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1. Epigenetic, transcriptional, and functional characterization of myeloid cells in familial Mediterranean fever

Author

Rutger J. Röring, Wenchao Li, Ruiqi Liu, Mariolina Bruno, Bowen Zhang, Priya A. Debisarun, Orsolya Gaal, Medeea Badii, Viola Klück, Simone J.C.F.M. Moorlag, Frank van de Veerdonk, Yang Li, Leo A.B. Joosten, and Mihai G. Netea

Subjects
Health sciences, Immunology, Immune response, Science
Abstract

Summary: Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1β dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1β and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.

Published
2024
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2. Lessons learned from rapid exome sequencing for 575 critically ill patients across the broad spectrum of rare disease

Author

Abderrahim Marouane, Kornelia Neveling, A. Chantal Deden, Simone van den Heuvel, Dimitra Zafeiropoulou, Steven Castelein, Frank van de Veerdonk, David A. Koolen, Annet Simons, Richard Rodenburg, Dineke Westra, Arjen R. Mensenkamp, Nicole de Leeuw, Marjolijn Ligtenberg, Rene Matthijsse, Rolph Pfundt, Erik Jan Kamsteeg, Han G. Brunner, Christian Gilissen, Ilse Feenstra, Willem P. de Boode, Helger G. Yntema, Wendy A. G. van Zelst-Stams, Marcel Nelen, and Lisenka E. L. M. Vissers

Subjects
rapid exome sequencing, diagnostic workflow, turnaround time, clinical outcome, diagnostic yield, Genetics, QH426-470
Abstract

Introduction: Rapid exome sequencing (rES) has become the first-choice genetic test for critically ill patients, mostly neonates, young infants, or fetuses in prenatal care, in time-sensitive situations and when it is expected that the genetic test result may guide clinical decision making. The implementation of rES has revolutionized medicine by enabling timely identification of genetic causes for various rare diseases. The utilization of rES has increasingly been recognized as an essential diagnostic tool for the identification of complex and undiagnosed genetic disorders.Methods: We conducted a retrospective evaluation of our experiences with rES performed on 575 critically ill patients from various age groups (prenatal to adulthood), over a four-year period (2016–2019). These patients presented with a wide spectrum of rare diseases, including but not limited to neurological disorders, severe combined immune deficiency, and cancer.Results: During the study period, there was a significant increase in rES referrals, with a rise from a total of two referrals in Q1-2016 to 10 referrals per week in Q4-2019. The median turnaround time (TAT) decreased from 17 to 11 days in the period 2016–2019, with an overall median TAT of 11 days (IQR 8–15 days). The overall diagnostic yield for this cohort was 30.4%, and did not significantly differ between the different age groups (e.g. adults 22.2% vs children 31.0%; p-value 0.35). However, variability in yield was observed between clinical entities: craniofacial anomalies yielded 58.3%, while for three clinical entities (severe combined immune deficiency, aneurysm, and hypogonadotropic hypogonadism) no diagnoses were obtained.Discussion: Importantly, whereas clinical significance is often only attributed to a conclusive diagnosis, we also observed impact on clinical decision-making for individuals in whom no genetic diagnosis was established. Hence, our experience shows that rES has an important role for patients of all ages and across the broad spectrum of rare diseases to impact clinical outcomes.

Published
2024
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3. Genome-Wide Association Study Reveals CLEC7A and PROM1 as Potential Regulators of Paracoccidioides brasiliensis-Induction of Cytokine Production in Peripheral Blood Mononuclear Cells

Author

Ana Marina B. de Figueiredo, Jéssica Cristina dos Santos, Brenda Kischkel, Edwin Ardiansyah, Marije Oosting, Grazzielle Guimarães Matos, Iara Barreto Neves Oliveira, Frank van de Veerdonk, Mihai G. Netea, Célia Maria de Almeida Soares, Fátima Ribeiro-Dias, and Leo A. B. Joosten

Subjects
Paracoccidioidomycosis, GWAS, genetic polymorphism, CLEC7A, PROM1, CD38, Biology (General), QH301-705.5
Abstract

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by fungi of the genus Paracoccidioides and the different clinical forms of the disease are associated with the host immune responses. Quantitative trait loci mapping analysis was performed to assess genetic variants associated with mononuclear-cells-derived cytokines induced by P. brasiliensis on 158 individuals. We identified the rs11053595 SNP, which is present in the CLEC7A gene (encodes the Dectin-1 receptor) and the rs62290169 SNP located in the PROM1 gene (encodes CD133) associated with the production of IL-1β and IL-22, respectively. Functionally, the blockade of the dectin-1 receptor abolished the IL-1β production in P. brasiliensis-stimulated PBMCs. Moreover, the rs62290169-GG genotype was associated with higher frequency of CD38+ Th1 cells in PBMCs cultured with P. brasiliensis yeasts. Therefore, our research indicates that the CLEC7A and PROM1 genes are important for the cytokine response induced by P. brasiliensis and may influence the Paracoccidioidomycosis disease outcome.

Published
2023
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4. Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19

Author

Zhaoli Liu, Gizem Kilic, Wenchao Li, Ozlem Bulut, Manoj Kumar Gupta, Bowen Zhang, Cancan Qi, He Peng, Hsin-Chieh Tsay, Chai Fen Soon, Yonatan Ayalew Mekonnen, Anaísa Valido Ferreira, Caspar I. van der Made, Bram van Cranenbroek, Hans J. P. M. Koenen, Elles Simonetti, Dimitri Diavatopoulos, Marien I. de Jonge, Lisa Müller, Heiner Schaal, Philipp N. Ostermann, Markus Cornberg, Britta Eiz-Vesper, Frank van de Veerdonk, Reinout van Crevel, Leo A. B. Joosten, Jorge Domínguez-Andrés, Cheng-Jian Xu, Mihai G. Netea, and Yang Li

Subjects
COVID-19, SARS-CoV-2, convalescence, multi-omics, single-cell sequencing, DNA methylation, Immunologic diseases. Allergy, RC581-607
Abstract

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

Published
2022
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5. Immune defects in patients with pulmonary Mycobacterium abscessus disease without cystic fibrosis

Author

Milou M.F. Schuurbiers, Mariolina Bruno, Sanne M.H. Zweijpfenning, Cecile Magis-Escurra, Martin Boeree, Mihai G. Netea, Jakko van Ingen, Frank van de Veerdonk, and Wouter Hoefsloot

Subjects
Medicine
Abstract

The prevalence of Mycobacterium abscessus infections in non-cystic fibrosis (CF) patients has increased in recent years. In this study, we investigate whether immune defects explain the apparent susceptibility to this opportunistic infection in non-CF patients. We performed stimulations of peripheral blood mononuclear cells and whole blood from 13 patients with M. abscessus pulmonary disease and 13 healthy controls to investigate their cytokine production after 24 h and 7 days. Patients were predominantly women (54%) with a mean age of 59 years; 62% had nodular bronchiectatic disease. Many patients had predisposing pulmonary diseases, such as COPD (46%), and asthma (23%). Patients with COPD showed an impaired interleukin (IL)-6 response to M. abscessus and a reduced IL-17 response to Candida, together with a M. abscessus-specific enhanced IL-22 production. Patients without COPD showed higher levels of interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory molecule. Within the non-COPD patients, those with bronchiectasis showed defective interferon (IFN)-γ production in response to Candida albicans. In conclusion, susceptibility to M. abscessus is likely determined by a combination of immunological defects and predisposing pulmonary disease. The main defect in the innate immune response was a shift of the ratio of IL-1β to IL-1Ra, which decreased the bioactivity of this pathway in the adaptive immune response. In the adaptive immune response there was defective IL-17 and IFN-γ production. Patients with COPD and bronchiectasis showed different cytokine defects. It is therefore crucial to interpret the immunological results within the clinical background of the patients tested.

Published
2020
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6. Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

Author

Ofer Zimmerman, Lindsey B. Rosen, Muthulekha Swamydas, Elise M. N. Ferre, Mukil Natarajan, Frank van de Veerdonk, Steven M. Holland, and Michail S. Lionakis

Subjects
STAT1, phosphorylation, chronic mucocutaneous candidiasis, AIRE, APECED, CD14+ monocytes, Immunologic diseases. Allergy, RC581-607
Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator (AIRE) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline and STAT1 phosphorylation (pSTAT1) upon interferon (IFN)-γ stimulation relative to healthy controls. AIRE interacts functionally with a protein that directly regulates STAT1, namely protein inhibitor of activated STAT1, which inhibits STAT1 activation. Given the common clinical features between patients with AIRE and STAT1 GOF mutations, we sought to determine whether APECED patients also exhibit increased levels of STAT1 protein and phosphorylation in CD14+ monocytes. We obtained peripheral blood mononuclear cells from 8 APECED patients and 13 healthy controls and assessed the levels of STAT1 protein and STAT1 tyrosine phosphorylation at rest and following IFN-γ stimulation, as well as the levels of STAT1 mRNA. The mean STAT1 protein levels in CD14+ monocytes exhibited a ~20% significant decrease in APECED patients both at rest and after IFN-γ stimulation relative to that of healthy donors. Similarly, the mean peak value of IFN-γ-induced pSTAT1 level was ~20% significantly lower in APECED patients compared to that in healthy controls. The decrease in STAT1 and peak pSTAT1 in APECED patients was not accompanied by decreased STAT1 mRNA or anti-IFN-γ autoantibodies; instead, it correlated with the presence of autoantibodies to type I IFN and decreased AIRE−/− monocyte surface expression of IFN-γ receptor 2. Our data show that, in contrast to patients with STAT1 GOF mutations, APECED patients show a moderate but consistent and significant decrease in total STAT1 protein levels, associated with lower peak levels of pSTAT1 molecules after IFN-γ stimulation.

Published
2017
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7. New insights in the immunobiology of IL 1 family members

Author

Frank Van De Veerdonk and Mihai eNetea

Subjects
Biology, Cytokines, Interleukin-1, review, ligands, Immunologic diseases. Allergy, RC581-607
Abstract

The interleukin-1 (IL 1) family of ligands is associated with acute and chronic inflammation, and plays an essential role in the non-specific innate response to infection. The biological properties of IL 1 family ligands are typically pro-inflammatory. The IL 1 family has 11 family members and can be catagorized into subfamilies according to the length of their precursor and the length of the propiece for each precursor (Figure 1). The IL 1 subfamily consists of IL 1α, IL 1β and IL 33, with the longest propieces of the IL 1 family. IL 18 and IL 37 belong to the IL 18 subfamily and contain smaller propieces then IL 1 and IL-33. Since IL 37 binds to the IL 18Rα chain it is part of the IL 18 subfamily, however it remains to be elucidated how the propiece of IL 37 is removed. IL 36α, β and γ as well as IL 36 Ra belong to the IL 36 subfamily. In addition, IL 38 likely belongs to this family since it has the ability to the IL 36R. The IL 36 subfamily has the shortest propiece. The one member of the IL 1 family that cannot be catagorized in these subfamilies is IL 1 receptor antagonist (IL 1Ra), which has a signal peptide and is readily secreted. In the present review we will describe the biological functions of the IL-1F members and new insights in their biology.

Published
2013
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8. IL-1beta processing in host defense: beyond the inflammasomes.

Author

Mihai G Netea, Anna Simon, Frank van de Veerdonk, Bart-Jan Kullberg, Jos W M Van der Meer, and Leo A B Joosten

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Stimulation and release of proinflammatory cytokines is an essential step for the activation of an effective innate host defense, and subsequently for the modulation of adaptive immune responses. Interleukin-1beta (IL-1beta) and IL-18 are important proinflammatory cytokines that on the one hand activate monocytes, macropages, and neutrophils, and on the other hand induce Th1 and Th17 adaptive cellular responses. They are secreted as inactive precursors, and the processing of pro-IL-1beta and pro-IL-18 depends on cleavage by proteases. One of the most important of these enzymes is caspase-1, which in turn is activated by several protein platforms called the inflammasomes. Inflammasome activation differs in various cell types, and knock-out mice defective in either caspase-1 or inflammasome components have an increased susceptibility to several types of infections. However, in other infections and in models of sterile inflammation, caspase-1 seems to be less important, and alternative mechanisms such as neutrophil-derived serine proteases or proteases released from microbial pathogens can process and activate IL-1beta. In conclusion, IL-1beta/IL-18 processing during infection is a complex process in which the inflammasomes are only one of several activation mechanisms.

Published
2010
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9. Immunogenicity of the mRNA-1273 COVID-19 vaccine in adult patients with inborn errors of immunity

Author

Leanne P.M. van Leeuwen, Corine H. GeurtsvanKessel, Pauline M. Ellerbroek, Godelieve J. de Bree, Judith Potjewijd, Abraham Rutgers, Hetty Jolink, Frank van de Veerdonk, Eric C.M. van Gorp, Faye de Wilt, Susanne Bogers, Lennert Gommers, Daryl Geers, Anke H.W. Bruns, Helen L. Leavis, Jelle W. van Haga, Bregtje A. Lemkes, Annelou van der Veen, S.F.J. de Kruijf-Bazen, Pieter van Paassen, Karina de Leeuw, Annick A.J.M. van de Ven, Petra H. Verbeek-Menken, Annelies van Wengen, Sandra M. Arend, Anja J. Ruten-Budde, Marianne W. van der Ent, P. Martin van Hagen, Rogier W. Sanders, Marloes Grobben, Karlijn van der Straten, Judith A. Burger, Meliawati Poniman, Stefan Nierkens, Marit J. van Gils, Rory D. de Vries, Virgil A.S.H. Dalm, Translational Immunology Groningen (TRIGR), MUMC+: MA Nefrologie (9), Interne Geneeskunde, MUMC+: MA Klinische Immunologie (9), RS: Carim - B02 Vascular aspects thrombosis and Haemostasis, Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, APH - Global Health, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Medical Microbiology and Infection Prevention, Graduate School, Virology, Epidemiology, Internal Medicine, and Immunology

Subjects
Adult, mRNA-1273 COVID-19 vaccine, XLA, COVID-19 Vaccines, Primary Immunodeficiency Diseases, Immunology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], immunogenicity, Antibodies, Viral, immuno-genicity, CID, primary immunodeficiency disorders, SDG 3 - Good Health and Well-being, PRIMARY IMMUNODEFICIENCY, Agammaglobulinemia, Humans, Immunology and Allergy, Prospective Studies, SARS-CoV-2, CVID, Genetic Diseases, Inborn, Immunologic Deficiency Syndromes, COVID-19, Genetic Diseases, X-Linked, Inborn errors of immunity, antibody response, Antibodies, Neutralizing, Common Variable Immunodeficiency, T-cell response, Spike Glycoprotein, Coronavirus, 2019-nCoV Vaccine mRNA-1273
Abstract

Contains fulltext : 251906.pdf (Publisher’s version ) (Open Access) BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.

Published
2022

10. Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities

Author

Eva L. Koekenbier, Konstantin Fohse, Josephine S. van de Maat, Jan Jelrik Oosterheert, Cees van Nieuwkoop, Jacobien J. Hoogerwerf, Martin P. Grobusch, Maurice A.A.J. van den Bosch, Janneke H.H. van de Wijgert, Mihai G. Netea, Frits R. Rosendaal, Marc J.M. Bonten, C.H. (Henri) van Werkhoven, Astrid Aardenburg-van Huisstede, Heidi S.M. Ammerlaan, Willem G. Boersma, Kees Brinkman, Patricia C.J. Bruijning-Verhagen, Reinout van Crevel, Corine Delsing, Thijs ten Doesschaten, Anton S.M. Dofferhoff, Ruud Duijkers, Rolf H.H. Groenwold, Corine de Haas, Robert-Jan Hassing, Marieke L.A. de Hoog, Susanne M. Huijts, Astrid van Hylckama-Vlieg, Eefje Jong, Hanna K. de Jong, Martijn Knap, Michael Koenders, Ilse J.E. Kouijzer, Henk Kramer, Roel van de Laar, Arief Lalmohamed, Karel-Jan D.F. Lensen, Willem M. Lijfering, Fabienne Magdelijns, Bob Meek, Rutger A. Middelburg, Hazra S. Moeniralam, Simon P. Mooijaart, Barbara C. van Munster, Jaap ten Oever, Marc Padros Goossens, Vincent Peters, Douwe F. Postma, Niels Pouw, Herre J. Reesink, Marieke J.A. de Regt, Anneli C.J. van der Reijden, R. Schaakxs, Kitty Slieker, Robbert J. Slingerland, Nicolette L.J. van Sluis, Coen D.A. Stehouwer, Frank van de Veerdonk, Annelies Verbon, Value, Affordability and Sustainability (VALUE), Molecular Neuroscience and Ageing Research (MOLAR), Infectious diseases, AII - Infectious diseases, and APH - Global Health

Subjects
Microbiology (medical), All institutes and research themes of the Radboud University Medical Center, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Infectious Diseases, SDG 3 - Good Health and Well-being, Randomized controlled trial, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], COVID-19, General Medicine, Respiratory tract infections, BCG vaccine, Bacillus Calmette-Guérin vaccine
Abstract

Contains fulltext : 293489.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To test whether Bacillus Calmette-Guérin (BCG) vaccination would reduce the incidence of COVID-19 and other respiratory tract infections (RTIs) in older adults with one or more comorbidities. METHODS: Community-dwelling adults aged 60 years or older with one or more underlying comorbidities and no contraindications to BCG vaccination were randomized 1:1 to BCG or placebo vaccination and followed for 6 months. The primary endpoint was a self-reported, test-confirmed COVID-19 incidence. Secondary endpoints included COVID-19 hospital admissions and clinically relevant RTIs (i.e. RTIs including but not limited to COVID-19 requiring medical intervention). COVID-19 and clinically relevant RTI episodes were adjudicated. Incidences were compared using Fine-Gray regression, accounting for competing events. RESULTS: A total of 6112 participants with a median age of 69 years (interquartile range, 65-74) and median of 2 (interquartile range, 1-3) comorbidities were randomized to BCG (n = 3058) or placebo (n = 3054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients [hazard ratio (HR), 1.12; 95% CI, 0.87-1.44]. COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR, 0.86; 95% CI, 0.46-1.61). During the study period, 13 BCG recipients died compared with 18 placebo recipients (HR, 0.71; 95% CI, 0.35-1.43), of which 11 deaths (35%) were COVID-19-related: six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR, 0.92; 95% CI, 0.66-1.28). DISCUSSION: BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization, or clinically relevant RTIs. 01 juni 2023

Published
2023

11. 478. Lung Hybrid Neutrophils and Subsequent Extracellular Traps Are Protective In COVID-19-Associated Pulmonary Aspergillosis

Author

Simon Feys, Sam Vanmassenhove, Sirima Kraisin, Seppe Cambier, Cato Jacobs, Bram Boeckx, Pierre Van Mol, Lore Vanderbeke, Katrien Lagrou, Johan Van Weyenbergh, Agostinho Carvalho, Frank Van De Veerdonk, Paul Proost, Kimberly Martinod, Joost Wauters, and Diether Lambrechts

Subjects
Infectious Diseases, Oncology
Abstract

Background COVID-19-associated pulmonary aspergillosis (CAPA) is a severe superinfection with the fungus Aspergillus frequently affecting critically ill COVID-19 patients. Pathophysiological insight, key to improve diagnostic and immunomodulatory therapeutic options, is lacking. Methods We performed single-cell RNA sequencing (scRNA-seq) on 37 bronchoalveolar lavage (BAL) samples from 37 critically ill COVID-19 patients. Three groups were defined: patients who did not develop aspergillosis (COVID-19-only, n=22), CAPA patients with sampling < 5 days after CAPA diagnosis (early CAPA, n=6) and CAPA patients with sampling 5-11 days after CAPA diagnosis (late CAPA, n=9). All CAPA patients had probable/proven CAPA according to the 2020 ECMM/ISHAM consensus criteria. Additionally, we assessed neutrophil extracellular trap (NET) levels in a separate cohort of 33 biobanked COVID-19-only BAL samples and 24 early CAPA samples. Results A total of 69008 cells passed quality filtering. CAPA patients had significantly lower BAL neutrophil proportions than COVID-19-only patients, particularly in early CAPA (Fig. 1A). Pseudotime inference revealed two neutrophil trajectories: a regular maturation trajectory, and a trajectory giving rise to “hybrid” neutrophils which express genes encoding proteins with antigen-presenting functions (Fig. 1B). The latter trajectory was dominant in CAPA patients (Fig. 1C). NETosis analyses revealed significantly higher levels of citrullinated histone H3 DNA complexes (H3Cit-DNA) in CAPA patients (Fig. 2A). This explains the low CAPA BAL neutrophil proportions, as neutrophils that underwent NETosis are no longer detected via scRNA-seq. CAPA patients with the lowest H3Cit-DNA levels had significantly decreased survival rates (Fig. 2B). Figure 1:Bronchoalveolar lavage fluid (BALF) neutrophil proportions are significantly decreased in CAPA patients, accompanied by a shift to hybrid neutrophil formation. Panel (A): BALF neutrophil proportions as analyzed by single-cell RNA sequencing using the Seurat R package are significantly lower in CAPA patients compared to COVID-19-only patients. Patients with early CAPA have significantly lower BALF neutrophil proportions than patients with late CAPA. Macrophage/monocyte and epithelial cell proportions are reciprocally increased in CAPA patients compared to COVID-19-only patients. P-values shown for differences between the pooled CAPA patients and the COVID-19-only patients. P-values were calculated using a generalized linear model correcting for age, Charlson Comorbidity Index at hospital admission, and administration of corticosteroids (prednisone equivalent dose 20 mg or higher) within 48 hours of BALF sampling. Panel (B): Two trajectories are defined using pseudotime inference calculated using the Slingshot R package: a trajectory dominant in COVID-19-only patients with regular maturation of progenitor neutrophils, and a trajectory dominant in CAPA patients with maturation towards a ‘hybrid neutrophil’ state, with neutrophils expression genes encoding proteins with functions in antigen presentation. Subsequently, the hybrid neutrophil proportion is significantly higher in CAPA patients compared to COVID-19-only patients, and is significantly higher in patients with early CAPA than those with late CAPA. The mature neutrophil proportion is reciprocally reduced in CAPA patients. P-values shown for differences between the pooled CAPA patients and the COVID-19-only patients. P-values were calculated using a generalized linear model correcting for age, Charlson Comorbidity Index at hospital admission, and administration of corticosteroids (prednisone equivalent dose 20 mg or higher) within 48 hours of BALF sampling. Figure 2:Neutrophil extracellular trap (NET) levels are increased in early CAPA and are associated with increased survival in CAPA patients specifically. Panel (A): Myeloperoxidase (MPO) DNA levels were analyzed as measure for general NET-formation, while citrullinated histone H3 bound DNA (H3Cit-DNA) levels were analyzed as more specific PAD4-dependent NET-formation, in BALF samples from early CAPA and COVID-19-only patients. A trend towards higher MPO-DNA levels was found in early CAPA patients, while H3Cit-DNA levels were significantly higher in early CAPA compared to COVID-19-only patients. P-values calculated using Mann-Whitney U test. Panel (B): Kaplan-Meier analysis of patients with NETosis analyses, divided in early CAPA and COVID-19-only patients and subdivided according to H3Cit-DNA levels (cut-off at 20000 ng/mL for early CAPA and at 8000 ng/mL for COVID-19-only). Log-rank test was used to compare survival distributions. For the comparison early CAPA (low H3Cit-DNA) versus early CAPA (high H3Cit-DNA), the log-rank p-value was 0.033. Conclusion CAPA patients display extremely high levels of released NETs in the lower respiratory tract, associated with a shift from the normal neutrophil maturation process towards “hybrid neutrophil” formation, probably upon encountering the fungus. In contrast to high NETosis contributing to mortality in severe COVID-19, CAPA patients likely require these NETs to survive aspergillosis. BAL NET levels hold promise as a tool to guide diagnosis, prognosis and treatment in these patients. Disclosures Simon Feys, MD, Pfizer: Travel support Katrien Lagrou, PharmD, PhD, FUJIFILM Wako: Speaker fee|Gilead: Advisor/Consultant|Gilead: Speaker fee|MRM Health: Advisor/Consultant|MSD: Advisor/Consultant|Pfizer: Speaker fee|Thermo fisher Scientific: Service fee Joost Wauters, MD, PhD, Gilead: Grant/Research Support|Gilead: Speaker's fee, travel support, advisory board|MSD: Grant/Research Support|MSD: Speaker's fee, travel support, posaconazole for interventional trial|Pfizer: Grant/Research Support|Pfizer: Speaker's fee, travel support, advisory board.

Published
2022

13. Activation of cytokine responses by Candida africana

Author

Diletta Rosati, Mariolina Bruno, Frank van de Veerdonk, Jaap ten Oever, Jacques F Meis, and Mihai G Netea

Subjects
All institutes and research themes of the Radboud University Medical Center, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Infectious Diseases, Candida albicans, Leukocytes, Mononuclear, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Animals, Cytokines, Humans, Female, General Medicine, Candidiasis, Vulvovaginal, Candida
Abstract

Candida africana is a fungal pathogen that rarely causes invasive infections, but is mainly isolated from patients with vaginal infections. Vulvovaginal candidiasis is associated with dysregulated inflammatory responses of the host, however, the innate immune responses against C. africana are currently unknown. In this study, we explored the cytokine production of human peripheral blood mononuclear cells (PBMCs) in response to different C. africana isolates (intra-species diversity), and compared it with that induced by other yeasts belonging to the C. albicans species complex such as C. dubliniensis and C. albicans. Candida africana isolates induced both pro- and anti-inflammatory cytokines broadly similar to other Candida species. Candida africana-stimulated PBMCs tended to produce lower Interleukin (IL)-17 and IL-22 levels in comparison with C. albicans, whereas the induction of trained immunity was similar between C. africana and other Candida species. Overall, our results demonstrate that C. africana induces similar innate immune responses as the other Candida species. Therefore, its propensity to cause vulvovaginal infections is not due to an increased capacity to induce cytokine-related immune pathology. Nor is the infrequent occurrence of invasive infection by C. africana explained by a quantitatively different cytokine induction.Candida africana has been reported to cause vulvovaginal candidiasis. This study shows that C. africana induces broadly similar cytokine production and trained immunity as other Candida species. Its propensity to cause vaginal infections is not due to an enhanced capacity to cause immune dysregulation.

Published
2022

14. Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19

Author

Zhaoli Liu, Gizem Kilic, Wenchao Li, Ozlem Bulut, Manoj Kumar Gupta, Bowen Zhang, Cancan Qi, He Peng, Hsin-Chieh Tsay, Chai Fen Soon, Yonatan Ayalew Mekonnen, Anaísa Valido Ferreira, Caspar I. van der Made, Bram van Cranenbroek, Hans J. P. M. Koenen, Elles Simonetti, Dimitri Diavatopoulos, Marien I. de Jonge, Lisa Müller, Heiner Schaal, Philipp N. Ostermann, Markus Cornberg, Britta Eiz-Vesper, Frank van de Veerdonk, Reinout van Crevel, Leo A. B. Joosten, Jorge Domínguez-Andrés, Cheng-Jian Xu, Mihai G. Netea, and Yang Li

Subjects
All institutes and research themes of the Radboud University Medical Center, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], SARS-CoV-2, Immunology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Disease Progression, Leukocytes, Mononuclear, Immunology and Allergy, COVID-19, Humans, Convalescence, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

Published
2021

15. The extended phenotype of LRBA deficiency

Author

Laura, Gámez-Díaz, primary, Dietrich, August, additional, Polina, Stepensky, additional, Shoshana, Revel-Vilk, additional, Markus, Seidel, additional, Mitsuiki, Noriko, additional, Tomohiro, Morio, additional, Austen, Worth, additional, Jacob, Bleesing, additional, Frank, Van De Veerdonk, additional, Tobias, Feuchtinger, additional, Maria, Kanariou, additional, Annette, Schmitt-Gräff, additional, Suranjith, Seneviratne, additional, Siobhan, Burns, additional, Bernd, Belohradsky, additional, Nima, Rezaei, additional, Shahrzad, Bakhtiar, additional, Carsten, Speckmann, additional, Michael, Jordan, additional, and Bodo, Grimbacher, additional

Published
2015
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16. IL-1 family nomenclature

Author

Charles, Dinarello, William, Arend, John, Sims, Dirk, Smith, Hal, Blumberg, Luke, O'Neill, Raphaela, Goldbach-Mansky, Theresa, Pizarro, H, Hoffman, Philip, Bufler, Marcel, Nold, Pietro, Ghezzi, Alberto, Mantovani, Cecilia, Garlanda, Diana, Boraschi, Anna, Rubartelli, Mihai, Netea, Jos, van der Meer, Leo, Joosten, Tom, Mandrup-Poulsen, Marc, Donath, Eli, Lewis, Josef, Pfeilschifter, Michael, Martin, Michael, Kracht, H, Muehl, Daniela, Novick, Miodrag, Lukic, Bruno, Conti, Alan, Solinger, Peyman, Kelk, Kelk, Peyman, Frank, van de Veerdonk, and Chiristopher, Gabel

Subjects
Genetics, Receptor complex, Innate immune system, Immunology, Interleukin-36, Interleukin, Biology, Article, Proinflammatory cytokine, Pathogenesis and modulation of inflammation [N4i 1], Terminology as Topic, Animals, Humans, Immunology and Allergy, Tumor necrosis factor alpha, Receptor, Function (biology), Interleukin-1
Abstract

To the Editor: Newly cloned interleukin 1 (IL-1) family members1–3 were originally given an IL-1 family (IL-1F) designation4, but as functions have now been elucidated for several of these5,6, we propose that each now be assigned an individual interleukin designation. IL-1F6, IL-1F8 and IL-1F9 are encoded by distinct genes but use the same receptor complex (IL-1Rrp2 and AcP), are proinflammatory and deliver nearly identical signals7–12. We propose these be designated IL-36α, IL-36β and IL-36γ, respectively. IL-1F5 also binds to IL-1Rrp2 but antagonizes those cytokines in a manner analogous to that used by IL-1Ra to antagonize IL-1α and IL-1β7–9. We propose that IL-1F5 be renamed IL-36Ra (for ‘receptor antagonist’). In the IL-1 nomenclature, IL-1Ra is used for the natural product, whereas IL-1ra is used for the recombinant product; therefore, IL-36Ra is appropriate for natural IL-1F5. IL-1F7 produces anti-inflammatory effects by suppressing innate immune responses; it does this by decreasing the production of inflammatory cytokines induced by Toll-like receptor agonists as well as that of IL-1 and tumor necrosis factor13,14. We propose this IL-1 family member be renamed IL-37. IL-1F7 has various splice forms1,2,15,16, of which IL-1F7b is the most studied. We propose that IL-1F7a, IL-1F7b and so on be renamed IL-37a, IL-37b and so on. The one remaining IL-1 family member, for which no function has yet been demonstrated, is IL-1F10; however, as evidence of its properties remains limited, we suggest that it retain its IL-1F designation until a function is clearly identified, although it might be prudent to reserve the designation IL-38 for this eventuality.

Published
2010

17. Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial

Author

Lore, Vanderbeke, Nico A F, Janssen, Dennis C J J, Bergmans, Marc, Bourgeois, Jochem B, Buil, Yves, Debaveye, Pieter, Depuydt, Simon, Feys, Greet, Hermans, Oscar, Hoiting, Ben, van der Hoven, Cato, Jacobs, Katrien, Lagrou, Virginie, Lemiale, Piet, Lormans, Johan, Maertens, Philippe, Meersseman, Bruno, Mégarbane, Saad, Nseir, Jos A H, van Oers, Marijke, Reynders, Bart J A, Rijnders, Jeroen A, Schouten, Isabel, Spriet, Karin, Thevissen, Arnaud W, Thille, Ruth, Van Daele, Frank L, van de Veerdonk, Paul E, Verweij, Alexander, Wilmer, Roger J M, Brüggemann, Joost, Wauters, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Radboud University Medical Center [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Ghent University Hospital, Canisius-Wilhelmina Hospital [Nijmegen, The Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Elisabeth-TweeSteden Hospital, Erasmus University Rotterdam, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Dutch-Belgian Mycosis Study Group: Bart Rijnders, Paul Verweij, Frank van de Veerdonk, Alexander Schauwvlieghe, Tom Wolfs, Joost Wauters, Katrien Lagrou, Mégarbane, Bruno, Intensive Care, Internal Medicine, MUMC+: MA Medische Staf IC (9), MUMC+: MA Arts Assistenten IC (9), and RS: NUTRIM - R2 - Liver and digestive health

Subjects
AZOLE RESISTANCE, Posaconazole, Original, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Critical Care and Intensive Care Medicine, Aspergillosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, law.invention, 0302 clinical medicine, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Clinical endpoint, Invasive Pulmonary Aspergillosis, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, education.field_of_study, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Incidence (epidemiology), Intensive care unit, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Intensive Care Units, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, VIRUS, medicine.drug, Adult, medicine.medical_specialty, Population, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Anesthesiology, SURVEILLANCE, Influenza, Human, medicine, Humans, education, FUMIGATUS, business.industry, Prophylaxis, 030208 emergency & critical care medicine, FLUCONAZOLE, Triazoles, medicine.disease, Influenza, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030228 respiratory system, Respiratory failure, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, Critical illness
Abstract

Purpose Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA. Methods We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population). Results Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI − 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment. Conclusion The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06431-0.

Published
2021

18. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19

Author

Angus, Derek, Derde, Lennie, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen, Beane, Abigail, van Bentum-Puijk, Wilma, Berry, Lindsay, Bhimani, Zahra, Bonten, Marc, Bradbury, Charlotte, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Cheng, Allen, de Jong, Menno, Detry, Michelle, Estcourt, Lise, Fitzgerald, Mark, Goossens, Herman, Green, Cameron, Haniffa, Rashan, Higgins, Alisa, Horvat, Christopher, Hullegie, Sebastiaan, Kruger, Peter, Lamontagne, Francois, Lawler, Patrick, Linstrum, Kelsey, Litton, Edward, Lorenzi, Elizabeth, Marshall, John, Mcauley, Daniel, Mcglothin, Anna, Mcguinness, Shay, Mcverry, Bryan, Montgomery, Stephanie, Mouncey, Paul, Murthy, Srinivas, Nichol, Alistair, Parke, Rachael, Parker, Jane, Rowan, Kathryn, Sanil, Ashish, Santos, Marlene, Saunders, Christina, Seymour, Christopher, Turner, Anne, van de Veerdonk, Frank, Venkatesh, Balasubramanian, Zarychanski, Ryan, Berry, Scott, Lewis, Roger, Mcarthur, Colin, Webb, Steven, Gordon, Anthony, NIHR, Hôpital Raymond Poincaré [AP-HP], Writing Committee for the REMAP-CAP Investigators, Farah Al-Beidh, Derek Angus, Djillali Annane, Yaseen Arabi, Wilma van Bentum-Puijk, Scott Berry, Abigail Beane, Zahra Bhimani, Marc Bonten, Charlotte Bradbury, Frank Brunkhorst, Meredith Buxton, Allen Cheng, Menno De Jong, Lennie Derde, Lise Estcourt, Herman Goossens, Anthony Gordon, Cameron Green, Rashan Haniffa, Francois Lamontagne, Patrick Lawler, Edward Litton, John Marshall, Colin McArthur, Daniel McAuley, Shay McGuinness, Bryan McVerry, Stephanie Montgomery, Paul Mouncey, Srinivas Murthy, Alistair Nichol, Rachael Parke, Kathryn Rowan, Christopher Seymour, Anne Turner, Frank van de Veerdonk, Steve Webb, Ryan Zarychanski, Lewis Campbell, Andrew Forbes, David Gattas, Stephane Heritier, Lisa Higgins, Peter Kruger, Sandra Peake, Jeffrey Presneill, Ian Seppelt, Tony Trapani, Paul Young, Sean Bagshaw, Nick Daneman, Niall Ferguson, Cheryl Misak, Marlene Santos, Sebastiaan Hullegie, Mathias Pletz, Gernot Rohde, Kathy Rowan, Brian Alexander, Kim Basile, Timothy Girard, Christopher Horvat, David Huang, Kelsey Linstrum, Jennifer Vates, Richard Beasley, Robert Fowler, Steve McGloughlin, Susan Morpeth, David Paterson, Bala Venkatesh, Tim Uyeki, Kenneth Baillie, Eamon Duffy, Rob Fowler, Thomas Hills, Katrina Orr, Asad Patanwala, Steve Tong, Mihai Netea, Shilesh Bihari, Marc Carrier, Dean Fergusson, Ewan Goligher, Ghady Haidar, Beverley Hunt, Anand Kumar, Mike Laffan, Patrick Lawless, Sylvain Lother, Peter McCallum, Saskia Middeldopr, Zoe McQuilten, Matthew Neal, John Pasi, Roger Schutgens, Simon Stanworth, Alexis Turgeon, Alexandra Weissman, Neill Adhikari, Matthew Anstey, Emily Brant, Angelique de Man, Francois Lamonagne, Marie-Helene Masse, Andrew Udy, Donald Arnold, Phillipe Begin, Richard Charlewood, Michael Chasse, Mark Coyne, Jamie Cooper, James Daly, Iain Gosbell, Heli Harvala-Simmonds, Tom Hills, Sheila MacLennan, David Menon, John McDyer, Nicole Pridee, David Roberts, Manu Shankar-Hari, Helen Thomas, Alan Tinmouth, Darrell Triulzi, Tim Walsh, Erica Wood, Carolyn Calfee, Cecilia O’Kane, Murali Shyamsundar, Pratik Sinha, Taylor Thompson, Ian Young, Shailesh Bihari, Carol Hodgson, John Laffey, Danny McAuley, Neil Orford, Ary Neto, Michelle Detry, Mark Fitzgerald, Roger Lewis, Anna McGlothlin, Ashish Sanil, Christina Saunders, Lindsay Berry, Elizabeth Lorenzi, Eliza Miller, Vanessa Singh, Claire Zammit, Wilma van Bentum Puijk, Wietske Bouwman, Yara Mangindaan, Lorraine Parker, Svenja Peters, Ilse Rietveld, Kik Raymakers, Radhika Ganpat, Nicole Brillinger, Rene Markgraf, Kate Ainscough, Kathy Brickell, Aisha Anjum, Janis-Best Lane, Alvin Richards-Belle, Michelle Saull, Daisy Wiley, Julian Bion, Jason Connor, Simon Gates, Victoria Manax, Tom van der Poll, John Reynolds, Marloes van Beurden, Evelien Effelaar, Joost Schotsman, Craig Boyd, Cain Harland, Audrey Shearer, Jess Wren, Giles Clermont, William Garrard, Kyle Kalchthaler, Andrew King, Daniel Ricketts, Salim Malakoutis, Oscar Marroquin, Edvin Music, Kevin Quinn, Heidi Cate, Karen Pearson, Joanne Collins, Jane Hanson, Penny Williams, Shane Jackson, Adeeba Asghar, Sarah Dyas, Mihaela Sutu, Sheenagh Murphy, Dawn Williamson, Nhlanhla Mguni, Alison Potter, David Porter, Jayne Goodwin, Clare Rook, Susie Harrison, Hannah Williams, Hilary Campbell, Kaatje Lomme, James Williamson, Jonathan Sheffield, Willian van’t Hoff, Phobe McCracken, Meredith Young, Jasmin Board, Emma Mart, Cameron Knott, Julie Smith, Catherine Boschert, Julia Affleck, Mahesh Ramanan, Ramsy D’Souza, Kelsey Pateman, Arif Shakih, Winston Cheung, Mark Kol, Helen Wong, Asim Shah, Atul Wagh, Joanne Simpson, Graeme Duke, Peter Chan, Brittney Cartner, Stephanie Hunter, Russell Laver, Tapaswi Shrestha, Adrian Regli, Annamaria Pellicano, James McCullough, Mandy Tallott, Nikhil Kumar, Rakshit Panwar, Gail Brinkerhoff, Cassandra Koppen, Federica Cazzola, Matthew Brain, Sarah Mineall, Roy Fischer, Vishwanath Biradar, Natalie Soar, Hayden White, Kristen Estensen, Lynette Morrison, Joanne Smith, Melanie Cooper, Monash Health, Yahya Shehabi, Wisam Al-Bassam, Amanda Hulley, Christina Whitehead, Julie Lowrey, Rebecca Gresha, James Walsham, Jason Meyer, Meg Harward, Ellen Venz, Patricia Williams, Catherine Kurenda, Kirsy Smith, Margaret Smith, Rebecca Garcia, Deborah Barge, Deborah Byrne, Kathleen Byrne, Alana Driscoll, Louise Fortune, Pierre Janin, Elizabeth Yarad, Naomi Hammond, Frances Bass, Angela Ashelford, Sharon Waterson, Steve Wedd, Robert McNamara, Heidi Buhr, Jennifer Coles, Sacha Schweikert, Bradley Wibrow, Rashmi Rauniyar, Erina Myers, Ed Fysh, Ashlish Dawda, Bhaumik Mevavala, Ed Litton, Janet Ferrier, Priya Nair, Hergen Buscher, Claire Reynolds, John Santamaria, Leanne Barbazza, Jennifer Homes, Roger Smith, Lauren Murray, Jane Brailsford, Loretta Forbes, Teena Maguire, Vasanth Mariappa, Judith Smith, Scott Simpson, Matthew Maiden, Allsion Bone, Michelle Horton, Tania Salerno, Martin Sterba, Wenli Geng, Pieter Depuydt, Jan De Waele, Liesbet De Bus, Jan Fierens, Stephanie Bracke, Brenda Reeve, William Dechert, Michaël Chassé, François Martin Carrier, Dounia Boumahni, Fatna Benettaib, Ali Ghamraoui, David Bellemare, Ève Cloutier, Charles Francoeur, François Lamontagne, Frédérick D’Aragon, Elaine Carbonneau, Julie Leblond, Gloria Vazquez-Grande, Nicole Marten, Maggie Wilson, Martin Albert, Karim Serri, Alexandros Cavayas, Mathilde Duplaix, Virginie Williams, Bram Rochwerg, Tim Karachi, Simon Oczkowski, John Centofanti, Tina Millen, Erick Duan, Jennifer Tsang, Lisa Patterson, Shane English, Irene Watpool, Rebecca Porteous, Sydney Miezitis, Lauralyn McIntyre, Laurent Brochard, Karen Burns, Gyan Sandhu, Imrana Khalid, Alexandra Binnie, Elizabeth Powell, Alexandra McMillan, Tracy Luk, Noah Aref, Zdravko Andric, Sabina Cviljevic, Renata Đimoti, Marija Zapalac, Gordan Mirković, Bruno Baršić, Marko Kutleša, Viktor Kotarski, Ana Vujaklija Brajković, Jakša Babel, Helena Sever, Lidija Dragija, Ira Kušan, Suvi Vaara, Leena Pettilä, Jonna Heinonen, Anne Kuitunen, Sari Karlsson, Annukka Vahtera, Heikki Kiiski, Sanna Ristimäki, Amine Azaiz, Cyril Charron, Mathieu Godement, Guillaume Geri, Antoine Vieillard-Baron, Franck Pourcine, Mehran Monchi, David Luis, Romain Mercier, Anne Sagnier, Nathalie Verrier, Cecile Caplin, Shidasp Siami, Christelle Aparicio, Sarah Vautier, Asma Jeblaoui, Muriel Fartoukh, Laura Courtin, Vincent Labbe, Cécile Leparco, Grégoire Muller, Mai-Anh Nay, Toufik Kamel, Dalila Benzekri, Sophie Jacquier, Emmanuelle Mercier, Delphine Chartier, Charlotte Salmon, PierreFrançois Dequin, Francis Schneider, Guillaume Morel, Sylvie L’Hotellier, Julio Badie, Fernando Daniel Berdaguer, Sylvain Malfroy, Chaouki Mezher, Charlotte Bourgoin, Bruno Megarbane, Sebastian Voicu, Nicolas Deye, Isabelle Malissin, Laetitia Sutterlin, Christophe Guitton, Cédric Darreau, Mickaël Landais, Nicolas Chudeau, Alain Robert, Pierre Moine, Nicholas Heming, Virginie Maxime, Isabelle Bossard, Tiphaine Barbarin Nicholier, Gwenhael Colin, Vanessa Zinzoni, Natacham Maquigneau, André Finn, Gabriele Kreß, Uwe Hoff, Carl Friedrich Hinrichs, Jens Nee, Mathias Pletz, Stefan Hagel, Juliane Ankert, Steffi Kolanos, Frank Bloos, Sirak Petros, Bastian Pasieka, Kevin Kunz, Peter Appelt, Bianka Schütze, Stefan Kluge, Axel Nierhaus, Dominik Jarczak, Kevin Roedl, Dirk Weismann, Anna Frey, Vivantes Klinikum Neukölln, Lorenz Reill, Michael Distler, Astrid Maselli, János Bélteczki, István Magyar, Ágnes Fazekas, Sándor Kovács, Viktória Szőke, Gábor Szigligeti, János Leszkoven, Daniel Collins, Patrick Breen, Stephen Frohlich, Ruth Whelan, Bairbre McNicholas, Michael Scully, Siobhan Casey, Maeve Kernan, Peter Doran, Michael O’Dywer, Michelle Smyth, Leanne Hayes, Oscar Hoiting, Marco Peters, Els Rengers, Mirjam Evers, Anton Prinssen, Jeroen Bosch Ziekenhuis, Koen Simons, Wim Rozendaal, F Polderman, P de Jager, M Moviat, A Paling, A Salet, Emma Rademaker, Anna Linda Peters, E de Jonge, J Wigbers, E Guilder, M Butler, Keri-Anne Cowdrey, Lynette Newby, Yan Chen, Catherine Simmonds, Rachael McConnochie, Jay Ritzema Carter, Seton Henderson, Kym Van Der Heyden, Jan Mehrtens, Tony Williams, Alex Kazemi, Rima Song, Vivian Lai, Dinu Girijadevi, Robert Everitt, Robert Russell, Danielle Hacking, Ulrike Buehner, Erin Williams, Troy Browne, Kate Grimwade, Jennifer Goodson, Owen Keet, Owen Callender, Robert Martynoga, Kara Trask, Amelia Butler, Livia Schischka, Chelsea Young, Eden Lesona, Shaanti Olatunji, Yvonne Robertson, Nuno José, Teodoro Amaro dos Santos Catorze, Tiago Nuno Alfaro de Lima Pereira, Lucilia Maria Neves Pessoa, Ricardo Manuel Castro Ferreira, Joana Margarida Pereira Sousa Bastos, Simin Aysel Florescu, Delia Stanciu, Miahela Florentina Zaharia, Alma Gabriela Kosa, Daniel Codreanu, Yaseen Marabi, Eman Al Qasim, Mohamned Moneer Hagazy, Lolowa Al Swaidan, Hatim Arishi, Rosana Muñoz-Bermúdez, Judith Marin-Corral, Anna Salazar Degracia, Francisco Parrilla Gómez, Maria Isabel Mateo López, Jorge Rodriguez Fernandez, Sheila Cárcel Fernández, Rosario Carmona Flores, Rafael León López, Carmen de la Fuente Martos, Angela Allan, Petra Polgarova, Neda Farahi, Stephen McWilliam, Daniel Hawcutt, Laura Rad, Laura O’Malley, Jennifer Whitbread, Olivia Kelsall, Laura Wild, Jessica Thrush, Hannah Wood, Karen Austin, Adrian Donnelly, Martin Kelly, Sinéad O’Kane, Declan McClintock, Majella Warnock, Paul Johnston, Linda Jude Gallagher, Clare Mc Goldrick, Moyra Mc Master, Anna Strzelecka, Rajeev Jha, Michael Kalogirou, Christine Ellis, Vinodh Krishnamurthy, Vashish Deelchand, Jon Silversides, Peter McGuigan, Kathryn Ward, Aisling O’Neill, Stephanie Finn, Barbara Phillips, Dee Mullan, Laura Oritz-Ruiz de Gordoa, Matthew Thomas, Katie Sweet, Lisa Grimmer, Rebekah Johnson, Jez Pinnell, Matt Robinson, Lisa Gledhill, Tracy Wood, Matt Morgan, Jade Cole, Helen Hill, Michelle Davies, David Antcliffe, Maie Templeton, Roceld Rojo, Phoebe Coghlan, Joanna Smee, Euan Mackay, Jon Cort, Amanda Whileman, Thomas Spencer, Nick Spittle, Vidya Kasipandian, Amit Patel, Suzanne Allibone, Roman Mary Genetu, Mohamed Ramali, Alison Ghosh, Peter Bamford, Emily London, Kathryn Cawley, Maria Faulkner, Helen Jeffrey, Tim Smith, Chris Brewer, Jane Gregory, James Limb, Amanda Cowton, Julie O’Brien, Nikitas Nikitas, Colin Wells, Liana Lankester, Mark Pulletz, Patricia Williams, Jenny Birch, Sophie Wiseman, Sarah Horton, Ana Alegria, Salah Turki, Tarek Elsefi, Nikki Crisp, Louise Allen, Iain McCullagh, Philip Robinson, Carole Hays, Maite Babio-Galan, Hannah Stevenson, Divya Khare, Meredith Pinder, Selvin Selvamoni, Amitha Gopinath, Richard Pugh, Daniel Menzies, Callum Mackay, Elizabeth Allan, Gwyneth Davies, Kathryn Puxty, Claire McCue, Susanne Cathcart, Naomi Hickey, Jane Ireland, Hakeem Yusuff, Graziella Isgro, Chris Brightling, Michelle Bourne, Michelle Craner, Malcolm Watters, Rachel Prout, Louisa Davies, Suzannah Pegler, Lynsey Kyeremeh, Gill Arbane, Karen Wilson, Linda Gomm, Federica Francia, Stephen Brett, Sonia Sousa Arias, Rebecca Elin Hall, Joanna Budd, Charlotte Small, Janine Birch, Emma Collins, Jeremy Henning, Stephen Bonner, Keith Hugill, Emanuel Cirstea, Dean Wilkinson, Michal Karlikowski, Helen Sutherland, Elva Wilhelmsen, Jane Woods, Julie North, Dhinesh Sundaran, Laszlo Hollos, Susan Coburn, Joanne Walsh, Margaret Turns, Phil Hopkins, John Smith, Harriet Noble, Maria Theresa Depante, Emma Clarey, Shondipon Laha, Mark Verlander, Alexandra Williams, Abby Huckle, Andrew Hall, Jill Cooke, Caroline Gardiner-Hill, Carolyn Maloney, Hafiz Qureshi, Neil Flint, Sarah Nicholson, Sara Southin, Andrew Nicholson, Barbara Borgatta, Ian Turner-Bone, Amie Reddy, Laura Wilding, Loku Chamara Warnapura, Ronan Agno Sathianathan, David Golden, Ciaran Hart, Jo Jones, Jonathan Bannard-Smith, Joanne Henry, Katie Birchall, Fiona Pomeroy, Rachael Quayle, Arystarch Makowski, Beata Misztal, Iram Ahmed, Thyra KyereDiabour, Kevin Naiker, Richard Stewart, Esther Mwaura, Louise Mew, Lynn Wren, Felicity Willams, Richard Innes, Patricia Doble, Joanne Hutter, Charmaine Shovelton, Benjamin Plumb, Tamas Szakmany, Vincent Hamlyn, Nancy Hawkins, Sarah Lewis, Amanda Dell, Shameer Gopal, Saibal Ganguly, Andrew Smallwood, Nichola Harris, Stella Metherell, Juan Martin Lazaro, Tabitha Newman, Simon Fletcher, Jurgens Nortje, Deirdre Fottrell-Gould, Georgina Randell, Mohsin Zaman, Einas Elmahi, Andrea Jones, Kathryn Hall, Gary Mills, Kim Ryalls, Helen Bowler, Jas Sall, Richard Bourne, Zoe Borrill, Tracey Duncan, Thomas Lamb, Joanne Shaw, Claire Fox, Jeronimo Moreno Cuesta, Kugan Xavier, Dharam Purohit, Munzir Elhassan, Dhanalakshmi Bakthavatsalam, Matthew Rowland, Paula Hutton, Archana Bashyal, Neil Davidson, Clare Hird, Manish Chhablani, Gunjan Phalod, Amy Kirkby, Simon Archer, Kimberley Netherton, Henrik Reschreiter, Julie Camsooksai, Sarah Patch, Sarah Jenkins, David Pogson, Steve Rose, Zoe Daly, Lutece Brimfield, Helen Claridge, Dhruv Parekh, Colin Bergin, Michelle Bates, Joanne Dasgin, Christopher McGhee, Malcolm Sim, Sophie Kennedy Hay, Steven Henderson, Mandeep-Kaur Phull, Abbas Zaidi, Tatiana Pogreban, Lace Paulyn Rosaroso, Daniel Harvey, Benjamin Lowe, Megan Meredith, Lucy Ryan, Anil Hormis, Rachel Walker, Dawn Collier, Sarah Kimpton, Susan Oakley, Kevin Rooney, Natalie Rodden, Emma Hughes, Nicola Thomson, Deborah McGlynn, Andrew Walden, Nicola Jacques, Holly Coles, Emma Tilney, Emma Vowell, Martin Schuster-Bruce, Sally Pitts, Rebecca Miln, Laura Purandare, Luke Vamplew, Michael Spivey, Sarah Bean, Karen Burt, Lorraine Moore, Christopher Day, Charly Gibson, Elizabeth Gordon, Letizia Zitter, Samantha Keenan, Evelyn Baker, Shiney Cherian, Sean Cutler, Anna Roynon-Reed, Kate Harrington, Ajay Raithatha, Kris Bauchmuller, Norfaizan Ahmad, Irina Grecu, Dawn Trodd, Jane Martin, Caroline Wrey Brown, Ana-Marie Arias, Thomas Craven, David Hope, Jo Singleton, Sarah Clark, Nicola Rae, Ingeborg Welters, David Oliver Hamilton, Karen Williams, Victoria Waugh, David Shaw, Zudin Puthucheary, Timothy Martin, Filipa Santos, Ruzena Uddin, Alastair Somerville, Kate Colette Tatham, Shaman Jhanji, Ethel Black, Arnold Dela Rosa, Ryan Howle, Redmond Tully, Andrew Drummond, Joy Dearden, Jennifer Philbin, Sheila Munt, Alain Vuylsteke, Charles Chan, Saji Victor, Ramprasad Matsa, Minerva Gellamucho, Ben Creagh-Brown, Joe Tooley, Laura Montague, Fiona De Beaux, Laetitia Bullman, Ian Kersiake, Carrie Demetriou, Sarah Mitchard, Lidia Ramos, Katie White, Phil Donnison, Maggie Johns, Ruth Casey, Lehentha Mattocks, Sarah Salisbury, Paul Dark, Andrew Claxton, Danielle McLachlan, Kathryn Slevin, Stephanie Lee, Jonathan Hulme, Sibet Joseph, Fiona Kinney, Ho Jan Senya, Aneta Oborska, Abdul Kayani, Bernard Hadebe, Rajalakshmi Orath Prabakaran, Lesley Nichols, Matt Thomas, Ruth Worner, Beverley Faulkner, Emma Gendall, Kati Hayes, Colin Hamilton-Davies, Carmen Chan, Celina Mfuko, Hakam Abbass, Vineela Mandadapu, Susannah Leaver, Daniel Forton, Kamal Patel, Elankumaran Paramasivam, Matthew Powell, Richard Gould, Elizabeth Wilby, Clare Howcroft, Dorota Banach, Ziortza Fernández de Pinedo Artaraz, Leilani Cabreros, Ian White, Maria Croft, Nicky Holland, Rita Pereira, Ahmed Zaki, David Johnson, Matthew Jackson, Hywel Garrard, Vera Juhaz, Alistair Roy, Anthony Rostron, Lindsey Woods, Sarah Cornell, Suresh Pillai, Rachel Harford, Tabitha Rees, Helen Ivatt, Ajay Sundara Raman, Miriam Davey, Kelvin Lee, Russell Barber, Manish Chablani, Farooq Brohi, Vijay Jagannathan, Michele Clark, Sarah Purvis, Bill Wetherill, Ahilanandan Dushianthan, Rebecca Cusack, Kim de Courcy-Golder, Simon Smith, Susan Jackson, Ben Attwood, Penny Parsons, Valerie Page, Xiao Bei Zhao, Deepali Oza, Jonathan Rhodes, Tom Anderson, Sheila Morris, Charlotte Xia Le Tai, Amy Thomas, Alexandra Keen, Stephen Digby, Nicholas Cowley, Laura Wild, David Southern, Harsha Reddy, Andy Campbell, Claire Watkins, Sara Smuts, Omar Touma, Nicky Barnes, Peter Alexander, Tim Felton, Susan Ferguson, Katharine Sellers, Joanne Bradley-Potts, David Yates, Isobel Birkinshaw, Kay Kell, Nicola Marshall, Lisa Carr-Knott, Charlotte Summers, and Mégarbane, Bruno

Subjects
[SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, General Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Writing Committee for the REMAP-CAP Investigators, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, General & Internal Medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 11 Medical and Health Sciences
Abstract

Importance Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Published
2020

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