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389 results on '"Maitland-Van Der Zee AH"'

1. Clinical utility of asthma biomarkers: from bench to bedside

Author

Vijverberg SJH, Hilvering B, Raaijmakers JA, Lammers JW, Maitland-van der Zee AH, and Koenderman L

Subjects
Medicine (General), R5-920
Abstract

Susanne JH Vijverberg,1,2,* Bart Hilvering,2,* Jan AM Raaijmakers,1 Jan-Willem J Lammers,2 Anke-Hilse Maitland-van der Zee,1,* Leo Koenderman2,* 1Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands; 2Department of Respiratory Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands *These authors contributed equally to this work Abstract: Asthma is a chronic disease characterized by airway inflammation, bronchial hyperresponsiveness, and recurrent episodes of reversible airway obstruction. The disease is very heterogeneous in onset, course, and response to treatment, and seems to encompass a broad collection of heterogeneous disease subtypes with different underlying pathophysiological mechanisms. There is a strong need for easily interpreted clinical biomarkers to assess the nature and severity of the disease. Currently available biomarkers for clinical practice – for example markers in bronchial lavage, bronchial biopsies, sputum, or fraction of exhaled nitric oxide (FeNO) – are limited due to invasiveness or lack of specificity. The assessment of markers in peripheral blood might be a good alternative to study airway inflammation more specifically, compared to FeNO, and in a less invasive manner, compared to bronchoalveolar lavage, biopsies, or sputum induction. In addition, promising novel biomarkers are discovered in the field of breath metabolomics (eg, volatile organic compounds) and (pharmaco)genomics. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches in which the clinical value of a combination of various markers is studied. This could eventually lead to the development of a clinically applicable algorithm composed of various markers and clinical features to phenotype asthma and improve diagnosis and asthma management. Keywords: asthma, airway inflammation, biological markers, pharmacogenomics, metabolomics

Published
2013

2. ST13 polymorphisms and their effect on exacerbations in steroid‐treated asthmatic children and young adults

Author

Vijverberg, SJH, Koster, ES, Tavendale, R, Leusink, M, Koenderman, L, Raaijmakers, JAM, Postma, DS, Koppelman, GH, Turner, SW, Mukhopadhyay, S, Tse, SM, Tantisira, KG, Hawcutt, DB, Francis, B, Pirmohamed, M, Pino-Yanes, M, Eng, C, Burchard, EG, Palmer, CNA, and Maitland-van der Zee, AH

Subjects
Biomedical and Clinical Sciences, Immunology, Clinical Research, Lung, Asthma, Pediatric, Clinical Trials and Supportive Activities, Genetics, Respiratory, Adolescent, Adrenal Cortex Hormones, Anti-Asthmatic Agents, Carrier Proteins, Child, Child, Preschool, Cohort Studies, Disease Progression, Female, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Treatment Outcome, Tumor Suppressor Proteins, Young Adult, childhood asthma, corticosteroids, exacerbations, pharmacogenomics, ST13, Nutrition and Dietetics, Public Health and Health Services, Allergy
Abstract

BackgroundThe clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.MethodsWe performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed.ResultsTwo SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively.Conclusion and clinical relevanceA novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Published
2015

3. Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation

Author

Versi, A, Ivan, FX, Abdel-Aziz, MI, Bates, S, Riley, J, Baribaud, F, Kermani, NZ, Montuschi, P, Dahlen, S-E, Djukanovic, R, Sterk, P, Maitland-Van Der Zee, AH, Chotirmall, SH, Howarth, P, Adcock, IM, Chung, KF, and U-BIOPRED consortium

Abstract

BACKGROUND: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. METHODS: Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). RESULTS: α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and β-diversities were stable at one year. CONCLUSIONS: Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.

Published
2023

4. Association of bronchial steroid inducible methylation quantitative trait loci with asthma and chronic obstructive pulmonary disease treatment response.

Author

Slob, EMA, Faiz, A, van Nijnatten, J, Vijverberg, SJH, Longo, C, Kutlu, M, Chew, FT, Sio, YY, Herrera-Luis, E, Espuela-Ortiz, A, Perez-Garcia, J, Pino-Yanes, M, Burchard, EG, Potočnik, U, Gorenjak, M, Palmer, C, Maroteau, C, Turner, S, Verhamme, K, Karimi, L, Mukhopadhyay, S, Timens, W, Hiemstra, PS, Pijnenburg, MW, Neighbors, M, Grimbaldeston, MA, Tew, GW, Brandsma, CA, Berce, V, Aliee, H, Theis, F, Sin, DD, Li, X, van den Berge, M, Maitland-van der Zee, AH, Koppelman, GH, Slob, EMA, Faiz, A, van Nijnatten, J, Vijverberg, SJH, Longo, C, Kutlu, M, Chew, FT, Sio, YY, Herrera-Luis, E, Espuela-Ortiz, A, Perez-Garcia, J, Pino-Yanes, M, Burchard, EG, Potočnik, U, Gorenjak, M, Palmer, C, Maroteau, C, Turner, S, Verhamme, K, Karimi, L, Mukhopadhyay, S, Timens, W, Hiemstra, PS, Pijnenburg, MW, Neighbors, M, Grimbaldeston, MA, Tew, GW, Brandsma, CA, Berce, V, Aliee, H, Theis, F, Sin, DD, Li, X, van den Berge, M, Maitland-van der Zee, AH, and Koppelman, GH

Published
2022

5. International Severe Asthma Registry Mission Statement

Author

Canonica, GW, Alacqua, M, Altraja, A, Backer, V, Bel, E, Bjermer, L, Bjornsdottir, U, Bourdin, A, Brusselle, GG, Christoff, GC, Cosio, BG, Costello, RW, FitzGerald, JM, Gibson, PG, Heaney, LG, Heffler, E, Hew, M, Iwanaga, T, Jones, RC, Siyue, MK, Rhee, CK, Lehmann, S, Lehtimaki, LA, Ludviksdottir, D, Maitland-van der Zee, AH, Menzies-Gow, AN, Papadopoulos, NG, Plaza, V, de Llano, LP, Peters, M, Porsbjerg, CM, Sadatsafavi, M, Cho, YS, Tohda, Y, Tran, TN, Wang, E, Zangrilli, J, Bulathsinhala, L, Carter, VA, Chaudhry, I, Eleangovan, N, Hosseini, N, Le, TL, Murray, RB, Price, CA, Price, DB, and ISAR Study Grp

Subjects
asma, ISAR, severe asthma, sistema de registros, International Cooperation, humanos, Humans, cooperación internacional, Registries, índice de gravedad de la enfermedad, Severity of Illness Index, Asthma
Abstract

Regional and/or national severe asthma registries provide valuable country-specific information. However, they are often limited in scope within the broader definitions of severe asthma, have insufficient statistical power to answer many research questions, lack intraoperability to share lessons learned, and have fundamental differences in data collected, making cross comparisons difficult. What is missing is a worldwide registry which brings all severe asthma data together in a cohesive way, under a single umbrella, based on standardized data collection protocols, permitting data to be shared seamlessly. The International Severe Asthma Registry (ISAR; http://isaregistries.org/) is the first global adult severe asthma registry. It is a joint initiative where national registries (both newly created and preexisting) retain ownership of their own data but open their borders and share data with ISAR for ethically approved research purposes. Its strength comes from collection of patient-level, anonymous, longitudinal, real-life, standardized, high-quality data (using a core set of variables) from countries across the world, combined with organizational structure, database experience, inclusivity/openness, and clinical, academic, and database expertise. This gives ISAR sufficient statistical power to answer important research questions, sufficient data standardization to compare across countries and regions, and the structure and expertise necessary to ensure its continuance and the scientific integrity and clinical applicability of its research. ISAR offers a unique opportunity to implement existing knowledge, generate new knowledge, and identify the unknown, therefore promoting new research. The aim of this commentary is to fully describe how ISAR may improve our understanding of severe asthma., ISAR is conducted by Optimum Patient Care Global (OPC) Limited, and cofunded by OPC Limited and AstraZeneca.

Published
2020

6. Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder: results of a discordant twin study

Author

Slob, EMA, Brew, BK, Vijverberg, SJH, Dijs, T, van Beijsterveldt, CEM, Koppelman, GH, Bartels, M, Dolan, CV, Larsson, H, Lundström, S, Lichtenstein, P, Gong, T, Maitland-van der Zee, AH, Kraneveld, AD, Almqvist, C, Boomsma, DI, Slob, EMA, Brew, BK, Vijverberg, SJH, Dijs, T, van Beijsterveldt, CEM, Koppelman, GH, Bartels, M, Dolan, CV, Larsson, H, Lundström, S, Lichtenstein, P, Gong, T, Maitland-van der Zee, AH, Kraneveld, AD, Almqvist, C, and Boomsma, DI

Abstract

BACKGROUND: Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. METHODS: We conducted a cohort study in twins (7-12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. RESULTS: Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). CONCLUSIONS: Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics.

Published
2021

9. Early-life antibiotic use and risk of asthma and eczema: Results of a discordant twin study

Author

Slob, EMA, Brew, BK, Vijverberg, SJH, Kats, CJAR, Longo, C, Pijnenburg, MW, van Beijsterveldt, TCEM, Dolan, CV, Bartels, M, Magnusson, P, Lichtenstein, P, Gong, T, Koppelman, GH, Almqvist, C, Boomsma, DI, Maitland-Van der Zee, AH, Slob, EMA, Brew, BK, Vijverberg, SJH, Kats, CJAR, Longo, C, Pijnenburg, MW, van Beijsterveldt, TCEM, Dolan, CV, Bartels, M, Magnusson, P, Lichtenstein, P, Gong, T, Koppelman, GH, Almqvist, C, Boomsma, DI, and Maitland-Van der Zee, AH

Abstract

Rationale: Early-life antibiotic use has been associated with the development of atopic diseases, but the aetiology remains unclear. To elucidate the aetiology, we used a discordant twin design to control for genetic and environmental confounding. Methods: We conducted a retrospective cohort study in twins aged 3-10 years from the Netherlands Twin Register (NTR, n=35365) and a replication study in twins aged 9 years from the Childhood and Adolescent Twin Study in Sweden (CATSS, n=7916). Antibiotic use was recorded at age 0-2 years. Doctor-diagnosed asthma and eczema were reported by parents when children were aged 3-12 years in both cohorts. Individuals were included in unmatched analyses and in co-twin control analyses with disease discordant twin pairs. Results: Early-life antibiotic use was associated with increased risk of asthma (NTR OR 1.34, 95% CI 1.28-1.41; CATSS OR 1.45, 95% CI 1.34-1.56) and eczema (NTR OR 1.08, 95% CI 1.03-1.13; CATSS OR 1.07, 95% CI 1.01-1.14) in unmatched analyses. Co-twin analyses in monozygotic and dizygotic twin pairs showed similar results for asthma (NTR OR 1.54, 95% CI 1.20-1.98; CATSS OR 2.00, 95% CI 1.28-3.13), but opposing results for eczema in the NTR (OR 0.99, 95% CI 0.80-1.25) and the CATSS (OR 1.67, 95% CI 1.12-2.49). The risk of asthma increased for antibiotics prescribed for respiratory infections (CATSS OR 1.45, 95% CI 1.34-1.56), but not for antibiotics commonly used for urinary tract/skin infections (CATSS OR 1.02, 95% CI 0.88-1.17). Conclusion: Children exposed to early-life antibiotic use, particularly prescribed for respiratory infections, may be at higher risk of asthma. This risk can still be observed when correcting for genetic and environmental factors. Our results could not elucidate whether the relationship between early-life antibiotic use and eczema is confounded by familial and genetic factors.

Published
2020

10. International severe asthma registry (ISAR): protocol for a global registry

Author

FitzGerald, JM, Tran, TN, Alacqua, M, Altraja, A, Backer, V, Bjermer, L, Bjornsdottir, U, Bourdin, A, Brusselle, G, Bulathsinhala, L, Busby, J, Canonica, GW, Carter, V, Chaudhry, I, Cho, YS, Christoff, G, Cosio, BG, Costello, RW, Eleangovan, N, Gibson, PG, Heaney, LG, Heffler, E, Hew, M, Hosseini, N, Iwanaga, T, Jackson, DJ, Jones, R, Koh, MS, Le, T, Lehtimaki, L, Ludviksdottir, D, Maitland-van der Zee, AH, Menzies-Gow, A, Murray, RB, Papadopoulos, NG, Perez-de-Llano, L, Peters, M, Pfeffer, PE, Popov, TA, Porsbjerg, CM, Price, CA, Rhee, CK, Sadatsafavi, M, Tohda, Y, Wang, E, Wechsler, ME, Zangrilli, J, Price, DB, FitzGerald, JM, Tran, TN, Alacqua, M, Altraja, A, Backer, V, Bjermer, L, Bjornsdottir, U, Bourdin, A, Brusselle, G, Bulathsinhala, L, Busby, J, Canonica, GW, Carter, V, Chaudhry, I, Cho, YS, Christoff, G, Cosio, BG, Costello, RW, Eleangovan, N, Gibson, PG, Heaney, LG, Heffler, E, Hew, M, Hosseini, N, Iwanaga, T, Jackson, DJ, Jones, R, Koh, MS, Le, T, Lehtimaki, L, Ludviksdottir, D, Maitland-van der Zee, AH, Menzies-Gow, A, Murray, RB, Papadopoulos, NG, Perez-de-Llano, L, Peters, M, Pfeffer, PE, Popov, TA, Porsbjerg, CM, Price, CA, Rhee, CK, Sadatsafavi, M, Tohda, Y, Wang, E, Wechsler, ME, Zangrilli, J, and Price, DB

Abstract

BACKGROUND: Severe asthma exerts a disproportionately heavy burden on patients and health care. Due to the heterogeneity of the severe asthma population, many patients need to be evaluated to understand the clinical features and outcomes of severe asthma in order to facilitate personalised and targeted care. The International Severe Asthma Registry (ISAR) is a multi-country registry project initiated to aid in this endeavour. METHODS: ISAR is a multi-disciplinary initiative benefitting from the combined experience of the ISAR Steering Committee (ISC; comprising 47 clinicians and researchers across 29 countries, who have a special interest and/or experience in severe asthma management or establishment and maintenance of severe asthma registries) in collaboration with scientists and experts in database management and communication. Patients (≥18 years old) receiving treatment according to the 2018 definitions of the Global Initiative for Asthma (GINA) Step 5 or uncontrolled on GINA Step 4 treatment will be included. Data will be collected on a core set of 95 variables identified using the Delphi method. Participating registries will agree to provide access to and share standardised anonymous patient-level data with ISAR. ISAR is a registered data source on the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. ISAR's collaborators include Optimum Patient Care, the Respiratory Effectiveness Group (REG) and AstraZeneca. ISAR is overseen by the ISC, REG, the Anonymised Data Ethics & Protocol Transparency Committee and the ISAR operational committee, ensuring the conduct of ethical, clinically relevant research that brings value to all key stakeholders. CONCLUSIONS: ISAR aims to offer a rich source of real-life data for scientific research to understand and improve disease burden, treatment patterns and patient outcomes in severe asthma. Furthermore, the registry will provide an international platform for research collaboration in respiratory medi

Published
2020

11. Characteristics and treatment regimens across ERS SHARP severe asthma registries

Author

van Bragt, JJMH, Adcock, IM, Bel, EHD, Braunstahl, G-J, ten Brinke, A, Busby, J, Canonica, GW, Cao, H, Chung, KF, Csoma, Z, Dahlen, B, Davin, E, Hansen, S, Heffler, E, Horvath, I, Korn, S, Kots, M, Kuna, P, Kwon, N, Louis, R, Plaza, V, Porsbjerg, C, Ramos-Barbon, D, Richards, LB, Skrgat, S, Sont, JK, Vijverberg, SJH, Weersink, EJM, Yasinska, V, Wagers, SS, Djukanovic, R, Maitland-van der Zee, AH, Abenhardt, B, Adler, J, Alfonso, R, Ali, R, Alkameh, S, Almonacid Sanchez, C, Alvares, L, Anderson, G, Assing, K, Ayre, S, Becker, J, Bergmann, K, Bieksiene, K, Bjerring, N, Blasi, F, Bloemen, P, Blum, H, Boeing, S, Bonavia, M, Bossios, A, Bourdin, A, Brons, A, Brusselle, G, Buis, J, Caiaffa, M, Calabrese, C, Camiciottoli, G, Caruso, C, Castilla Martinez, M, Centanni, S, Cisneros Serrano, C, Corsico, A, Cosmi, L, Costantino, M, Costello, R, Crimi, N, Dahlen, S, D'Amato, M, Davies, D, Garcia-Cosio Piqueras, FDB, Decarlo, G, Deimling, A, Del Giacco, S, Diaz Campos, R, Djandji, M, Doberer, D, Dupont, L, Dyett, K, Edelbaher, N, Edelmann, M, Ehmann, R, Ekberg-Jansson, A, Farsi, A, Favero, E, Feimer, J, Fletcher, M, Foschino, B, Frankemolle, B, Gaga, M, Gappa, M, Garcia de Pedro, J, Garcia Rivero, J, Gasplmayr, M, Gebhardt, R, Geldmacher, H, Geltner, C, Gerstlauer, M, Gibson, T, Giuseppe, G, Gogoll, C, Grimm-Sachs, V, Grisle, I, Gruen, B, Gruenewaldt, A, Guarnieri, G, Gullon Blanco, J, Hamelmann, E, Hamerlijnck, D, Hammers-Reinhard, A, Hanon, S, Harzheim, D, Heaney, L, Hellmich, S, Herden, M, Hering, T, Herth, F, Hilberg, O, Howarth, P, Hubatsch, M, Humbert, M, Husemann, K, Idzko, M, Jackson, D, Jandl, M, Jaumont, X, Joos, G, Joest, M, Juech, M, Kabesch, M, Kaiser-Labusch, P, Kardos, P, Kaessner, F, Keeley, T, Kerr, W, Kirschner, J, Klimek, L, Koca, M, Koczulla, R, Koerner-Rettberg, C, Kopac, P, Kronsbein, J, Lipinska, IK, Langer, M, Langeveld, B, Lantz, A, Lazarinis, N, Lazic, Z, Lehtimaki, L, Leuppi, J, Lombardi, C, Lommatzsch, M, Lopez-Vina, A, Luca, R, Ludviksdottir, D, Luettecke-Hecht, C, Macchia, L, Magni, T, Martinez Rivera, C, Mastoridis, P, Mazza, F, Menzella, F, Menzies-Gow, A, Michils, A, Mihaltan, F, Milanese, M, Milger-Kneidinger, K, Molinska, J, Montagna, I, Montuschi, P, Muelleneisen, N, Munoz Esquerre, M, Nanzer-Kelly, A, Nenasheva, N, Neurohr, C, Nucera, E, Otker, J, Oud, K, Paggiaro, P, Parente, R, Parkinson, J, Passalacqua, G, Patberg, N, Patella, V, Patino, O, Paulsson, T, Peche, R, Pelaia, G, Peress, E, Perez de Llano, L, Pfeffer, P, Pfister, P, Pilette, C, Pinedo Sierra, C, Pini, L, Powitz, F, Ranger, T, Rasmussen, L, Rasmussen, K, Rezelj, M, Ricciardi, L, Ricciardolo, F, Ridolo, E, Rijssenbeek-Nouwens, L, Rolla, G, Romero Ribate, D, Ruediger, S, Safioti, G, Sandstrom, T, Santus, P, Sauer, R, Schauerte, G, Schipmann, R, Schleich, F, Schmid, J, Schmidt, F, Schmidt, O, Schmitz, M, Schrag, T, Schroeer, S, Schultz, K, Schulz, C, Scichilone, N, Sedlak, V, Selb, J, Senna, G, Sergejeva, S, Serrano Pariente, J, Sichau, M, Simona, D, Singer, A, Skowasch, D, Smeenk, F, Smith, S, Solidoro, P, Spadaro, G, Spanevello, A, Stefansdottir, M, Steinmetz, K, Steiss, J, Stephan, M, Stieglitz, S, Suhling, H, Taube, C, Yavuz, ST, Tudoric, N, Ulrik, C, van de Ven, M, van den Elshout, F, Van Dyke, M, Van Nederveen-Bendien, S, van Veen, I, Vandenplas, O, Velthove, K, Vianello, A, Vogelberg, C, Wallen-Nielsen, E, Weersink, EJ, Wisskirchen, T, Yacoub, M, Yancey, S, Zappa, M, Zielen, S, Zimmermann, C, Zimmermann, R, van Bragt, JJMH, Adcock, IM, Bel, EHD, Braunstahl, G-J, ten Brinke, A, Busby, J, Canonica, GW, Cao, H, Chung, KF, Csoma, Z, Dahlen, B, Davin, E, Hansen, S, Heffler, E, Horvath, I, Korn, S, Kots, M, Kuna, P, Kwon, N, Louis, R, Plaza, V, Porsbjerg, C, Ramos-Barbon, D, Richards, LB, Skrgat, S, Sont, JK, Vijverberg, SJH, Weersink, EJM, Yasinska, V, Wagers, SS, Djukanovic, R, Maitland-van der Zee, AH, Abenhardt, B, Adler, J, Alfonso, R, Ali, R, Alkameh, S, Almonacid Sanchez, C, Alvares, L, Anderson, G, Assing, K, Ayre, S, Becker, J, Bergmann, K, Bieksiene, K, Bjerring, N, Blasi, F, Bloemen, P, Blum, H, Boeing, S, Bonavia, M, Bossios, A, Bourdin, A, Brons, A, Brusselle, G, Buis, J, Caiaffa, M, Calabrese, C, Camiciottoli, G, Caruso, C, Castilla Martinez, M, Centanni, S, Cisneros Serrano, C, Corsico, A, Cosmi, L, Costantino, M, Costello, R, Crimi, N, Dahlen, S, D'Amato, M, Davies, D, Garcia-Cosio Piqueras, FDB, Decarlo, G, Deimling, A, Del Giacco, S, Diaz Campos, R, Djandji, M, Doberer, D, Dupont, L, Dyett, K, Edelbaher, N, Edelmann, M, Ehmann, R, Ekberg-Jansson, A, Farsi, A, Favero, E, Feimer, J, Fletcher, M, Foschino, B, Frankemolle, B, Gaga, M, Gappa, M, Garcia de Pedro, J, Garcia Rivero, J, Gasplmayr, M, Gebhardt, R, Geldmacher, H, Geltner, C, Gerstlauer, M, Gibson, T, Giuseppe, G, Gogoll, C, Grimm-Sachs, V, Grisle, I, Gruen, B, Gruenewaldt, A, Guarnieri, G, Gullon Blanco, J, Hamelmann, E, Hamerlijnck, D, Hammers-Reinhard, A, Hanon, S, Harzheim, D, Heaney, L, Hellmich, S, Herden, M, Hering, T, Herth, F, Hilberg, O, Howarth, P, Hubatsch, M, Humbert, M, Husemann, K, Idzko, M, Jackson, D, Jandl, M, Jaumont, X, Joos, G, Joest, M, Juech, M, Kabesch, M, Kaiser-Labusch, P, Kardos, P, Kaessner, F, Keeley, T, Kerr, W, Kirschner, J, Klimek, L, Koca, M, Koczulla, R, Koerner-Rettberg, C, Kopac, P, Kronsbein, J, Lipinska, IK, Langer, M, Langeveld, B, Lantz, A, Lazarinis, N, Lazic, Z, Lehtimaki, L, Leuppi, J, Lombardi, C, Lommatzsch, M, Lopez-Vina, A, Luca, R, Ludviksdottir, D, Luettecke-Hecht, C, Macchia, L, Magni, T, Martinez Rivera, C, Mastoridis, P, Mazza, F, Menzella, F, Menzies-Gow, A, Michils, A, Mihaltan, F, Milanese, M, Milger-Kneidinger, K, Molinska, J, Montagna, I, Montuschi, P, Muelleneisen, N, Munoz Esquerre, M, Nanzer-Kelly, A, Nenasheva, N, Neurohr, C, Nucera, E, Otker, J, Oud, K, Paggiaro, P, Parente, R, Parkinson, J, Passalacqua, G, Patberg, N, Patella, V, Patino, O, Paulsson, T, Peche, R, Pelaia, G, Peress, E, Perez de Llano, L, Pfeffer, P, Pfister, P, Pilette, C, Pinedo Sierra, C, Pini, L, Powitz, F, Ranger, T, Rasmussen, L, Rasmussen, K, Rezelj, M, Ricciardi, L, Ricciardolo, F, Ridolo, E, Rijssenbeek-Nouwens, L, Rolla, G, Romero Ribate, D, Ruediger, S, Safioti, G, Sandstrom, T, Santus, P, Sauer, R, Schauerte, G, Schipmann, R, Schleich, F, Schmid, J, Schmidt, F, Schmidt, O, Schmitz, M, Schrag, T, Schroeer, S, Schultz, K, Schulz, C, Scichilone, N, Sedlak, V, Selb, J, Senna, G, Sergejeva, S, Serrano Pariente, J, Sichau, M, Simona, D, Singer, A, Skowasch, D, Smeenk, F, Smith, S, Solidoro, P, Spadaro, G, Spanevello, A, Stefansdottir, M, Steinmetz, K, Steiss, J, Stephan, M, Stieglitz, S, Suhling, H, Taube, C, Yavuz, ST, Tudoric, N, Ulrik, C, van de Ven, M, van den Elshout, F, Van Dyke, M, Van Nederveen-Bendien, S, van Veen, I, Vandenplas, O, Velthove, K, Vianello, A, Vogelberg, C, Wallen-Nielsen, E, Weersink, EJ, Wisskirchen, T, Yacoub, M, Yancey, S, Zappa, M, Zielen, S, Zimmermann, C, and Zimmermann, R

Abstract

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m-2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day-1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day-1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Published
2020

12. Exhaled volatile organic compounds as markers for medication use in asthma

Author

Brinkman, P, Ahmed, Wm, Gómez, C, Knobel, Hh, Weda, H, Vink, Tj, Nijsen, Tm, Wheelock, Ce, Dahlen, Se, Montuschi, Paolo, Knowles, Rg, Vijverberg, Sj, Maitland-van der Zee, Ah, Sterk, Pj, Fowler, Sj, Montuschi P (ORCID:0000-0001-5589-1750), Brinkman, P, Ahmed, Wm, Gómez, C, Knobel, Hh, Weda, H, Vink, Tj, Nijsen, Tm, Wheelock, Ce, Dahlen, Se, Montuschi, Paolo, Knowles, Rg, Vijverberg, Sj, Maitland-van der Zee, Ah, Sterk, Pj, Fowler, Sj, and Montuschi P (ORCID:0000-0001-5589-1750)

Abstract

INTRODUCTION: Asthma is a heterogeneous condition, characterised by chronic inflammation of the airways, typically managed with inhaled bronchodilators and corticosteroids. In the case of uncontrolled asthma, oral corticosteroids (OCSs) are often prescribed. Good adherence and inhalation technique are associated with improved outcomes; however, it is difficult to monitor appropriate drug intake and effectiveness in individual patients. Exhaled breath contains thousands of volatile organic compounds (VOCs) that reflect changes in the body's chemistry and may be useful for monitoring drug pharmacokinetics/pharmacodynamics. We aimed to investigate the association of exhaled VOCs in severe asthma patients from the U-BIOPRED cohort (by gas chromatography coupled with time-of-flight mass spectrometry) with urinary levels of salbutamol and OCSs (by liquid chromatography coupled with high-resolution mass spectrometry). METHODS: Samples were collected at baseline and after 12-18 months of follow-up. Statistical analysis was based on univariate and multivariate modelling, followed by area under the receiver operating characteristic curve (AUC) calculation. Results were verified through longitudinal replication and independent validation. RESULTS: Data were available for 78 patients (baseline n=48, replication n=30 and validation n=30). Baseline AUC values were 82.1% (95% CI 70.4-93.9%) for salbutamol and 78.8% (95% CI 65.8-91.8%) for OCS. These outcomes could be adequately replicated and validated. Additional regression analysis between qualified exhaled VOCs and urinary concentrations of salbutamol and prednisone showed statistically significant correlations (p<0.01). CONCLUSION: We have linked exhaled VOCs to urinary detection of salbutamol and OCSs. This merits further development of breathomics into a point-of-care tool for therapeutic drug monitoring

Published
2020

14. Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma

Author

Brinkman, P, Wagener, Ah, Hekking, Pp, Bansal, At, Maitland-van der Zee, Ah, Wang, Y, Weda, H, Knobel, Hh, Vink, Tj, Rattray, Nj, D'Amico, Arnaldo, Pennazza, G, Santonico, M, Lefaudeux, D, De Meulder, B, Auffray, C, Bakke, P, Caruso, Massimo, Chanez, P, Chung, Kf, Corfield, J, Dahlén, Se, Djukanovic, R, Geiser, T, Horvath, I, Krug, N, Musial, J, Sun, K, Riley, Jh, Shaw, De, Sandström, T, Sousa, Ar, Montuschi, Paolo, Fowler, Sj, Sterk, Pj, Montuschi P (ORCID:0000-0001-5589-1750), Brinkman, P, Wagener, Ah, Hekking, Pp, Bansal, At, Maitland-van der Zee, Ah, Wang, Y, Weda, H, Knobel, Hh, Vink, Tj, Rattray, Nj, D'Amico, Arnaldo, Pennazza, G, Santonico, M, Lefaudeux, D, De Meulder, B, Auffray, C, Bakke, P, Caruso, Massimo, Chanez, P, Chung, Kf, Corfield, J, Dahlén, Se, Djukanovic, R, Geiser, T, Horvath, I, Krug, N, Musial, J, Sun, K, Riley, Jh, Shaw, De, Sandström, T, Sousa, Ar, Montuschi, Paolo, Fowler, Sj, Sterk, Pj, and Montuschi P (ORCID:0000-0001-5589-1750)

Abstract

Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes. Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to within-patient clinical and inflammatory changes. Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability. Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNose-driven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P =.045) and neutrophil (P =.017) percentages and ratios of patients using oral corticosteroids (P =.035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P =.045). Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma

Published
2019

15. 17q21 gene variation increases the risk of exacerbations in asthmatic children treated with inhaled corticosteroids: A meta-analysis in the multi-ethnic pica consortium

Author

Farzan, N, Vijverberg, SJ, Hernandez-Pacheco, N, Berce, V, Burchard, EG, Canino, G, Celedon, JC, Cloutier, MM, Forno, E, Francis, B, Hawcutt, DB, Kabesch, M, Karimi, L, Melen, E, Mukhopadhyay, S, Nilsson, S, Palmer, CN, Pino-Yanes, M, Pirmohamed, M, Potocnik, U, Raaijmakers, JA, Repnik, K, Schieck, M, Smyth, RL, Tantisira, KG, Tavendale, R, Tse, SM, Turner, S, Verhamme, KM, and Maitland-Van der Zee, AH

Published
2017

16. Characteristics and treatment regimens across ERS SHARP severe asthma registries

Author

van Bragt, JJMH, Adcock, IM, Bel, EHD, Braunstahl, GJ, ten Brinke, A, Busby, J, Canonica, GW, Cao, H, Chung, KF, Csoma, Z, Dahlen, B, Davin, E, Hansen, S, Heffler, E, Horvath, I, Korn, S, Kots, M, Kuna, P, Kwon, N, Louis, R, Plaza, V, Porsbjerg, C, Ramos-Barbon, D, Richards, LB, Skrgat, S, Sont, JK, Vijverberg, SJH, Weersink, EJM, Yasinska, V, Wagers, SS, Djukanovic, R, Maitland-van der Zee, AH, Abenhardt, B, Adler, J, Alfonso, R, Ali, R, Alkameh, S, Sanchez, CA, Alvares, L, Anderson, G, Assing, K, Ayre, S, Becker, J, Bergmann, K, Bieksiene, K, Bjerring, N, Blasi, F, Bloemen, P, Blum, H, Boing, S, Bonavia, M, Bossios, A, Bourdin, A, Brons, A, Brusselle, G, Buis, J, Caiaffa, M, Calabrese, C, Camiciottoli, G, Caruso, C, Martinez, MC, Centanni, S, Serrano, CC, Corsico, A, Cosmi, L, Costantino, M, Costello, R, Crimi, N, Dahlen, S, D'Amato, M, Davies, D, Piqueras, FDGC, Decarlo, G, Deimling, A, Del Giacco, S, Campos, RD, Djandji, M, Doberer, D, Dupont, L, Dyett, K, Edelbaher, N, Edelmann, M, Ehmann, R, Ekberg-Jansson, A, Farsi, A, Favero, E, Feimer, J, Fletcher, M, Foschino, B, Frankemolle, B, Gaga, M, Gappa, M, de Pedro, JG, Rivero, JG, Gasplmayr, M, Gebhardt, R, Geldmacher, H, Geltner, C, Gerstlauer, M, Gibson, T, Giuseppe, G, Gogoll, C, Grimm-Sachs, V, Grisle, I, Grun, B, Grunewaldt, A, Guarnieri, G, Blanco, JG, Hamelmann, E, Hamerlijnck, D, Hammers-Reinhard, A, Hanon, S, Harzheim, D, Heaney, L, Hellmich, S, Herden, M, Hering, T, Herth, F, Hilberg, O, Howarth, P, Hubatsch, M, Humbert, M, Husemann, K, Idzko, M, Jackson, D, Jandl, M, Jaumont, X, Joos, G, Jost, M, Juch, M, Kabesch, M, Kaiser-Labusch, P, Kardos, P, Kassner, F, Keeley, T, Kerr, W, Kirschner, J, Klimek, L, Koca, M, Koczulla, R, Koerner-Rettberg, C, Kopac, P, Kronsbein, J, Lipinska, IK, Langer, M, Langeveld, B, Lantz, A, Lazarinis, N, Lazic, Z, Lehtimaki, L, Leuppi, J, Lombardi, C, Lommatzsch, M, Lopez-Vina, A, Luca, R, Ludviksdottir, D, Luttecke-Hecht, C, Macchia, L, Magni, T, Rivera, CM, Mastoridis, P, Mazza, F, Menzella, F, Menzies-Gow, A, Michils, A, Mihaltan, F, Milanese, M, Milger-Kneidinger, K, Molinska, J, Montagna, I, Montuschi, P, Mulleneisen, N, Esquerre, MM, Nanzer-Kelly, A, Nenasheva, N, Neurohr, C, Nucera, E, Otker, J, Oud, K, Paggiaro, P, Parente, R, Parkinson, J, Passalacqua, G, Patberg, N, Patella, V, Patino, O, Paulsson, T, Peche, R, Pelaia, G, Peress, E, de Llano, LP, Pfeffer, P, Pfister, P, Pilette, C, Sierra, CP, Pini, L, Powitz, F, Ranger, T, Rasmussen, L, Rasmussen, K, Rezelj, M, Ricciardi, L, Ricciardolo, F, Ridolo, E, Rijssenbeek-Nouwens, L, Rolla, G, Ribate, DR, Rudiger, S, Safioti, G, Sandstrom, T, Santus, P, Sauer, R, Schauerte, G, Schipmann, R, Schleich, F, Schmid, J, Schmidt, F, Schmidt, O, Schmitz, M, Schrag, T, Schroer, S, Schultz, K, Schulz, C, Scichilone, N, Sedlak, V, Selb, J, Senna, G, Sergejeva, S, Pariente, JS, Sichau, M, Simona, D, Singer, A, Skowasch, D, Smeenk, F, Smith, S, Solidoro, P, Spadaro, G, Spanevello, A, Stefansdottir, M, Steinmetz, K, Steiss, J, Stephan, M, Stieglitz, S, Suhling, H, Taube, C, Yavuz, ST, Tudoric, N, Ulrik, C, van de Ven, M, van den Elshout, F, Van Dyke, M, Van Nederveen-Bendien, S, van Veen, I, Vandenplas, O, Velthove, K, Vianello, A, Vogelberg, C, Wallen-Nielsen, E, Weersink, EJ, Wisskirchen, T, Yacoub, M, Yancey, S, Zappa, M, Zielen, S, Zimmermann, C, Zimmermann, R, Graduate School, AII - Inflammatory diseases, APH - Personalized Medicine, Pulmonology, Paediatric Pulmonology, van Bragt, J. J. M. H., Adcock, I. M., Bel, E. H. D., Braunstahl, G. -J., ten Brinke, A., Busby, J., Canonica, G. W., Cao, H., Chung, K. F., Csoma, Z., Dahlen, B., Davin, E., Hansen, S., Heffler, E., Horvath, I., Korn, S., Kots, M., Kuna, P., Kwon, N., Louis, R., Plaza, V., Porsbjerg, C., Ramos-Barbon, D., Richards, L. B., Skrgat, S., Sont, J. K., Vijverberg, S. J. H., Weersink, E. J. M., Yasinska, V., Wagers, S. S., Djukanovic, R., Maitland-Van der Zee, A. H., Abenhardt, B., Adler, J., Alfonso, R., Ali, R., Alkameh, S., Almonacid Sanchez, C., Alvares, L., Anderson, G., Assing, K., Ayre, S., Becker, J., Bergmann, K., Bieksiene, K., Bjerring, N., Blasi, F., Bloemen, P., Blum, H., Boing, S., Bonavia, M., Bossios, A., Bourdin, A., Brons, A., Brusselle, G., Buis, J., Caiaffa, M., Calabrese, C., Camiciottoli, G., Caruso, C., Castilla Martinez, M., Centanni, S., Cisneros Serrano, C., Corsico, A., Cosmi, L., Costantino, M., Costello, R., Crimi, N., Dahlen, S., D'Amato, M., Davies, D., de Borja Garcia-Cosio Piqueras, F., Decarlo, G., Deimling, A., Del Giacco, S., Diaz Campos, R., Djandji, M., Doberer, D., Dupont, L., Dyett, K., Edelbaher, N., Edelmann, M., Ehmann, R., Ekberg-Jansson, A., Farsi, A., Favero, E., Feimer, J., Fletcher, M., Foschino, B., Frankemolle, B., Gaga, M., Gappa, M., Garcia de Pedro, J., Garcia Rivero, J., Gasplmayr, M., Gebhardt, R., Geldmacher, H., Geltner, C., Gerstlauer, M., Gibson, T., Giuseppe, G., Gogoll, C., Grimm-Sachs, V., Grisle, I., Grun, B., Grunewaldt, A., Guarnieri, G., Gullon Blanco, J., Hamelmann, E., Hamerlijnck, D., Hammers-Reinhard, A., Hanon, S., Harzheim, D., Heaney, L., Hellmich, S., Herden, M., Hering, T., Herth, F., Hilberg, O., Howarth, P., Hubatsch, M., Humbert, M., Husemann, K., Idzko, M., Jackson, D., Jandl, M., Jaumont, X., Joos, G., Jost, M., Juch, M., Kabesch, M., Kaiser-Labusch, P., Kardos, P., Kassner, F., Keeley, T., Kerr, W., Kirschner, J., Klimek, L., Koca, M., Koczulla, R., Koerner-Rettberg, C., Kopac, P., Kronsbein, J., Kuprys Lipinska, I., Langer, M., Langeveld, B., Lantz, A., Lazarinis, N., Lazic, Z., Lehtimaki, L., Leuppi, J., Lombardi, C., Lommatzsch, M., Lopez-Vina, A., Luca, R., Ludviksdottir, D., Luttecke-Hecht, C., Macchia, L., Magni, T., Martinez Rivera, C., Mastoridis, P., Mazza, F., Menzella, F., Menzies-Gow, A., Michils, A., Mihalthan, F., Milanese, M., Milger-Kneidinger, K., Molinska, J., Montagna, I., Montuschi, P., Mulleneisen, N., Munoz Esquerre, M., Nanzer-Kelly, A., Nenasheva, N., Neurohr, C., Nucera, E., Otker, J., Oud, K., Paggiaro, P., Parente, R., Parkinson, J., Passalacqua, G., Patberg, N., Patella, V., Patino, O., Paulsson, T., Peche, R., Pelaia, G., Peress, E., Perez de Llano, L., Pfeffer, P., Pfister, P., Pilette, C., Pinedo Sierra, C., Pini, L., Powitz, F., Ranger, T., Rasmussen, L., Rasmussen, K., Rezelj, M., Ricciardi, L., Ricciardolo, F., Ridolo, E., Rijssenbeek-Nouwens, L., Rolla, G., Romero Ribate, D., Rudiger, S., Safioti, G., Sandstrom, T., Santus, P., Sauer, R., Schauerte, G., Schipmann, R., Schleich, F., Schmid, J., Schmidt, F., Schmidt, O., Schmitz, M., Schrag, T., Schroer, S., Schultz, K., Schulz, C., Scichilone, N., Sedlak, V., Selb, J., Senna, G., Sergejeva, S., Serrano Pariente, J., Sichau, M., Simona, D., Singer, A., Skowasch, D., Smeenk, F., Smith, S., Solidoro, P., Spadaro, G., Spanevello, A., Stefansdottir, M., Steinmetz, K., Steiss, J., Stephan, M., Stieglitz, S., Suhling, H., Taube, C., Tolga Yavuz, S., Tudoric, N., Ulrik, C., van de Ven, M., van den Elshout, F., van Dyke, M., van Nederveen-Bendien, S., van Veen, I., Vandenplas, O., Velthove, K., Vianello, A., Vogelberg, C., Wallen-Nielsen, E., Wisskirchen, T., Yacoub, M., Yancey, S., Zappa, M., Zielen, S., Zimmermann, C., Zimmermann, R., UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, UCL - (MGD) Service de pneumologie, van Bragt J.J.M.H., Adcock I.M., Bel E.H.D., Braunstahl G.-J., ten Brinke A., Busby J., Canonica G.W., Cao H., Chung K.F., Csoma Z., Dahlen B., Davin E., Hansen S., Heffler E., Horvath I., Korn S., Kots M., Kuna P., Kwon N., Louis R., Plaza V., Porsbjerg C., Ramos-Barbon D., Richards L.B., Skrgat S., Sont J.K., Vijverberg S.J.H., Weersink E.J.M., Yasinska V., Wagers S.S., Djukanovic R., Maitland-Van der Zee A.H., Abenhardt B., Adler J., Alfonso R., Ali R., Alkameh S., Almonacid Sanchez C., Alvares L., Anderson G., Assing K., Ayre S., Becker J., Bergmann K., Bieksiene K., Bjerring N., Blasi F., Bloemen P., Blum H., Boing S., Bonavia M., Bossios A., Bourdin A., Brons A., Brusselle G., Buis J., Caiaffa M., Calabrese C., Camiciottoli G., Caruso C., Castilla Martinez M., Centanni S., Cisneros Serrano C., Corsico A., Cosmi L., Costantino M., Costello R., Crimi N., Dahlen S., D'Amato M., Davies D., de Borja Garcia-Cosio Piqueras F., Decarlo G., Deimling A., Del Giacco S., Diaz Campos R., Djandji M., Doberer D., Dupont L., Dyett K., Edelbaher N., Edelmann M., Ehmann R., Ekberg-Jansson A., Farsi A., Favero E., Feimer J., Fletcher M., Foschino B., Frankemolle B., Gaga M., Gappa M., Garcia de Pedro J., Garcia Rivero J., Gasplmayr M., Gebhardt R., Geldmacher H., Geltner C., Gerstlauer M., Gibson T., Giuseppe G., Gogoll C., Grimm-Sachs V., Grisle I., Grun B., Grunewaldt A., Guarnieri G., Gullon Blanco J., Hamelmann E., Hamerlijnck D., Hammers-Reinhard A., Hanon S., Harzheim D., Heaney L., Hellmich S., Herden M., Hering T., Herth F., Hilberg O., Howarth P., Hubatsch M., Humbert M., Husemann K., Idzko M., Jackson D., Jandl M., Jaumont X., Joos G., Jost M., Juch M., Kabesch M., Kaiser-Labusch P., Kardos P., Kassner F., Keeley T., Kerr W., Kirschner J., Klimek L., Koca M., Koczulla R., Koerner-Rettberg C., Kopac P., Kronsbein J., Kuprys Lipinska I., Langer M., Langeveld B., Lantz A., Lazarinis N., Lazic Z., Lehtimaki L., Leuppi J., Lombardi C., Lommatzsch M., Lopez-Vina A., Luca R., Ludviksdottir D., Luttecke-Hecht C., Macchia L., Magni T., Martinez Rivera C., Mastoridis P., Mazza F., Menzella F., Menzies-Gow A., Michils A., Mihalthan F., Milanese M., Milger-Kneidinger K., Molinska J., Montagna I., Montuschi P., Mulleneisen N., Munoz Esquerre M., Nanzer-Kelly A., Nenasheva N., Neurohr C., Nucera E., Otker J., Oud K., Paggiaro P., Parente R., Parkinson J., Passalacqua G., Patberg N., Patella V., Patino O., Paulsson T., Peche R., Pelaia G., Peress E., Perez de Llano L., Pfeffer P., Pfister P., Pilette C., Pinedo Sierra C., Pini L., Powitz F., Ranger T., Rasmussen L., Rasmussen K., Rezelj M., Ricciardi L., Ricciardolo F., Ridolo E., Rijssenbeek-Nouwens L., Rolla G., Romero Ribate D., Rudiger S., Safioti G., Sandstrom T., Santus P., Sauer R., Schauerte G., Schipmann R., Schleich F., Schmid J., Schmidt F., Schmidt O., Schmitz M., Schrag T., Schroer S., Schultz K., Schulz C., Scichilone N., Sedlak V., Selb J., Senna G., Sergejeva S., Serrano Pariente J., Sichau M., Simona D., Singer A., Skowasch D., Smeenk F., Smith S., Solidoro P., Spadaro G., Spanevello A., Stefansdottir M., Steinmetz K., Steiss J., Stephan M., Stieglitz S., Suhling H., Taube C., Tolga Yavuz S., Tudoric N., Ulrik C., van de Ven M., van den Elshout F., van Dyke M., van Nederveen-Bendien S., van Veen I., Vandenplas O., Velthove K., Vianello A., Vogelberg C., Wallen-Nielsen E., Wisskirchen T., Yacoub M., Yancey S., Zappa M., Zielen S., Zimmermann C., Zimmermann R., Amsterdam UMC, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, Kleiweg 500, 3045 PM, Rotterdam, The Netherlands., Medical Centre Leeuwarden, Queen's University [Belfast] (QUB), Humanitas University [Milan] (Hunimed), Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, Korányi National Institute of Pulmonology (OKPI), Karolinska University Hospital [Stockholm], The European Lung Foundation (ELF), Bispebjerg and Frederiksberg Hospitals, Humanitas Clinical and Research Center [Rozzano, Milan, Italy], University Medical Center of the Johannes Gutenberg-University Mainz, Chiesi Farmaceutici, Medical University of Łódź (MUL), GlaxoSmithKline, Brentford, Middlesex, Centre Hospitalier Universitaire de Liège (CHU-Liège), Hospital de la Santa Creu i Sant Pau, Copenhagen University Hospital, Respiratory and Allergic Diseases [Golnik, Slovenia], University Clinic of Respiratory and Allergic Diseases Golnik, Leiden University Medical Center (LUMC), Biosci Consulting, University Hospital Southampton NHS Foundation Trust, SHARP Clinical Research, Hôpital Arnaud de Villeneuve [CHRU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Severe asthma, Pediatrics, MESH: Registries, MESH: Asthma, Cross-sectional study, Respiratory System, Medizin, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, MESH: Belgium, Belgium, Medicine research, Anti-Asthmatic Agents, Registries, 030212 general & internal medicine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, 10. No inequality, 11 Medical and Health Sciences, Netherlands, 2. Zero hunger, education.field_of_study, SHARP CRC, MESH: Administration, Inhalation, MESH: Anti-Asthmatic Agents, 3. Good health, Europe, Italy, MESH: Poland, MESH: Sweden, medicine.drug, Pulmonary and Respiratory Medicine, medicine.medical_specialty, MESH: Hungary, Population, Investigació mèdica, Settore MED/10 - Malattie Dell'Apparato Respiratorio, 03 medical and health sciences, MESH: Cross-Sectional Studies, Administration, Inhalation, MESH: Spain, medicine, Humans, education, Asma, Retrospective Studies, Asthma, Sweden, Hungary, MESH: Humans, business.industry, Settore MED/09 - MEDICINA INTERNA, MESH: Italy, MESH: Retrospective Studies, Retrospective cohort study, Original Articles, asthma, medicine.disease, Clinical trial, Cross-Sectional Studies, Clinical research, 030228 respiratory system, Spain, MESH: Netherlands, MESH: Europe, Poland, business, Body mass index, Mepolizumab
Abstract

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Published
2019
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17. 2013 Late-Breaking Clinical Trial Abstracts

Author

Patrick Kesteven, Niclas Eriksson, Andrea L. Jorgensen, Maitland-van, der, Zee, Ah, Munir Pirmohamed, Clare Prince, CH Toh, Peter Avery, Mia Wadelius, Timothy R Nicholson, Paula R Williamson, J Stoddern, Farhad Kamali, Ann K. Daly, and Girvan Burnside

Subjects
Gerontology, medicine.medical_specialty, business.industry, General surgery, ST elevation, Warfarin, medicine.disease, law.invention, Reperfusion therapy, Randomized controlled trial, law, Physiology (medical), medicine, cardiovascular diseases, Dosing, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, Pharmacogenetics, TIMI, medicine.drug
Abstract

Nitrites in Acute Myocardial Infarction Nishat Siddiqi1, Margaret Bruce1, Christopher J. Neil1, Graeme MacLennan2, Seonaidh Cotton2, Sofia A. Papadopoulou3, Baljit Jagpal1, Sue Brown3, Fatima Perez Gonzalez3, Satnam Singh1, Konstantin Schwarz1, Martin Feelisch4, Nicholas Bunce5, Pitt O Lim5, David Hildick-Smith6, John Horowitz7, Melanie Madhani8, Nicholas Boon9, Dana Dawson10, Juan-Carlos Kaski3, Michael P Frenneaux10. 1Dept of Cardiovascular Rsch, Univ of Aberdeen, Aberdeen, United Kingdom, 2Health Sciences Building (third floor), Centre for Healthcare Randomised Trials (CHaRT), Aberdeen, United Kingdom, 3Cardiovascular Sciences Rsch Centre, St George’s Univ of London, London, United Kingdom, 4Faculty of Medicine, Univ of Southampton, Southampton, 5Cardiology Dept, St George’s Healthcare NHS Trust, 6Cardiology Research Unit, Brighton and Sussex Univ Hospitals, Brighton, United Kingdom, 7Basil Hetzel Unit for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, 8Centre for Cardiovascular Sciences, Univ of Birmingham, Birmingham, United Kingdom, 9Centre for Cardiovascular Sciences, Univ of Edinburgh, Edinburgh, United Kingdom, 10School of Medicine and Dentistry, Univ of Aberdeen, Aberdeen Introduction :Despite reperfusion therapy for acute myocardial infarction (AMI), heart failure remains a major sequel. Reperfusion leads to further damage, described as ischemia-reperfusion-injury (IRI). This contributes up to 50% of the final infarct size. In pre-clinical models nitrite potently protects against IRI in the heart and other organs. Hypothesis :Intravenous (iv) sodium nitrite, administered immediately before opening of the infarct-related artery, results in significant reduction of IRI in patients with acute ST elevation MI (STEMI). Methods :In this phase II, randomised, placebo-controlled, double-blind, multicentre trial, 220 patients with first acute STEMI and TIMI 0 or 1 flow were randomised …

Published
2013
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18. Defining uncontrolled childhood asthma in the global PiCA consortium

Author

Farzan, N, Vijverberg, SJ, Andiappan, A, Palmer, CJ, Tantisira, KG, Duijts, L, Pino-Yanes, M, Melen, E, Hawcutt, D, Verhamme, KM, Flores, C, Daley, D, Mukhopadhyay, S, Chew, FT, Bonnelykke, K, Manolopoulos, VG, Kabesch, M, Koppelman, GH, Potocnik, U, Carleton, B, Turner, S, Raaijmakers, J, and Maitland-van der Zee, AH

Published
2016

19. Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Author

Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)

Subjects
Male, Cancer Research, Candidate gene, Epidemiology, Genome-wide association study, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular, 0302 clinical medicine, GENETICS & HEREDITY, Genetics (clinical), Genetics, 0303 health sciences, Cardiovascular diseases [NCEBP 14], Middle Aged, 3. Good health, CYP17A1, Genetic Epidemiology, Genome-wide association, Myocardial-infarction, Susceptibility loci, Risk, Atherosclerosis, Metanalysis, Lipoprotein, Medicine, Female, Life Sciences & Biomedicine, Research Article, Asian Continental Ancestry Group, Adult, SUSCEPTIBILITY LOCI, lcsh:QH426-470, European Continental Ancestry Group, Biology, Polymorphism, Single Nucleotide, coronary artery disease, genetics, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Asian People, Genetic variation, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Molecular Biology, Gene, METAANALYSIS, Ecology, Evolution, Behavior and Systematics, Genetic Association Studies, Cardiovascular Disease Epidemiology, Alleles, 030304 developmental biology, Aged, 0604 Genetics, Science & Technology, Case-control study, Genetic Variation, Human Genetics, Odds ratio, large-scale gene analysis, lcsh:Genetics, LIPOPROTEIN, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Case-Control Studies, Genetics of Disease, IBC 50K CAD Consortium, Developmental Biology, Genome-Wide Association Study
Abstract

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.

Published
2016

20. Erratum: Meta-analysis of dense genecentric association studies reveals common and uncommon variants associated with height ((The American Journal of Human Genetics (2010) 88 (6-18))

Author

Lanktree, MB, Guo, Y, Murtaza, M, Glessner, JT, Bailey, SD, Onland-Moret, NC, Lettre, G, Ongen, H, Rajagopalan, R, Johnson, T, Shen, H, Nelson, CP, Klopp, N, Baumert, J, Padmanabhan, S, Pankratz, N, Pankow, JS, Shah, S, Taylor, K, Barnard, J, Peters, BJ, Maloney, CM, Lobmeyer, MT, Stanton, A, Zafarmand, MH, Romaine, SPR, Mehta, A, Van Iperen, EPA, Gong, Y, Price, TS, Smith, EN, Kim, CE, Li, YR, Asselbergs, FW, Atwood, LD, Bailey, KM, Bhatt, D, Bauer, F, Behr, ER, Bhangale, T, Boer, JMA, Boehm, BO, Bradfield, JP, Brown, M, Braund, PS, Burton, PR, Carty, C, Chandrupatla, HR, Chen, W, Connell, J, Dalgeorgou, C, De Boer, A, Drenos, F, Elbers, CC, Fang, JC, Fox, CS, Frackelton, EC, Fuchs, B, Furlong, CE, Gibson, Q, Gieger, C, Goel, A, Grobbee, DE, Hastie, C, Howard, PJ, Huang, G-H, Johnson, WC, Li, Q, Kleber, ME, Klein, BEK, Klein, R, Kooperberg, C, Ky, B, Lacroix, A, Lanken, P, Lathrop, M, Li, M, Marshall, V, Melander, O, Mentch, FD, Meyer, NJ, Monda, KL, Montpetit, A, Murugesan, G, Nakayama, K, Nondahl, D, Onipinla, A, Rafelt, S, Newhouse, SJ, Otieno, FG, Patel, SR, Putt, ME, Rodriguez, S, Safa, RN, Sawyer, DB, Schreiner, PJ, Simpson, C, Sivapalaratnam, S, Srinivasan, SR, Suver, C, Swergold, G, Sweitzer, NK, Thomas, KA, Thorand, B, Timpson, NJ, Tischfield, S, Tobin, M, Tomaszewski, M, Verschuren, WMM, Wallace, C, Winkelmann, B, Zhang, H, Zheng, D, Zhang, L, Zmuda, JM, Clarke, R, Balmforth, AJ, Danesh, J, Day, IN, Schork, NJ, De Bakker, PIW, Delles, C, Duggan, D, Hingorani, AD, Hirschhorn, JN, Hofker, MH, Humphries, SE, Kivimaki, M, Lawlor, DA, Kottke-Marchant, K, Mega, JL, Mitchell, BD, Morrow, DA, Palmen, J, Redline, S, Shields, DC, Shuldiner, AR, Sleiman, PM, Smith, GD, Farrall, M, Jamshidi, Y, Christiani, DC, Casas, JP, Hall, AS, Doevendans, PA, Christie, JD, Berenson, GS, Murray, SS, Illig, T, Dorn, GW, Cappola, TP, Boerwinkle, E, Sever, P, Rader, DJ, Reilly, MP, Caulfield, M, Talmud, PJ, Topol, E, Engert, JC, Wang, K, Dominiczak, A, Hamsten, A, Curtis, SP, Silverstein, RL, Lange, LA, Sabatine, MS, Trip, M, Saleheen, D, Peden, JF, Cruickshanks, KJ, März, W, O'Connell, JR, Klungel, OH, Wijmenga, C, Maitland-Van Der Zee, AH, Schadt, EE, Johnson, JA, Jarvik, GP, Papanicolaou, GJ, Grant, SFA, Munroe, PB, North, KE, Samani, NJ, Koenig, W, Gaunt, TR, Anand, SS, Van Der Schouw, YT, Soranzo, N, Fitzgerald, GA, Reiner, A, Hegele, RA, Hakonarson, H, and Keating, BJ

Published
2012

21. Future of Pharmacogenetics in Cardiovascular Diseases

Author

van Schie, RMF, Verhoef, TI, Maitland-van der Zee, AH, de Boer, A, van der Meer, FJM, Redekop, Ken, Thariani, R, Gallelli, L., Erasmus MC other, and Health Economics (HE)

Subjects
SDG 3 - Good Health and Well-being
Published
2012

22. The effect of omeprazole and esomeprazole on the maintenance dose of phenprocoumon

Author

Verhoef, TI, Zuurhout, MJL, van Schie, RMF, Redekop, Ken, van der Meer, FJM, le Cessie, S, Schalekamp, T, de Boer, A, Maitland-van der Zee, AH, Health Economics (HE), and Department of Strategic Management and Entrepreneurship

Abstract

The response to vitamin K antagonists (VKAs) is determined by many different factors like age, weight, height, vitamin K intake and genetic polymorphisms [1]. The proton pump inhibitors (PPIs) omeprazole and esomeprazole may enhance the effect of VKAs by inhibition of the hepatic metabolism of coumarins [2]. Some isolated cases have been reported of clinically significant elevated INRs in patients concomitantly using omeprazole and phenprocoumon, a VKA frequently used in Europe [3].Practical experience suggests an interaction between omeprazole or esomeprazole and phenprocoumon, but scientific evidence is still lacking.

Published
2012

23. Homocysteine and coronary heart disease: Meta-analysis of MTHFR case-control studies, avoiding publication bias

Author

Holm, H, Thorsteinsdottir, U, Gretarsdottir, S, Gulcher, Jr, Thorgeirsson, G, Andersen, K, Stefansson, K, Parish, S, Bennett, Da, Clarke, R, Peto, R, Sleight, P, Collins, R, Hopewell, Jc, Watkins, H, Saleheen, D, Danesh, J, Rasheed, A, Zaidi, M, Frossard, P, Shah, N, Samuel, M, Tanaka, T, Ozaki, K, Sato, H, Sakata, Y, Komuro, I, Anand, Ss, Yusuf, S, Engert, Jc, Chambers, J, Kooner, J, Armitage, J, Samani, Nj, Braund, Ps, Nelson, Cp, Hall, As, Balmforth, A, Ball, Sg, Kleber, Me, Hoffmann, Mm, März, Wa, Bugert, P, Winkelmann, B, Böhm, Bo, Ouwehand, Wh, Sivapalaratnam, S, Kastelein, Jj, Trip, Md, Bezzina, Cr, Ouwehand, W, Yamada, Y, Elbers, Cc, Onland Moret NC, Bauer, F, van der Schouw YT, Verschuren, Wm, de Boer JM, Wijmenga, C, Hofker, Mh, de Bakker PI, Peters, Bj, Maitland van der Zee AH, de Boer, A, Klungel, Oh, Grobbee, De, Stewart, Af, Roberts, R, Mcpherson, R, Chen, L, Wells, Ga, Reilly, Mm, Li, M, Qu, I, Rader, Dj, Thorand, B, Illig, T, Peters, A, Koenig, W, Assimes, Tl, Fortmann, S, Iribarren, C, Abbate, R, Marcucci, R, Anderson, Jl, Zebrack, Js, Ardissino, D, Merlini, Fm, Bonomi, Ab, Ashfield Watt PA, Clark, Ze, van Bockxmeer FM, Brownrigg, L, Kooner, Js, Ferrer Antunes, C, Palmeiro, A, Fernandez Arcas, N, Reyes Engel, A, Folsom, Ar, Fowkes, Fg, Lee, Aj, Gaziano, Jm, Gemmati, D, Scapoli, Gl, Genest, J, Rozen, R, Girelli, Domenico, Corrocher, Roberto, Rossi, Gb, Meleady, R, Graham, Im, Gulec, S, Hopkins, Pn, Inbal, A, Selighson, U, Jukema, Jw, Litynsky, P, Kluijtmans, La, Kozich, V, Janosikova, B, Ma, J, Stampfer, Mj, Malinow, Mr, Meisel, C, Stangl, K, Morita, H, Nagai, R, Nakai, K, Nordestgaard, Bg, Zacho, J, Rimm, Eb, Schwartz, Sm, Siscovick, Ds, Silberberg, Js, Szczeklik, A, Domagala, Bt, Tanis, Bc, Rosendaal, Fm, Thogersen, Am, Nilsson, Tk, Todesco, L, Tokgozoglu, Sl, Tsai, My, Hanson, Nq, Verhoeff, Bj, Yamakawa Kobayashi, K, Hamaguchi, H., Medical Research Council (MRC), Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Pulmonology, and Other departments

Subjects
Homocysteine, coronary heart disease, methylene tetrahydrofolate reductase, Coronary Disease, FOLIC-ACID, 030204 cardiovascular system & hematology, PLACEBO-CONTROLLED TRIAL, Gastroenterology, Methylenetetrahydrofolate reductase gene, Placebo-controlled trial, Cardiovascular-disease, Mendelian randomization, Myocardial-infarction, Vascular-disease, Common mutation, B vitamins, Folic-acid, Ethnic-groups, chemistry.chemical_compound, MTHFR, risk factors, publication bias, GWA, genome-wide association, meta-analysis, 0302 clinical medicine, Polymorphism (computer science), 030212 general & internal medicine, Myocardial infarction, 11 Medical and Health Sciences, Genetics, biology, VASCULAR-DISEASE, General Medicine, ETHNIC-GROUPS, 3. Good health, CARDIOVASCULAR-DISEASE, Meta-analysis, MENDELIAN RANDOMIZATION, Medicine, MTHFR Studies Collaborative Group, Life Sciences & Biomedicine, Research Article, medicine.medical_specialty, Genotype, METHYLENETETRAHYDROFOLATE REDUCTASE GENE, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Medicine, General & Internal, Folic Acid, Bias, Internal medicine, General & Internal Medicine, medicine, Humans, Methylenetetrahydrofolate Reductase (NADPH2), Science & Technology, Polymorphism, Genetic, business.industry, Case-control study, Odds ratio, Publication bias, medicine.disease, COMMON MUTATION, chemistry, MYOCARDIAL-INFARCTION, Methylenetetrahydrofolate reductase, biology.protein, B VITAMINS, business
Abstract

Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease., Background Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality. Methods and Findings Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR, Editors' Summary Background Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits (atherosclerotic plaques) coat the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant restriction of the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and sometimes fatal heart attacks. Many established risk factors for CHD, including smoking, physical inactivity, being overweight, and eating a fat-rich diet, can be modified by lifestyle changes. Another possible modifiable risk factor for CHD is a high blood level of the amino acid homocysteine. Methylene tetrahydofolate reductase, which is encoded by the MTHFR gene, uses folate to break down and remove homocysteine so fortification of cereals with folate can reduce population homocysteine blood levels. Pooled results from prospective observational studies that have looked for an association between homocysteine levels and later development of CHD suggest that the reduction in homocysteine levels that can be achieved by folate supplementation is associated with an 11% lower CHD risk. Why Was This Study Done? Prospective observational studies cannot prove that high homocysteine levels cause CHD because of confounding, the potential presence of other unknown shared characteristics that really cause CHD. However, an approach called “Mendelian randomization” can test whether high blood homocysteine causes CHD. A common genetic variant of the MTHFR gene—the C677T polymorphism—reduces MTHFR efficiency so TT homozygotes (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677; the human genome contains two copies of most genes) have 25% higher blood homocysteine levels than CC homozygotes. In meta-analyses (statistical pooling of the results of several studies) of published Mendelian randomized studies, TT homozygotes have a higher CHD risk than CC homozygotes. Because gene variants are inherited randomly, they are not subject to confounding, so this result suggests that high blood homocysteine causes CHD. But what if only Mendelian randomization studies that found an association have been published? Such publication bias would affect this aggregate result. Here, the researchers investigate the association of the MTHFR C677T polymorphism with CHD in unpublished datasets that have analyzed this polymorphism incidentally during other genetic studies. What Did the Researchers Do and Find? The researchers obtained 19 unpublished datasets that contained data on the MTHFR C677T polymorphism in thousands of people with and without CHD. Meta-analysis of these datasets indicates that the excess CHD risk in TT homozygotes compared to CC homozygotes was 2% (much lower than predicted from the prospective observational studies), a nonsignificant difference (that is, it could have occurred by chance). When the probable folate status of the study populations (based on when national folic acid fortification legislation came into effect) was taken into account, there was still no evidence that TT homozygotes had an excess CHD risk. By contrast, in an updated meta-analysis of 86 published studies of the association of the polymorphism with CHD, the excess CHD risk in TT homozygotes compared to CC homozygotes was 15%. Finally, in a meta-analysis of randomized trials on the use of vitamin B supplements for homocysteine reduction, folate supplementation had no significant effect on the 5-year incidence of CHD. What Do These Findings Mean? These analyses of unpublished datasets are consistent with lifelong moderate elevation of homocysteine levels having no significant effect on CHD risk. In other words, these findings indicate that circulating homocysteine levels within the normal range are not causally related to CHD risk. The meta-analysis of the randomized trials of folate supplementation also supports this conclusion. So why is there a discrepancy between these findings and those of meta-analyses of published Mendelian randomization studies? The discrepancy is too large to be dismissed as a chance finding, suggest the researchers, but could be the result of publication bias—some studies might have been prioritized for publication because of the positive nature of their results whereas the unpublished datasets used in this study would not have been affected by any failure to publish null results. Overall, these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing CHD risk. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001177. The American Heart Association provides information about CHD and tips on keeping the heart healthy; it also provides information on homocysteine, folic acid, and CHD, general information on supplements and heart health, and personal stories about CHD The UK National Health Service Choices website provides information about CHD, including personal stories about CHD Information is available from the British Heart Foundation on heart disease and keeping the heart healthy The US National Heart Lung and Blood Institute also provides information on CHD (in English and Spanish) MedlinePlus provides links to many other sources of information on CHD (in English and Spanish) Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Published
2012

24. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Author

Wensley, F, Gao, P, Burgess, S, Kaptoge, S, Di Angelantonio, E, Shah, T, Engert, JC, Clarke, R, Davey-Smith, G, Nordestgaard, BG, Saleheen, D, Samani, NJ, Sandhu, M, Anand, S, Pepys, MB, Smeeth, L, Whittaker, J, Casas, JP, Thompson, SG, Hingorani, AD, Danesh, J, Eiriksdottir, G, Harris, TB, Launer, LJ, Gudnason, V, Folsom, AR, Andrews, G, Ballantyne, CM, Hall, AS, Braund, PS, Balmforth, AJ, Whincup, PH, Morris, R, Lawlor, DA, Lowe, GDO, Timpson, N, Ebrahim, S, Ben-Shlomo, Y, Tybjaerg-Hansen, A, Zacho, J, Brown, M, Ricketts, SL, Ashford, S, Lange, L, Reiner, A, Cushman, M, Tracy, R, Wu, C, Ge, J, Zou, Y, Sun, A, Hung, J, McQuillan, B, Thompson, P, Beilby, J, Warrington, N, Palmer, LJ, Wanner, C, Drechsler, C, Hoffmann, MM, Fowkes, FGR, Tzoulaki, I, Kumari, M, Miller, M, Marmot, M, Onland-Moret, C, van der Schouw, YT, Boer, JM, Wijmenga, C, Khaw, K-T, Vasan, RS, Schnabel, RB, Yamamoto, JF, Benjamin, EJ, Schunkert, H, Erdmann, J, Koenig, IR, Hengstenberg, C, Chiodini, B, Franzosi, MG, Pietri, S, Gori, F, Rudock, M, Liu, Y, Lohman, K, Humphries, SE, Hamsten, A, Norman, PE, Hankey, GJ, Jamrozik, K, Rimm, EB, Pai, JK, Psaty, BM, Heckbert, SR, Bis, JC, Yusuf, S, Xie, C, Collins, R, Bennett, D, Kooner, J, Chambers, J, Elliott, P, Maerz, W, Kleber, ME, Boehm, BO, Winkelmann, BR, Melander, O, Berglund, G, Koenig, W, Thorand, B, Baumert, J, Peters, A, Manson, J, Cooper, JA, Talmud, PJ, Ladenvall, P, Johansson, L, Jansson, J-H, Hallmans, G, Reilly, MP, Qu, L, Li, M, Rader, DJ, Watkins, H, Hopewell, J, Frossard, P, Sattar, N, Robertson, M, Shepherd, J, Schaefer, E, Hofman, A, Witteman, JCM, Kardys, I, Dehghan, A, de Faire, U, Bennet, A, Gigante, B, Leander, K, Peters, B, Maitland-van der Zee, AH, de Boer, A, Klungel, O, Greenland, P, Dai, J, Liu, S, Brunner, E, Kivimaki, M, O'Reilly, D, Ford, I, Packard, CJ, Dis, CRPCH, CIHDS, CC, CUPID, C, Medical Research Council (MRC), University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Pulmonology, and Coronel Institute of Occupational Health

Subjects
Male, Coronary Disease, Bioinformatics, Gene Frequency, MARKERS, Polymorphism (computer science), Risk Factors, Myocardial infarction, Prospective Studies, Prospective cohort study, General Environmental Science, Genetics, RISK, biology, General Engineering, Mendelian Randomization Analysis, General Medicine, Middle Aged, C-Reactive Protein, 1117 Public Health And Health Services, CARDIOVASCULAR-DISEASE, Meta-analysis, symbols, Female, Life Sciences & Biomedicine, Ischaemic Heart Disease, Polymorphism, Single Nucleotide, Molecular Genetics, symbols.namesake, Medicine, General & Internal, INFLAMMATION, Drugs: Cardiovascular System, General & Internal Medicine, medicine, INSTRUMENTAL VARIABLES, Humans, C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Allele frequency, METAANALYSIS, POLYMORPHISMS, Science & Technology, business.industry, Research, C-reactive protein, medicine.disease, GENE, MYOCARDIAL-INFARCTION, ATHEROSCLEROSIS, Mendelian inheritance, biology.protein, General Earth and Planetary Sciences, business
Abstract

Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries. Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors. Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals. Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P

Published
2011

31. Future of Pharmacogenetics in Cardiovascular Diseases

Author

Gallelli, L., van Schie, RMF, Verhoef, TI, Maitland-van der Zee, AH, de Boer, A, van der Meer, FJM, Redekop, Ken, Thariani, R, Gallelli, L., van Schie, RMF, Verhoef, TI, Maitland-van der Zee, AH, de Boer, A, van der Meer, FJM, Redekop, Ken, and Thariani, R

Published
2012

33. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design

Author

van Schie, RMF, Wadelius, M, Kamali, F, Daly, AK, Manolopoulos, VG, Boer, A, Barallon, R, Verhoef, TI, Kirchheiner, J, Haschke-Becher, M, Briz, M, Rosendaal, FR, Redekop, Ken, Pirmohamed, M, Maitland - van der Zee, AH, van Schie, RMF, Wadelius, M, Kamali, F, Daly, AK, Manolopoulos, VG, Boer, A, Barallon, R, Verhoef, TI, Kirchheiner, J, Haschke-Becher, M, Briz, M, Rosendaal, FR, Redekop, Ken, Pirmohamed, M, and Maitland - van der Zee, AH

Published
2009

36. Interaction between the Gly460Trp alpha-adducin gene variant and diuretics on the risk of myocardial infarction.

Author

van Wieren-de Wijer DB, Maitland-van der Zee AH, de Boer A, Kroon AA, de Leeuw PW, Schiffers P, Janssen RG, Psaty BM, van Duijn CM, Stricker BH, Klungel OH, van Wieren-de Wijer, Diane B M A, Maitland-van der Zee, Anke-Hilse, de Boer, Anthonius, Kroon, Abraham A, de Leeuw, Peter W, Schiffers, Paul, Janssen, Rob G J H, Psaty, Bruce M, and van Duijn, Cornelia M

Published
2009
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37. Genotype-Guided Asthma Treatment Reduces Exacerbations in Children: Meta-Analysis of Two RCTs.

Author

Slob EMA, Vijverberg SJH, Ruffles T, Noij LCE, Biermann J, Brouwer AFJ, van den Brink K, de Bruin-Kok A, Van Ewijk BE, Haarman E, Hammer SC, Hashimoto S, Hogarth F, Jones CJ, Kamps AWA, Kersten ETG, de Kleer I, Lipworth BJ, Littleford R, Mérelle M, Moeller A, Palmer CNA, Pilvinyte K, Rutjes NW, van Schaik RHN, Smith HE, Tavendale R, Terheggen-Lagro SWJ, Turner S, Twisk JWR, Vaessen-Verberne A, Verwaal M, de Vries T, Wesseling J, Pijnenburg MW, Koppelman GH, Mukhopadhyay S, and Maitland-van der Zee AH

Abstract

Background: Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are commonly used to treat asthma, however, some children lack response to the addition of LABA. This might be partially due to the presence of the Arg16Gly polymorphism, encoded by rs1042713 G>A in the ADRB2 gene. Carrying the A allele (Arg16) at this variant has been associated with an increased risk of exacerbations despite LABA treatment. We investigated whether genotype-guided treatment improved asthma-related outcomes., Methods: We conducted an individual participant data meta-analysis of two randomised controlled trials: PUFFIN (Dutch and Swiss 6-18 year-olds) and PACT (English and Scottish 12-18 year-olds). Children with uncontrolled asthma despite ICS who required a step-up in treatment were included. Participants were randomised to genotype-guided treatment or the control group with a follow-up of at least 6 months. Genotype-guided treatment consisted of adding LABA for children with ADRB2 Gly16/Gly16, whilst children with ADRB2 Arg16/Arg16 or Arg16/Gly16 were treated with double dose ICS (PUFFIN) or add-on montelukast (PACT). The primary outcome was a change in asthma control; secondary outcomes included exacerbation rate and time to exacerbation. Repeated measures mixed models and Cox regression were used., Results: Fifty-nine out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one Arg (A allele). Amongst all 193 children, no difference was observed in asthma control between the study groups. However, genotype-guided treatment resulted in lower asthma exacerbation rates (-0.08 (95%CI -0.16 to -0.00, p = 0.04)) compared to the control group., Conclusion: Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates and may be useful for personalising asthma care., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Published
2024
Full Text
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38. Association of blood inflammatory phenotypes and asthma burden in children with moderate-to-severe asthma.

Author

Alizadeh Bahmani AH, Vijverberg SJH, Hashimoto S, Wolff C, Almqvist C, Bloemsma LD, Brandstetter S, Corcuera-Elosegui P, Gorenjak M, Harner S, Hedman AM, Kabesch M, López-Fernández L, Kraneveld AD, Neerincx AH, Pino-Yanes M, Potočnik U, Sardón-Prado O, Dierdorp BS, Dekker T, Metwally NKA, Duitman JW, Lutter R, Brinkman P, Abdel-Aziz MI, and Maitland-van der Zee AH

Abstract

Background: Underlying immunological mechanisms in children with moderate-to-severe asthma are complex and unclear. We aimed to investigate the association between blood inflammatory parameters and asthma burden in children with moderate-to-severe asthma., Methods: Blood inflammatory parameters (eosinophil and neutrophil counts and inflammatory mediators using multiplex immunoassay technology) were measured in children (6-17 years) with moderate-to-severe asthma from the SysPharmPediA cohort across four European countries. Based upon low/high blood eosinophil (LBE/HBE) counts of 9 ·L -1 , respectively and low/high blood neutrophil (LBN/HBN) counts of 9 ·L -1 , respectively, mixed (HBE-HBN), eosinophilic (HBE-LBN), neutrophilic (LBE-HBN) and paucigranulocytic (LBE-LBN) phenotypes were defined. Inflammatory mediator profiles and burden of disease (asthma control status, exacerbations and school days missed in the past year) were compared between phenotypes using adjusted logistic regression models., Results: Among 126 included children (41% girls and mean (sd) age of 11.94 (2.76)), 22%, 44%, 11% and 23% were classified as mixed, eosinophilic, neutrophilic and paucigranulocytic phenotypes, respectively. Neutrophilic children had the lowest lung function (forced expiratory volume in 1 s % predicted pre-salbutamol) compared with other groups. Children with mixed asthma were most often uncontrolled and had the highest asthma-related school absence in the past year. Interleukin (IL)-6 and matrix metalloproteinase-9 levels were significantly higher in patients with mixed or neutrophilic asthma, whereas tissue inhibitor of metalloproteinase-2 was lower in patients with neutrophilic asthma compared with eosinophilic or paucigranulocytic asthma. IL-5 was increased in eosinophilic group compared with the neutrophilic and paucigranulocytic groups, irrespective of the chosen cut-off for eosinophilia., Conclusion: Differences in asthma burden-related clinical expression and distinct blood inflammatory mediator profiles were found between phenotypes, highlighting implications for optimising personalised treatment and management strategies in children with moderate-to-severe asthma., Competing Interests: Conflict of interest: A.H. Alizadeh Bahrani, S.J.H. Vijverberg, S. Hashimoto, C. Wolff, C. Almqvist, S. Brandstetter, P. Corcuera-Elosegui, S. Harner, A.M. Hedman, L. López-Fernández, A.D. Kraneveld, O. Sardón-Prado, B.S. Dierdop, T. Dekker, N.K.A. Metwally, R. Lutter and P. Brinkman have no conflicts of interest to disclose. L.D. Bloemsma received funding from partners in the Precision Medicine for More Oxygen (P4O2) consortium, which are the Amsterdam UMC, Leiden University Medical Center, Maastricht UMC+, Maastricht University, UMC Groningen, UMC Utrecht, Utrecht University, TNO, Aparito, Boehringer Ingelheim, Breathomix, Clear, Danone Nutricia Research, Fluidda, MonitAir, Ncardia, Ortec Logiqcare, Philips, Proefdiervrij, Quantib-U, RespiQ, Roche, Smartfish, SODAQ, Thirona, TopMD, Lung Alliance Netherlands, the Lung Foundation Netherlands (Longfonds), PPP Allowance made available by Health∼Holland, and Top Sector Life Sciences and Health (LSHM20104 and LSHM20068), to stimulate public–private partnerships and by Novartis. M. Gorenjak received SysPharmPediA grant, cofinanced by the Ministry of Education, Science and Sport Slovenia (MIZS) (contract number C3330-16-500106) and funded by the Slovenian Research Agency (research core funding number P3-0427), and by the Ministry of Education, Science and Sport of the Republic of Slovenia grant PERMEABLE (contract number C3330-19-252012). M. Kabesch received funding from Bundesministerium für Bildung und Forschung (BMFB) grant SysPharmPediA, European Union, BMFB, German Research Foundation, Infectopharm, Bavarian Minsitry of Education and Research, and Bavarian Ministry of Health. He received consulting fees from Bionorica, Sanofi, Novartis and Bencard; he also received honoraria from ERS, EAACI, ATS, Novartis, Glaxo, Chiesi, Sanofi, Nutricia, Hipp and Allergopharma. A.H. Neerincx has received ERANET Systems Medicine and ZonMW grants (project number 9003035001). M. Pino-Yanes received funding from Instituto de Salud Carlos III (AC15/00015) as part of the SysPharmPediA consortium, and grants from MCIN/AEI/10.13039/501100011033, GlaxoSmithKline Spain and CSL Berhing outside of the submitted work. U. Potočnik received SysPharmPediA grant, cofinanced by the Ministry of Higher Education, Science and Innovation Slovenia (MVZI) (contract number C3330-16-500106) and Slovenian Research Agency (research core funding number P3-0427 and research grant number J3-4497). J.W. Duitman received grants from Abbvie and Boehringer Ingelheim in the past 36 months. M.I. Abdel-Aziz was funded by a full PhD scholarship from the Ministry of Higher Education of the Arab Republic of Egypt during the conduct of the study. A.H. Maitland-van der Zee is the principal investigator of a public–private consortium (P4O2) sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (AbbVie, Boehringer Ingelheim, Breathomix, Clear, Fluidda, Ortec Logiqcare, Olive, Philips, Quantib-U, Smartfish, Clear, SODAQ, Thirona, Roche, TopMD, Novartis and RespiQ); she received unrestricted research grants from GSK and Boehringer Ingelheim, and a Vertex Innovation Award grant; and she has received honoraria from Boehringer Ingelheim, GSK and AstraZeneca., (Copyright ©The authors 2024.)

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2024
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40. Pharmacotherapy from Pre-COVID to Post-COVID: Longitudinal Trends and Predictive Indicators for Long COVID Symptoms.

Author

Baalbaki N, Verbeek ST, Bogaard HJ, Blankestijn JM, van den Brink VC, Cornelissen MEB, Twisk JWR, Golebski K, and Maitland-van der Zee AH

Abstract

Background/objectives: A significant number of COVID-19 cases experience persistent symptoms after the acute infection phase, a condition known as long COVID or post-acute sequelae of COVID-19. Approved prevention and treatment options for long COVID are currently lacking. Given the heterogeneous nature of long COVID, a personalized medicine approach is essential for effective disease management. This study aimed to describe trends in pharmacotherapy from pre-COVID to post-COVID phases to gain insights into COVID-19 treatment strategies and assess whether pre-COVID pharmacotherapy can predict long COVID symptoms as a health status indicator., Methods: In the Precision Medicine for more Oxygen (P4O2) COVID-19 study, 95 long COVID patients were comprehensively evaluated through post-COVID outpatient clinics and study visits. This study focused on descriptive analysis of the pharmacotherapy patterns across different phases: pre-COVID-19, acute COVID, and post-COVID. Furthermore, associations between pre-COVID medication and long COVID outcomes were analyzed with regression analyses., Results: We observed peaks in the use of certain medications during the acute infection phase, including corticosteroids and antithrombotic agents, with a decrease in the use of renin-angiotensin system inhibitors. Consistently high use of alimentary tract medications was found across all phases. Pre-COVID respiratory medications were associated with fatigue symptoms, while antiinfectives and cardiovascular drugs were linked to fewer persisting long COVID symptom categories., Conclusion: Our findings provide longitudinal, descriptive pharmacotherapy insights and suggest that medication history can be a valuable health status indicator in characterizing patients for personalized disease management strategies, considering the heterogeneous nature of long COVID.

Published
2024
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41. Radiomultiomics: quantitative CT clusters of severe asthma associated with multiomics.

Author

Zounemat Kermani N, Chung KF, Macis G, Santini G, Clemeno FAA, Versi A, Sun K, Abdel-Aziz MI, Andersson LI, Auffray C, Badi Y, Bakke P, Brightling C, Brinkman P, Caruso M, Chanez P, De Meulder B, Djukanovic R, Fabbri L, Fowler SJ, Horvath I, Howarth P, James AJ, Kolmert J, Kraft M, Li CX, Maitland-van der Zee AH, Malerba M, Papi A, Rabe K, Sanak M, Shaw DE, Singh D, Sparreman Mikus M, van Den Berge M, Wheelock AM, Wheelock CE, Yasinska V, Guo YK, Wagers S, Barnes PJ, Bush A, Sterk PJ, Dahlen SE, Adcock IM, Siddiqui S, and Montuschi P

Subjects
Humans, Female, Male, Middle Aged, Adult, Proteomics, rac1 GTP-Binding Protein metabolism, Sputum metabolism, Cohort Studies, Cluster Analysis, Severity of Illness Index, Machine Learning, Aged, Multiomics, Asthma diagnostic imaging, Asthma metabolism, Tomography, X-Ray Computed, Lung diagnostic imaging
Abstract

Background: Lung quantitative computed tomography (qCT) severe asthma clusters have been reported, but their replication and underlying disease mechanisms are unknown. We identified and replicated qCT clusters of severe asthma in two independent asthma cohorts and determined their association with molecular pathways, using radiomultiomics, integrating qCT, multiomics and machine learning/artificial intelligence., Methods: We used consensus clustering on qCT measurements of airway and lung CT scans, performed in 105 severe asthmatic adults from the U-BIOPRED cohort. The same qCT measurements were used to replicate qCT clusters in a subsample of the ATLANTIS asthma cohort (n=97). We performed integrated enrichment analysis using blood, sputum, bronchial biopsies, bronchial brushings and nasal brushings transcriptomics and blood and sputum proteomics to characterise radiomultiomic-associated clusters (RACs)., Results: qCT clusters and clinical features in U-BIOPRED were replicated in the matched ATLANTIS cohort. In the U-BIOPRED cohort, RAC1 (n=30) was predominantly female with elevated body mass index, mild airflow limitation, decreased CT lung volume and increased lung density and upregulation of the complement pathway. RAC2 (n=34) subjects had airway wall thickness and a mild degree of airflow limitation, with upregulation of proliferative pathways including neurotrophic receptor tyrosine kinase 2/tyrosine kinase receptor B, and downregulation of semaphorin pathways. RAC3 (n=41) showed increased lung attenuation area and air trapping, severe airflow limitation, hyperinflation, and upregulation of cytokine signalling and signalling by interleukin pathways, and matrix metallopeptidase 1, 2 and 9., Conclusions: U-BIOPRED severe asthma qCT clusters were replicated in a matched independent asthmatic cohort and associated with specific molecular pathways. Radiomultiomics might represent a novel strategy to identify new molecular pathways in asthma pathobiology., Competing Interests: Conflict of interest: K.F. Chung reports grants from the MRC, EPSRC, GSK, Merck and NIEHS, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, Novartis and AstraZeneca, and participation on a data safety monitoring board or advisory board with GSK, AstraZeneca, Novartis, Roche, Merck, Trevi, Rickett-Beckinson, Nocion, Shionogi and Clean Breathing Institute supported by Haleon. C. Auffray reports support for the present study from the Innovative Medicines Initiative. Y. Badi reports support for the present study from the Innovative Medicines Initiative. P. Bakke reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK and Sanofi. C. Brightling reports support for the present study from the ATLANTIS study (Chiesi grant) and Leicester NIHR BRC, grants from 4D Pharma, Areteia, AstraZeneca, Chiesi, Genentech, GSK, Mologic, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi, and consultancy fees from 4D Pharma, Areteia, AstraZeneca, Chiesi, Genentech, GSK, Mologic, Novartis, Regeneron Pharmaceuticals, Roche and Sanofi. P. Chanez reports grants from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis and Sanofi Aventis, consultancy fees from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis and Sanofi Aventis, payment or honoraria for lectures, presentations, manuscript writing or educational events from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis and Sanofi Aventis, and support for attending meetings from ALK, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Menarini, Novartis and Sanofi Aventis. B. De Meulder reports support for the present study from the Innovative Medicines Initiative. R. Djukanovic reports consultancy fees from Synairgen plc, GSK, ZenasBio and Celltrion, leadership role as Chair of the European Respiratory Society's clinical research collaboration on severe asthma (SHARP), and stock (or stock options) with Synairgen plc. L. Fabbri reports consultancy fees from Chiesi Farmaceutici and AstraZeneca, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi Farmaceutici, AstraZeneca, GSK, Alfasigma and Novartis, support for attending meetings from Chiesi Farmaceutici, GSK and Novartis, and participation on a data safety monitoring board or advisory board with Novartis and Chiesi. S.J. Fowler reports grants from the NIHR, and payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim. P. Howarth reports employment with GSK. J. Kolmert reports consultancy fees from Gesynta Pharma AB and Lipum AB. M. Kraft reports grants from the NIH, American Lung Association, Synairgen, Janssen, AstraZeneca and Sanofi, consultancy fees from AstraZeneca, Sanofi, Chiesi, GSK, Kinaset and Genentech, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, support for attending meetings from the European Respiratory Society, one patent issued and tiled filed to development of therapeutics for inflammatory lung disease as CoFounder and Chief Medical Officer, RaeSedo, Inc., participation on a data safety monitoring board or advisory board with ALung, leadership role with the National Heart, Lung and Blood Advisory Council, stock (or stock options) with RaeSedo, Inc. (equity ownership), and the following financial (or non-financial) interests: Section Editor of UpToDate. A.H. Maitland-van der Zee reports grants from Health Holland, GSK, Boehringer Ingelheim and Vertex, consultancy fees from Boehringer Ingelheim and AstraZeneca, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, and participation on a data safety monitoring board or advisory board for a study on BPD in neonates. A. Papi reports grants from Chiesi, AstraZeneca, GSK and Sanofi, consultancy fees from Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals, Moderna and Roche, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, AstraZeneca, GSK, Menarini, Zambon, Mundipharma, Sanofi, Edmond Pharma, Iqvia, Avillion, Sanofi and Regeneron, participation on a data safety monitoring board or advisory board with Chiesi, AstraZeneca, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals and Moderna, receipt of equipment, materials, drugs, medical writing, gifts or other services from Consorzio Futuro in Ricerca. K. Rabe reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi Pharmaceuticals, Novartis, Sanofi/Regeneron, GSK, Berlin Chemie and Roche Pharma, participation on a data safety monitoring board or advisory board with AstraZeneca, Boehringer Ingelheim, Sanofi/Regeneron and CSL Behring, and leadership roles with the German Center for Lung Research (DZL), German Chest Society (DGP) and American Thoracic Society. D.E. Shaw reports consultancy fees from GSK, AstraZeneca and Novartis, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK and AstraZeneca, and support for attending meetings from GSK. D. Singh reports consultancy fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, EpiEndo, Genentech, GSK, Glenmark, Gossamer Bio, Kinaset Therapeutics, Menarini, Novartis, Orion, Pulmatrix, Sanofi, Synairgen, Teva, Theravance, Biopharma and Verona Pharma. M. van Den Berge reports grants from GSK, Roche, Genentech and Novartis. Y. Guo reports support for the present study from the Innovative Medicines Initiative. S. Wagers reports consultancy fees from King's College Hospital NHS Foundation Trust, Academic Medical Research, AMC Medical Research BV, Asthma UK, Athens Medical School, Boehringer Ingelheim International GmbH, CHU de Toulouse, CIRO, DS Biologicals Ltd, École Polytechnique Fédérale De Lausanne, European Respiratory Society, FISEVI, Fluidic Analytics Ltd, Fraunhofer IGB, Fraunhofer ITEM, GSK Research & Development Ltd, Holland & Knight, Karolinska Institutet Fakturor, KU Leuven, Longfonds, National Heart and Lung Institute, Novartis Pharma AG, Owlstone Medical Limited, PExA AB, UCB Biopharma SPRL, Umeå University, University Hospital Southampton NHS Foundation Trust, Università Campus Bio-Medico di Roma, Universita Cattolica Del Sacro Cuore, Universität Ulm, University of Bern, University of Edinburgh, University of Hull, University of Leicester, University of Loughborough, University of Luxembourg, University of Manchester, University of Nottingham, Vlaams Brabant, Dienst Europa, Imperial College London, Boehringer Ingelheim, Breathomix, Gossamer Bio, AstraZeneca, CIBER, OncoRadiomics, University of Leiden, University of Wurzburg, Chiesi Pharmaceutical, University of Liege, Teva Pharmaceuticals, Sanofi, Pulmonary Fibrosis Foundation and Three Lakes Foundation. P.J. Sterk reports consultancy fees from SME Breathomix, and stock (or stock options) with SME Breathomix. S-E. Dahlen reports grants from AstraZeneca, GSK and Sanofi, consultancy fees from AstraZeneca, Cayman Chemicals, GSK and Regeneron, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, GSK and Sanofi. I.M. Adcock reports support for the present study from the Innovative Medicines Initiative, grants from GSK, MRC, EPSRC and Sanofi, consultancy fees from GSK, Sanofi, Chiesi and Kinaset, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, Sanofi, Eurodrug and Sunovion, and support for attending meetings from AstraZeneca. S. Siddiqui consultancy fees from AstraZeneca, GSK, CSL Behring, Areteia Therapeutics, ERT Medical, Chiesi and Roche, and payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, Chiesi and AstraZeneca. P. Montuschi reports support for the present study from the Innovative Medicines Initiative. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

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2024
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43. Exhaled Volatile Organic Compounds for Asthma Control Classification in Children with Moderate to Severe Asthma: Results from the SysPharmPediA Study.

Author

Shahbazi Khamas S, Van Dijk Y, Abdel-Aziz MI, Neerincx AH, Maarten Blankestijn J, Vijverberg SJH, Hashimoto S, Bush A, Kraneveld AD, Hedman AM, Toncheva AA, Almqvist C, Wolff C, Murray CS, Hedlin G, Roberts G, Adcock IM, Korta-Murua J, Bønnelykke K, Fleming LJ, Pino-Yanes M, Gorenjak M, Kabesch M, Sardón-Prado O, Montuschi P, Singer F, Elosegui PC, Fowler SJ, Brandstetter S, Harner S, Dahlén SE, Potočnik U, Frey U, van Aalderen W, Brinkman P, and Maitland-van der Zee AH

Subjects
Humans, Child, Male, Female, Adolescent, Exhalation, Gas Chromatography-Mass Spectrometry, Severity of Illness Index, Child, Preschool, Asthma metabolism, Asthma drug therapy, Volatile Organic Compounds analysis, Breath Tests methods, Biomarkers analysis, Biomarkers metabolism
Abstract

Rationale: The early identification of children with poorly controlled asthma is imperative for optimizing treatment strategies. The analysis of exhaled volatile organic compounds (VOCs) is an emerging approach to identify prognostic and diagnostic biomarkers in pediatric asthma. Objectives: To assess the accuracy of gas chromatography-mass spectrometry-based exhaled metabolite analysis to differentiate between controlled and uncontrolled pediatric asthma. Methods: This study encompassed discovery (SysPharmPediA [Systems Pharmacology Approach to Uncontrolled Paediatric Asthma]) and validation (U-BIOPRED [Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes] and PANDA [Paediatric-Asthma-Non-Invasive-Diagnostic-Approaches]) phases. First, exhaled VOCs that discriminated degrees of asthma control were identified. Subsequently, outcomes were validated in two independent cohorts. Patients were classified as controlled or uncontrolled on the basis of asthma control test scores and the number of severe attacks in the past year. In addition, the potential of VOCs to predict two or more future severe asthma attacks in SysPharmPediA was evaluated. Measurements and Main Results: Complete data were available for 196 children (SysPharmPediA, n  = 100; U-BIOPRED, n  = 49; PANDA, n  = 47). In SysPharmPediA, after randomly splitting the population into training ( n  = 51) and test ( n  = 49) sets, three compounds (acetophenone, ethylbenzene, and styrene) distinguished between patients with uncontrolled and controlled asthma. The areas under the receiver operating characteristic curves (AUROCCs) for training and test sets were, respectively, 0.83 (95% confidence interval [CI], 0.65-1.00) and 0.77 (95% CI, 0.58-0.96). Combinations of these VOCs resulted in AUROCCs of 0.74 ± 0.06 (U-BIOPRED) and 0.68 ± 0.05 (PANDA). Attack prediction tests resulted in AUROCCs of 0.71 (95% CI, 0.51-0.91) and 0.71 (95% CI, 0.52-0.90) for the training and test sets. Conclusions: Exhaled metabolite analysis might enable asthma control classification in children. This should stimulate the further development of exhaled metabolite-based point-of-care tests in asthma.

Published
2024
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44. Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

Author

Brinkman P, Wilde M, Ahmed W, Wang R, van der Schee M, Abuhelal S, Schaber C, Cunoosamy D, Clarke GW, Maitland-van der Zee AH, Dahlén SE, Siddiqui S, and Fowler SJ

Subjects
Humans, Metabolomics methods, Lung Diseases diagnosis, Lung Diseases metabolism, Breath Tests methods, Biomarkers analysis, Biomarkers metabolism, Volatile Organic Compounds analysis, Exhalation physiology
Abstract

The exhaled breath represents an ideal matrix for noninvasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review, we specifically address volatile organic compounds in the breath, with a view toward fulfilling the promise of these as actionable biomarkers, in particular, for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

Published
2024
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45. The Progression of Symptoms in Post COVID-19 Patients: A Multicentre, Prospective, Observational Cohort Study.

Author

Cornelissen MEB, Haarman MM, Twisk JWR, Houweling L, Baalbaki N, Sondermeijer B, Beijers RJHCG, Gach D, Bloemsma LD, and Maitland-van der Zee AH

Abstract

Background: Although the coronavirus disease 2019 (COVID-19) pandemic is no longer a public health emergency of international concern, 30% of COVID-19 patients still have long-term complaints. A better understanding of the progression of symptoms after COVID-19 is needed to reduce the burden of the post COVID-19 condition., Objective: This study aims to investigate the progression of symptoms, identify patterns of symptom progression, and assess their associations with patient characteristics., Methods: Within the P4O2 COVID-19 study, patients aged 40-65 years were recruited from five Dutch hospitals. At 3-6 and 12-18 months post COVID-19, medical data were collected, and pulmonary function tests were performed. In between, symptoms were assessed monthly with a questionnaire. Latent class mixed modelling was used to identify symptom progression patterns over time, with multinomial logistic regression to examine associations with patient characteristics., Results: Eighty-eight patients (aged 54.4 years, 48.9% males) were included. Three trajectories were identified for fatigue and dyspnoea: decreasing, high persistent, and low persistent. The odds of "decreasing fatigue" was higher for never smokers and participants in the lifestyle intervention and lower for those having a comorbidity. The odds of "decreasing dyspnoea" was higher for moderate COVID-19 patients and lifestyle intervention participants and lower for males, mild COVID-19 patients, and those with a higher age., Conclusions: Three distinct trajectories were identified for fatigue and dyspnoea, delineating patterns of symptom persistence following COVID-19. Sex, age, smoking status, participation in lifestyle interventions and COVID-19 severity were associated with the likelihood of belonging to different trajectories. These findings highlight the heterogeneity of the long-term symptoms experienced by post COVID-19 patients and emphasise the importance of personalised treatment strategies.

Published
2024
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46. Fatigue in severe pediatric asthma patients: Results of the PANDA study.

Author

van Dijk YE, Keuker VSL, Hashimoto S, Rutjes NW, van Muilekom MM, Golebski K, Van Litsenburg RRL, Terheggen-Lagro SWJ, van Ewijk BE, Gemke RJBJ, Maitland-van der Zee AH, and Vijverberg SJH

Subjects
Humans, Child, Female, Male, Adolescent, Netherlands epidemiology, Prevalence, Surveys and Questionnaires, Cohort Studies, Self Report, Asthma epidemiology, Asthma diagnosis, Asthma complications, Quality of Life, Fatigue epidemiology, Fatigue etiology, Severity of Illness Index
Abstract

Background: Fatigue is a commonly reported clinical symptom, yet research on fatigue in children with severe asthma is missing. We aimed to explore the extent of fatigue in severe pediatric asthma and identify associated factors., Method: This study was conducted within the Pediatric Asthma Non-Invasive Diagnostic Approaches (PANDA), an observational cohort of 6- to 17-year-old Dutch children with severe asthma. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL™-MFS) was used to measure self-reported fatigue. Fatigue levels were compared with a general pediatric Dutch population using linear regression, and quantifying the prevalence of "fatigued" (-2 < Standard deviations [SD] ≤ -1) and "severely fatigued" (SD ≤ -2) children. Secondly, we performed linear regression analyses to explore whether fatigue levels were independently associated with asthma attacks, comorbidities, medication, pulmonary function, symptom control, and asthma-related quality of life (QoL)., Results: Severe pediatric asthma patients (n = 78, mean age 11.8 ± 3.1 years) reported significantly more fatigue than Dutch peers (n = 328, mean age 11.8 ± 3.2 years) mean difference in z-score: -0.68; 95%CI -0.96, -0.40. In the severe asthma group, 28.2% scored as "fatigued" and 15.4% as "severely fatigued," compared with 14.0% and 3.4% in the general population. In pediatric asthma patients, asthma-related QoL (β = 0.77, p < .01, ΔR 2  = .43), symptom control (β = 0.56, p < .01, ΔR 2  = .24) and a dysfunctional breathing pattern (β = -0.36, p < .01, ΔR 2  = .12) were most strongly associated with fatigue scores., Conclusion: Fatigue is a common symptom in children with severe asthma and is associated with multiple clinical factors and patient-reported outcomes. It should be considered as an important treatment target., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Published
2024
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47. Post-COVID-19 condition in children: epidemiological evidence stratified by acute disease severity.

Author

Lap CR, Brackel CLH, Winkel AMAM, Hashimoto S, Haverkort M, Noij LCE, Alsem MW, von Asmuth EGJ, Bannier MAGE, Buddingh EP, van Goudoever JB, Haverman L, Maitland-van der Zee AH, Mooij MG, Oostrom K, Pijnenburg MW, Kloosterman S, Teela L, Luijten M, Tulling AJ, Lugthart G, Bogaert D, Biesbroek G, van Houten MA, and Terheggen-Lagro SWJ

Abstract

Background: To determine the prevalence of pediatric Post-COVID-19 condition (PPCC), identify risk factors, and assess the quality of life in children with differing severities of acute COVID-19., Methods: During a prospective longitudinal study with a 1-year follow-up, we compared non-hospitalized (mild) and hospitalized (severe) COVID-19 cases to a negatively tested control group., Results: 579 children were included in this study. Of these, 260 had mild acute disease (median age:8, IQR:6-10), 60 had severe acute disease (median age:1, IQR:0.1-4.0), and 259 tested negative for SARS-CoV-2 (NT) (median age:8, IQR:5-10). At three months, 14.6% of the SARS-CoV-2 positive mild group (RR:6.31 (CI 95%: 2.71-14.67)) and 29.2% of the severe group (RR:12.95 (CI 95%: 5.37-31.23)) reported sequelae, versus 2.3% of the NT group. PPCC prevalence in the mild group decreased from 16.1% at one month to 4.4% at one year. Children with PPCC exhibited lower physical health-related quality of life scores and higher fatigue scores than the NT children., Conclusions: Severe acute COVID-19 in children leads to a higher PPCC prevalence than in mild cases. PPCC prevalence decreases over time. Risk factors at three months include prior medical history, hospital admission, and persistent fatigue one month after a positive test., Impact: We demonstrate children with severe COVID-19 are more likely to develop Post-COVID-19 condition than those with mild or no infections, and highlights the risk factors. Here we have stratified by acute disease severity, prospectively included a negative control group, and have demonstrated the heterogeneity in prevalence when utilizing various recent definitions of post-COVID. Identifying risk factors for pediatric post-COVID and highlighting the heterogeneity in prevalence based on various current definitions for post-COVID should aid in correctly identifying potential pediatric post-COVID cases, aiding in early intervention., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Published
2024
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48. Host-microbial interactions differ with age of asthma onset.

Author

Versi A, Azim A, Ivan FX, Abdel-Aziz MI, Bates S, Riley J, Maitland-Van Der Zee AH, Dahlen SE, Djukanovic R, Chotirmall SH, Howarth P, Kermani NZ, Chung KF, and Adcock IM

Subjects
Humans, Male, Female, Adult, Host Microbial Interactions, Child, Adolescent, Middle Aged, Young Adult, Asthma microbiology, Asthma physiopathology, Age of Onset
Abstract

Competing Interests: Conflict of interest: A. Azim is a paid employee of AstraZeneca, and holds stock or stock options in AstraZeneca. S. Bates is an employee of and holds stock in Johnson & Johnson. S. Bates previously worked for and holds stock in GSK. J. Riley previously worked for and held stock in GSK. A.H. Maitland-Van Der Zee reports grants from Health Holland, GSK, Boehringer Ingelheim and Vertex, consultancy fees from Boehringer Ingelheim and AstraZeneca, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, and participation on a data safety monitoring board or advisory board for a study on BPD in neonates. S-E. Dahlen reports support for the present study from EU funding through IMI, grants from AstraZeneca, Cayman Chemical, GSK and Sanofi, consultancy fees from AstraZeneca, GSK and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca and Sanofi, and a leadership role with 3TR IMI as a Steering Board member. R. Djukanovic reports consultancy fees from Synairgen plc, GSK, ZenasBio and Celltrion, a leadership role with the European Respiratory Society's Clinical collaboration on severe asthma (SHARP) as Chair, and stock (or stock options) with Synairgen. S.H. Chotirmall reports support for the present manuscript from the Singapore Ministry of Health's National Medical Research Council under its Clinician-Scientist Individual Research Grant (MOH-001356), the Singapore Ministry of Health's National Medical Research Council under its Clinician Scientist Award (MOH-000710), consultancy fees from CSL Behring, Boehringer Ingelheim and Pneumagen Ltd, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca and Chiesi Farmaceutici, and participation on a data safety monitoring board or advisory board with Inovio Pharmaceuticals Inc., Imam Abdulrahman Bin Faisal University. P. Howarth is an employee of GSK. N.Z. Kermani reports support for the present study from Data Science Institute, Imperial College London, National Heart and Lung Institute, Imperial College London. K.F. Chung reports grants from MRC, EPSRC, GSK, Merck and NIEHS, payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, Novartis and AZ, participation on a data safety monitoring board or advisory board with GSK, AZ, Novartis, Roche, Merck, Trevi, Rickett-Beckinson, Nocion and Shionogi Clean Breathing Institute supported by Haleon. I.M. Adcock reports support for the present study from EU funding through IMI, grants from GSK, MRC, EPSRC and Sanofi, consultancy fees from GSK, Sanofi and Kinaset, and payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca and Sanofi. The remaining authors have no potential conflicts of interest to disclose.

Published
2024
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49. Association between butyrate-producing gut bacteria and the risk of infectious disease hospitalisation: results from two observational, population-based microbiome studies.

Author

Kullberg RFJ, Wikki I, Haak BW, Kauko A, Galenkamp H, Peters-Sengers H, Butler JM, Havulinna AS, Palmu J, McDonald D, Benchraka C, Abdel-Aziz MI, Prins M, Maitland van der Zee AH, van den Born BJ, Jousilahti P, de Vos WM, Salomaa V, Knight R, Lahti L, Nieuwdorp M, Niiranen T, and Wiersinga WJ

Subjects
Humans, Middle Aged, Adult, Male, Female, Aged, Finland epidemiology, Netherlands epidemiology, Young Adult, Feces microbiology, Adolescent, Communicable Diseases microbiology, Communicable Diseases epidemiology, Cohort Studies, Risk Factors, Hospitalization statistics & numerical data, Gastrointestinal Microbiome physiology, Butyrates metabolism, RNA, Ribosomal, 16S genetics, RNA, Ribosomal, 16S analysis, Bacteria genetics, Bacteria classification, Bacteria isolation & purification
Abstract

Background: Microbiota alterations are common in patients hospitalised for severe infections, and preclinical models have shown that anaerobic butyrate-producing gut bacteria protect against systemic infections. However, the relationship between microbiota disruptions and increased susceptibility to severe infections in humans remains unclear. We investigated the relationship between gut microbiota and the risk of future infection-related hospitalisation in two large population-based cohorts., Methods: In this observational microbiome study, gut microbiota were characterised using 16S rRNA gene sequencing in independent population-based cohorts from the Netherlands (HELIUS study; derivation cohort) and Finland (FINRISK 2002 study; validation cohort). HELIUS was conducted in Amsterdam, Netherlands, and included adults (aged 18-70 years at inclusion) who were randomly sampled from the municipality register of Amsterdam. FINRISK 2002 was conducted in six regions in Finland and is a population survey that included a random sample of adults (aged 25-74 years). In both cohorts, participants completed questionnaires, underwent a physical examination, and provided a faecal sample at inclusion (Jan 3, 2013, to Nov 27, 2015, for HELIUS participants and Jan 21 to April 19, 2002, for FINRISK participants. For inclusion in our study, a faecal sample needed to be provided and successfully sequenced, and national registry data needed to be available. Primary predictor variables were microbiota composition, diversity, and relative abundance of butyrate-producing bacteria. Our primary outcome was hospitalisation or mortality due to any infectious disease during 5-7-year follow-up after faecal sample collection, based on national registry data. We examined associations between microbiota and infection risk using microbial ecology and Cox proportional hazards., Findings: We profiled gut microbiota from 10 699 participants (4248 [39·7%] from the derivation cohort and 6451 [60·3%] from the validation cohort). 602 (5·6%) participants (152 [3·6%] from the derivation cohort; 450 [7·0%] from the validation cohort) were hospitalised or died due to infections during follow-up. Gut microbiota composition of these participants differed from those without hospitalisation for infections (derivation p=0·041; validation p=0·0002). Specifically, higher relative abundance of butyrate-producing bacteria was associated with a reduced risk of hospitalisation for infections (derivation cohort cause-specific hazard ratio 0·75 [95% CI 0·60-0·94] per 10% increase in butyrate producers, p=0·013; validation cohort 0·86 [0·77-0·96] per 10% increase, p=0·0077). These associations remained unchanged following adjustment for demographics, lifestyle, antibiotic exposure, and comorbidities., Interpretation: Gut microbiota composition, specifically colonisation with butyrate-producing bacteria, was associated with protection against hospitalisation for infectious diseases in the general population across two independent European cohorts. Further studies should investigate whether modulation of the microbiome can reduce the risk of severe infections., Funding: Amsterdam UMC, Porticus, National Institutes of Health, Netherlands Organisation for Health Research and Development (ZonMw), and Leducq Foundation., Competing Interests: Declaration of interests DM owns stock in and is a consultant for Biomesense. AHMvdZ reports grants from Health Hjolland, GSK, Boehringer Ingelheim, and Vertx; consulting fees from Boehringer Ingelheim and AstraZeneca; and honoraria from GSK, all outside the submitted work; and is a chair of the data safety monitoring board of a study on bronchopulmonary dysplasia in neonates. B-JvdB is the chair of the cardiovasular theme of HELIUS, the Netherlands Society of Hypertension, and Amsterdam Cardiovascular Sciences; and participates on the committee of the Dutch Cardiovascular Alliance. RK is on the Scientific Advisory Board of Gencirq, Cybele, DayTwo, Biomesense, and Micronoma; owns stock in Gencirq, Cybele, Biomesense, Micronoma, and Biota; is a consultant for DayTwo and Biomesense; and is a cofounder of Micronoma and Biota. MN is on the Scientific Advisory Board of Caelus Pharmaceuticals. TN reports grants from the Finnish Research Council, Emil Aaltonen Foundation, Sigrid Jusélius Foundation, and Finnish Foundation for Cardiovascular Research; and honoraria from Servier Finland and AstraZeneca. WJW reports grants from ZonMw/NWO and EU (Eurostars); and ad hoc consultancy for AstraZeneca and Shionogi, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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50. A severe asthma phenotype of excessive airway Haemophilus influenzae relative abundance associated with sputum neutrophilia.

Author

Versi A, Azim A, Ivan FX, Abdel-Aziz MI, Bates S, Riley J, Uddin M, Zounemat Kermani N, Maitland-Van Der Zee AH, Dahlen SE, Djukanovic R, Chotirmall SH, Howarth P, Adcock IM, and Chung KF

Subjects
Humans, Male, Female, Adult, Middle Aged, Phenotype, Haemophilus Infections microbiology, Asthma microbiology, Haemophilus influenzae pathogenicity, Haemophilus influenzae genetics, Sputum microbiology, Neutrophils metabolism
Abstract

Background: Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome., Methods: Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α-diversity of mild-moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS)., Findings: Fifty-one out of 97 SA samples were classified as RDSs with Haemophilus influenzae RDS being most common (n = 16), followed by Actinobacillus unclassified (n = 10), Veillonella unclassified (n = 9), Haemophilus aegyptius (n = 9), Streptococcus pseudopneumoniae (n = 7), Propionibacterium acnes (n = 5), Moraxella catarrhalis (n = 5) and Tropheryma whipplei (n = 5). Haemophilus influenzae RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (n = 9) of highest relative abundance of exclusively Haemophilus influenzae RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF-κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 Haemophilus influenzae RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6-transignalling signature and neutrophil activation., Conclusion: We describe a Haemophilus influenzae cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Published
2024
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