was significantly associated with fissured skin on the hands and/or fingers in adults (odds ratio 1·93, 95% confidence interval 1·05-3·55) and showed a nearly significant negative interaction with atopic dermatitis (P=0·055), suggesting that the effect was predominantly in subjects without atopic dermatitis.Filaggrin loss-of-function mutations seem not only to increase the risk of atopic dermatitis and dry skin but also the risk of fissures on the hands and/or fingers in subjects without atopic dermatitis. Prophylactic emollient therapy should be particularly encouraged in filaggrin loss-of-function mutation carriers.

Published
2011

28. Heterogeneity of FeNO response to inhaled steroid in asthmatic children

Author

F, Buchvald, H, Eiberg, and H, Bisgaard

Subjects
Male, Cross-Over Studies, Adolescent, Nebulizers and Vaporizers, Anti-Inflammatory Agents, Nitric Oxide, Asthma, Breath Tests, Double-Blind Method, Case-Control Studies, Administration, Inhalation, Humans, Regression Analysis, Female, Budesonide, Child, Lung, Biomarkers
Abstract

Nitric oxide in exhaled air is regarded as an inflammation marker, and may be used to monitor the anti-inflammatory control from inhaled corticosteroids (ICSs). However, this response to ICSs exhibits a heterogeneous pattern.The study aimed to describe the independent variables associated with the heterogeneity in the response of exhaled nitric oxide to ICSs.Exhaled nitric oxide (FeNO), lung function, bronchial hyper-responsiveness (BHR), specific IgE to common inhalant allergens, blood eosinophils, other atopic manifestations and variants in nitric oxide synthethase 1 (NOS1) gene were studied in a double-blind, placebo-controlled crossover comparison of budesonide (BUD) Turbohaler 1600 mcg daily vs. placebo in asthmatic schoolchildren.Forty children were included in the study from a screening of 184 asthmatic children with moderately persistent asthma, well controlled on regular BUD 400 mcg daily: 20 children with normal FeNO and 20 with raised FeNO. FeNO, BHR and forced expiratory volume in 1 s improved significantly after BUD 1600 mcg (BUD1600). However, FeNO after ICS treatment exhibited a Gaussian distribution and FeNO was significantly raised in 15 children. Allergy and BHR, but none of the other independent variables under study were significantly related to FeNO after BUD1600.Exhaled nitric oxide exhibited a heterogeneous response to ICS in asthmatic schoolchildren. Allergy and BHR were driving FeNO level independently of high-dose steroid treatment. This should be considered when using FeNO for steroid dose titration and monitoring of ICS anti-inflammatory control in asthmatic children.

Published
2003

29. Leukotrienes, leukotriene receptor antagonists, and rhinitis

Author

N, Mygind, R, Dahl, and H, Bisgaard

Subjects
Clinical Trials as Topic, Leukotrienes, Histamine H1 Antagonists, Animals, Humans, Leukotriene Antagonists, Drug Therapy, Combination, Anti-Asthmatic Agents, Rhinitis
Published
2000

31. Evidence-based medicines for children: ethical aspects

Author

H. Bisgaard and A. Gammelgaard

Subjects
Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Evidence-based practice, business.industry, Law, Alternative medicine, Medicine, European commission, Legislation, business
Abstract

To the Editors: In an editorial in the December issue of the European Respiratory Journal , Bush 1 describes and welcomes newly proposed legislation from the European Commission requiring testing of all new medicine in children. We certainly agree that this new proposal is a step forward in terms of developing evidence-based therapies for children. We also agree that the creation of a new Paediatric Committee is an opportunity for the scientific community to influence the direction …

Published
2007
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32. Repeatability of methacholine challenges in 2- to 4-year-old children with asthma, using a new technique for quantitative delivery of aerosol

Author

B, Klug and H, Bisgaard

Subjects
Aerosols, Bronchoconstrictor Agents, Male, Child, Preschool, Terbutaline, Humans, Reproducibility of Results, Female, Asthma, Bronchial Provocation Tests, Methacholine Chloride
Abstract

To determine the repeatability of bronchial responsiveness in awake young children, two methacholine challenge tests were performed on separate days in 16 children with stable asthma (mean age, 3 3/4 years). Methacholine was administered using a new method for quantitative delivery of aerosol that eliminates the effect of dilution of the aerosol by entrainment of air and enables quantitative delivery of aerosol according to body weight. Respiratory function was monitored by measurement of respiratory resistance by the interrupter technique (Rint), respiratory resistance and reactance at 5 Hz (Rrs5, Xrs5) by the impulse oscillation technique, transcutaneous measurements of oxygen (PtcO2), and specific airway resistance (sRaw). Repeatability was evaluated by determining the provocative dose that caused a defined percentage of change relative to baseline (PD%: Rint PD30, Rrs5 PD30, Xrs5 PD80, PtcO2 PD10, and sRaw PD80. Repeatability was estimated from the difference between the PD% obtained at the time of the two tests. Using the numeric value of these differences, the repeatability of Xrs5 PD60, PtcO2 PD10, and sRaw PD50 was [mean (SD)]: [0.8 (0.5)] [0.5 (0.4)] and [0.7 (0.6)] doubling doses, respectively. Rint PD30 and Rrs5 PD30 proved to be less reproducible: [1.2 (1)] and [1.6 (0.9)] doubling doses, respectively. The new method of aerosol delivery offers a means of standardizing the bronchoconstrictor stimulus, and the results show that estimates of bronchial responsiveness in young children can be obtained reproducibly within one doubling dose of methacholine.

Published
1997

35. Foreword

Author

H. Bisgaard and S. Pedersen

Subjects
Immunology, Immunology and Allergy
Published
1999
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36. 264 IMPROVED HOLDING CHAMBER FOR TREATMENT OF YOUNG ASTHMA CHILDREN WITH PRESSURIZED METERED DOSE INHALERS (P-MDI)

Author

H Bisgaard

Subjects
Budesonide, medicine.medical_specialty, business.industry, Dead space, HOLDING CHAMBER, medicine.disease, Confounding effect, Surgery, Face masks, Inspiratory flow, Anesthesia, Pediatrics, Perinatology and Child Health, medicine, business, medicine.drug, Asthma
Abstract

In vitro T½ (aerosol) was less than 10 sec in a polycarbonate holding chamber compared to a T½ (aerosol) of longer than 30 sec in a steel holding chamber. A prototype holding chamber of 220 mL was cast in steel, and was equipped with a two-way low-resistance valve with a small dead space to ensure a rectified inspiratory flow from the spacer and expiratory flow outside the spacer. This prototype was tested against a traditional 750 mL polycarbonate single-valved holding chamber for the delivery of budesonide aerosol from P-MDI to children in the age-range of 0-7 years suspected of asthma. The polycarbonate was primed with benzalkonium chloride prior to use to avoid the confounding effect of the material. Both holding chambers were equipped with closely fitted face masks for children less than 48 months old. One hundred and sixty five children suspected of asthma, equally distributed as regards age from 0 to 7 years, inhaled one dose of budesonide from one of the holding chambers for 60 seconds. A filter was interposed between the holding chamber and the face mask adsorbing all particles delivered to the child. The mean dose fraction inhaled from the prototype approximated 38% irrespective of age, whereas the large-volume holding chamber exhibited a highly significant age-related decrease from approximately 44% in the older children down to 19% in infants. The difference in the doses of aerosol delivered was significant among children less than 3 years of age.

Published
1994
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37. Nebulization and selective deposition of LTD4in human lungs

Author

H. Bisgaard, L. Poulsen, and I. Søndergaard

Subjects
Adult, Male, medicine.medical_specialty, Depot, medicine.medical_treatment, Immunology, Bronchial Provocation Tests, Settling, Forced Expiratory Volume, medicine, Humans, Immunology and Allergy, Lung, Saline, Chromatography, High Pressure Liquid, Aerosols, Chromatography, Inhalation, Chemistry, Nebulizers and Vaporizers, respiratory system, Asthma, Surgery, Aerosol, Nebulizer, Deposition (aerosol physics), Female, SRS-A, Particle size, Pulmonary Ventilation
Abstract

The process of nebulization and deposition of LTD4 was studied in detail. The concentration of LTD4 in a saline solution decreased by approximately 90% after 2 min of nebulization in a DeVilbiss 35B ultrasonic nebulizer. This decrease was prevented by diluting LTD4 in a phosphate buffer, pH 7.4. Nebulization of tritiated LTD4 in this phosphate buffer did not cause any appreciable deterioration of the leukotriene, as demonstrated by an unchanged ratio between radioactivity and LTD4 concentration in the test solution before and after nebulization as well as in the condensed aerosol. The aerosol generated by the DeVilbiss 35B ultrasonic nebulizer was shown to generate particles with a mass median diameter of 1.3 microns (dry particle size). Interposition of a settling bag reduced the amount of large particles, reducing the mass median diameter to 0.84 microns (dry particle size). Nine healthy volunteers were challenged on separate days with 40 nmol LTD4 or 100 mumol histamine, and the changes in FEV1 and partial flow volume curves initiated at 50% of vital capacity (Vmax30) were measured. A relative diffuse deposition pattern was ensured by inhalation via a settling bag. These results were compared to challenges with a relatively central deposition pattern as ensured by inhalation directly from the nebulizer with brisk inhalation maneuvers. The diffuse deposition pattern caused minimal changes in FEV1 but pronounced effect in Vmax30. The effects of LTD4 and histamine on FEV1 and Vmax30 changed in parallel when the deposition of the mediators was changed to a more central pattern. This indicates that the two mediators do not differ with respect to any selective effects on different parts of the airways.

Published
1987
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39. [Diseases in Greenland]

Author

H, BISGAARD-FRANTZEN

Subjects
Vital Statistics, Epidemiology, Greenland, Humans
Published
1952

45. Early growth and the risk of childhood asthma: A meta-analysis of 147,000 European children

Author

Sonnenschein-Van Voort, A. M. M., Arends, L. R., Jongste, J. C., Annesi-Maesano, I., Barros, H., Basterrechea, M., Bisgaard, H., Chatzi, L., Corpeleijn, E., Correia, S., Craig, L. C., Devereux, G., Di Oregon, V., Cristian Dogaru, Dostal, M., Duchen, K., Eggesbo, M., Ent, C. K., Fantini, M. P., Forastiere, F., Frey, U., Gehring, U., Gugten, A. C., Hanke, W., Henderson, A. J., Heude, B., Iniguez, C., Inskip, H. M., Keil, T., Kelleher, C. C., Kogevinas, M., Kreiner-Moller, E., Kuehni, C. E., Kupers, L. K., Lancz, K., Larsen, P. S., Lau, S., Ludvigsson, J., Mommers, M., Andersen, A. M. N., Palkovicova, L., Pike, K. C., Pizzi, C., Polanska, K., Porta, D., Richiardi, L., Roberts, G., Schmidt, A., Sram, R. J., Sunyer, J., Thijs, C., Torrent, M., Viljoen, K., Wijga, A. H., Vrijheid, M., Jaddoe, V. W. V., Duijts, L., A.M.M. Sonnenschein-van der Voort, L.R. Arend, J.C. de Jongste, I. Annesi-Maesano, H. Barro, M. Basterrechea, H. Bisgaard, L. Chatzi, E. Corpeleijn, S. Correia, L.C. Craig, G. Devereux, V. Di Gregori, C.M. Dogaru, M. Dostal, K. Duchen, M. Eggesbo, C.K. van der Ent, M.P. Fantini, F. Forastiere, U. Frey, U. Gehring, A.C. van der Gugten, W. Hanke, A.J. Henderson, B. Heude, C. Iñiguez, H.M. Inskip, T. Keil, C.C. Kelleher, M. Kogevina, E. Kreiner-Moller, C.E. Kuehni, L.K. Küper, K. Lancz, P.S. Larsen, S. Lau, J. Ludvigsson, M. Mommer, A.M. Nybo Andersen, L. Palkovicova, K.C. Pike, C. Pizzi, K. Polanska, D. Porta, L. Richiardi, G. Robert, A. Schmidt, R.J. Sram, J. Sunyer, C. Thij, M. Torrent, K. Viljoen, A.H. Wijga, M. Vrijheid, and V.W.V. Jaddoe and L. Duijts

Subjects
LONGITUDINAL STUDY, CHILDREN, asthma
Abstract

Background. Low birth weight, preterm birth and rapid infant growth seem to be associated with increased risks of childhood asthma. We examined the association of birth and infant growth characteristics with the risks of preschool wheezing and school age asthma using data from 147,252 subjects of 31 European cohort studies. Methods. Studies were eligible if they included children from 1989 onwards, had information on at least gestational age and weight at birth, and preschool wheezing (1-4 years) or school-age asthma (5-10 years). Adjusted pooled odds ratios (OR) from random effect models were calculated, and ORs from individual participant data were used to assess the combined effect of birth weight and gestational age. Results. Compared with term birth, preterm birth (< 37 weeks) was positively associated with increased risks of preschool wheezing and school-age asthma, independent of birth weight (OR 1.34 (1.25, 1.43) and 1.40 (1.18, 1.67)). Birth weight was not associated with preschool wheezing and school-age asthma after adjustment for gestational age at birth. Infant weight gain was positively associated with preschool wheezing and school-age asthma (OR 1.83 (1.61, 2.08) and 1.62 (1.22, 2.14) per 500 gram weight gain per month). We observed the strongest effects on preschool wheezing and school-age asthma for children born preterm with a high birth weight for gestational age, compared with term born children with an appropriate birth weight for gestational age (OR 2.40 (1.53, 3.75) and 2.77 (1.56, 4.95)). Conclusions. Preterm birth and higher infant weight gain, but not low birth weight, are associated with increased risks of wheezing and asthma in childhood.

Published
2013

46. Co-localization of antibiotic resistance genes is widespread in the infant gut microbiome and associates with an immature gut microbial composition.

Author

Li X, Brejnrod A, Trivedi U, Russel J, Thorsen J, Shah SA, Vestergaard GA, Rasmussen MA, Nesme J, Bisgaard H, Stokholm J, and Sørensen SJ

Subjects
Humans, Infant, Denmark, Drug Resistance, Bacterial genetics, Genes, Bacterial genetics, Female, Feces microbiology, Drug Resistance, Microbial genetics, Male, Cohort Studies, Infant, Newborn, Gastrointestinal Microbiome genetics, Gastrointestinal Microbiome drug effects, Anti-Bacterial Agents pharmacology, Bacteria genetics, Bacteria classification, Bacteria drug effects, Bacteria isolation & purification
Abstract

Background: In environmental bacteria, the selective advantage of antibiotic resistance genes (ARGs) can be increased through co-localization with genes such as other ARGs, biocide resistance genes, metal resistance genes, and virulence genes (VGs). The gut microbiome of infants has been shown to contain numerous ARGs, however, co-localization related to ARGs is unknown during early life despite frequent exposures to biocides and metals from an early age., Results: We conducted a comprehensive analysis of genetic co-localization of resistance genes in a cohort of 662 Danish children and examined the association between such co-localization and environmental factors as well as gut microbial maturation. Our study showed that co-localization of ARGs with other resistance and virulence genes is common in the early gut microbiome and is associated with gut bacteria that are indicative of low maturity. Statistical models showed that co-localization occurred mainly in the phylum Proteobacteria independent of high ARG content and contig length. We evaluated the stochasticity of co-localization occurrence using enrichment scores. The most common forms of co-localization involved tetracycline and fluoroquinolone resistance genes, and, on plasmids, co-localization predominantly occurred in the form of class 1 integrons. Antibiotic use caused a short-term increase in mobile ARGs, while non-mobile ARGs showed no significant change. Finally, we found that a high abundance of VGs was associated with low gut microbial maturity and that VGs showed even higher potential for mobility than ARGs., Conclusions: We found that the phenomenon of co-localization between ARGs and other resistance and VGs was prevalent in the gut at the beginning of life. It reveals the diversity that sustains antibiotic resistance and therefore indirectly emphasizes the need to apply caution in the use of antimicrobial agents in clinical practice, animal husbandry, and daily life to mitigate the escalation of resistance. Video Abstract., (© 2024. The Author(s).)

Published
2024
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47. Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors.

Author

Chen Y, Checa A, Zhang P, Huang M, Kelly RS, Kim M, Chen YS, Lee-Sarwar KA, Prince N, Mendez KM, Begum S, Kachroo P, Chu SH, Stokholm J, Bønnelykke K, Litonjua AA, Bisgaard H, Weiss ST, Chawes BL, Wheelock CE, and Lasky-Su JA

Subjects
Child, Humans, Chromatography, Liquid, Tandem Mass Spectrometry, Ceramides metabolism, Risk Factors, Sphingolipids metabolism, Asthma etiology, Asthma genetics
Abstract

Background: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship., Methods: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC 2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together., Results: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes., Conclusion: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Published
2024
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48. Bacterial colonisation of the airway in neonates and risk of asthma and allergy until age 18 years.

Author

Sunde RB, Thorsen J, Kim M, Schoos AM, Stokholm J, Bønnelykke K, Bisgaard H, and Chawes B

Subjects
Infant, Newborn, Humans, Child, Preschool, Adolescent, Child, Infant, Respiratory System, Streptococcus pneumoniae, Respiratory Sounds etiology, Asthma etiology, Hypersensitivity complications, Dermatitis, Atopic complications
Abstract

Background: We previously showed an association between neonatal bacterial airway colonisation and increased risk of persistent wheeze/asthma until age 5 years. Here, we study the association with persistent wheeze/asthma and allergy-related traits until age 18 years., Methods: We investigated the association between airway colonisation with Streptococcus pneumoniae , Moraxella catarrhalis and/or Haemophilus influenzae in 1-month-old neonates from the COPSAC 2000 mother-child cohort and the development of persistent wheeze/asthma and allergy-related traits longitudinally until age 18 years using generalised estimating equations. Replication was sought in the similarly designed COPSAC 2010 cohort of 700 children., Results: Neonatal airway colonisation was present in 66 (21%) out of 319 children and was associated with a 4-fold increased risk of persistent wheeze/asthma (adjusted OR 4.01 (95% CI 1.76-9.12); p<0.001) until age 7 years, but not from age 7 to 18 years. Replication in the COPSAC 2010 cohort showed similar results using 16S data. Colonisation was associated with an increased number of exacerbations (adjusted incidence rate ratio 3.20 (95% CI 1.38-7.44); p<0.01) until age 7 years, but not from age 7 to 18 years. Colonisation was associated with increased levels of blood eosinophils (adjusted geometric mean ratio 1.24 (95% CI 1.06-1.44); p<0.01) and tumour necrosis factor (TNF)-α (adjusted geometric mean ratio 1.09 (95% CI 1.02-1.16); p=0.01) until age 12 years. There were no associations with lung function, bronchial reactivity, fractional exhaled nitric oxide, allergic sensitisation, total IgE or atopic dermatitis up to age 18 years., Conclusions: Neonatal airway colonisation was associated with early-onset persistent wheeze/asthma, exacerbations, elevated blood eosinophils and elevated TNF-α in blood, most prominent in early childhood, thereafter diminishing and no longer evident by age 18 years., Competing Interests: Conflict of interest: J. Thorsen reports lecture honoraria from AstraZeneca, outside the submitted work. A-M.M. Schoos reports lecture honoraria from Thermo Fisher Scientific, and advisory board participation with ALK, outside the submitted work. J. Stokholm reports support for the present work from the Lundbeck Foundation (grant number R16-A1694), the Ministry of Health (grant number 903516), the Danish Council for Strategic Research (grant number 0603-00280B) and the Capital Region Research Foundation; outside the submitted work, J. Stokholm reports grants from Novo Nordisk Foundation, TANDEM grant and DFF (Starting Grant – Research Leader and Danish ERC programme). K. Bønnelykke reports consulting fees from Sanofi and AstraZeneca, lecture honoraria from Boehringer Ingelheim, and advisory board participation with ALK-Abelló Nordic, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Published
2024
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49. Maternal vitamin D-related metabolome and offspring risk of asthma outcomes.

Author

Kim M, Brustad N, Ali M, Gürdeniz G, Arendt M, Litonjua AA, Wheelock CE, Kelly RS, Chen Y, Prince N, Guo F, Zhou X, Stokholm J, Bønnelykke K, Weiss ST, Bisgaard H, Lasky-Su J, and Chawes B

Subjects
Child, Preschool, Female, Humans, Pregnancy, Metabolome, Prospective Studies, Respiratory Sounds, Sphingomyelins, Clinical Trials as Topic, Asthma, Vitamin D
Abstract

Background: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown., Objective: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling., Methods: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010 ) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC 2010 , we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models., Results: In COPSAC 2010 , higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D 3 showed an increased cytoplasmic sphingolipid level (P < .01)., Conclusions: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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50. Atopic and non-atopic effects of fish oil supplementation during pregnancy.

Author

Bisgaard H, Mikkelsen M, Rasmussen MA, Sevelsted A, Schoos AM, Brustad N, Eliasen AU, Thorsen J, Chawes B, Gürdeniz G, Morin A, Stark K, Stokholm J, Ober C, Pedersen CET, and Bønnelykke K

Subjects
Child, Female, Humans, Pregnancy, Fish Oils therapeutic use, Dietary Supplements, Fatty Acids, Fatty Acids, Omega-3, Asthma prevention & control
Abstract

Background: We recently conducted a double-blinded randomised controlled trial showing that fish-oil supplementation during pregnancy reduced the risk of persistent wheeze or asthma in the child by 30%. Here, we explore the mechanisms of the intervention., Methods: 736 pregnant women were given either placebo or n-3 long-chain polyunsaturated fatty acids (LCPUFAs) in the third trimester in a randomised controlled trial. Deep clinical follow-up of the 695 children in the trial was done at 12 visits until age 6 years, including assessment of genotype at the fatty acid desaturase (FADS) locus, plasma fatty acids, airway DNA methylation, gene expression, microbiome and metabolomics., Results: Supplementation with n-3 LCPUFA reduced the overall risk of non-atopic asthma by 73% at age 6 (relative risk (RR) 0.27 (95% CI 0.06 to 0.85), p=0.042). In contrast, there was no overall effect on asthma with atopic traits (RR 1.42 (95% CI 0.63 to 3.38), p=0.40), but this was significantly modified by maternal FADS genotype and LCPUFA blood levels (interaction p<0.05), and supplementation did reduce the risk of atopic asthma in the subgroup of mothers with FADS risk variants and/or low blood levels of n-3 LCPUFA before the intervention (RR 0.31 (95% CI 0.11 to 0.75), p=0.016). Furthermore, n-3 LCPUFA significantly reduced the number of infections (croup, gastroenteritis, tonsillitis, otitis media and pneumonia) by 16% (incidence rate ratio 0.84 (95% CI 0.74 to 0.96), p=0.009)., Conclusions: n-3 LCPUFA supplementation in pregnancy showed protective effects on non-atopic asthma and infections. Protective effects on atopic asthma depended on maternal FADS genotype and n-3 LCPUFA levels. This indicates that the fatty acid pathway is involved in multiple mechanisms affecting the risk of asthma subtypes and infections., Trial Registration Number: NCT00798226., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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