{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:43:55Z","timestamp":1786977835113,"version":"build-2736575974"},"reference-count":59,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["0430102110010"],"award-info":[{"award-number":["0430102110010"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Treatment guidelines for acute respiratory distress syndrome (ARDS) recommend the use of high\u2010dose corticosteroids based on their anti\u2010inflammatory effects, yet the efficacy of this therapeutic strategy in patients with COVID\u201019 related ARDS is inconclusive. To more thoroughly understand the mechanism of action for high\u2010dose corticosteroids in patients with COVID\u201019\u2010related ARDS, we hypothesized that the reduction of inflammatory markers induced by high\u2010dose corticosteroids would reduce mortality (i.e., inflammation as a mediator).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design and Methods<\/jats:title>\n                    <jats:p>\n                      In this retrospective cohort study, we included patients with COVID\u201019\u2010related ARDS admitted to the intensive care unit (ICU) of an academic hospital in Rotterdam, the Netherlands between March 2020 and June 2022. High\u2010dose corticosteroids were defined as &gt;\u20096\u2009mg of dexamethasone\/day or equivalent. Biomarkers included C\u2010reactive protein (CRP),\n                      <jats:sc>d<\/jats:sc>\n                      \u2010dimer, ferritin, leukocyte count, interleukin\u20106 (IL\u20106), lactate dehydrogenase, and neutrophil\u2010to\u2010lymphocyte ratio (NLR). Using a causal mediation framework, we estimated the average mediation effect (AME) and % mediation for each biomarker, allowing to quantify the degree to which continuous levels of inflammatory markers mediate the association between receiving high\u2010dose corticosteroids and mortality. The models used in this framework accounted for time\u2010varying treatment\/mediation with inverse probability of treatment weights, determined from the covariates PaO\n                      <jats:sub>2<\/jats:sub>\n                      \/FiO\n                      <jats:sub>2<\/jats:sub>\n                      ratio, sex at birth, age, NLR, and ICU length of stay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of the 327 patients included, 122 (37.3%) received high\u2010dose corticosteroids. The risk of death was higher in patients who did vs. did not receive high\u2010dose corticosteroids [incidence rate\u2009=\u20090.54, 95% confidence interval (CI)\u2009=\u20090.42\u20130.71 and 0.21, 95% CI\u2009=\u20090.15\u20130.29\/person\u2010month, respectively;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001]. This effect remained in most analyses accounting for time\u2010varying treatment\/mediation. The association between high\u2010dose corticosteroids and mortality was reduced (i.e., mediated) with lower levels of CRP (AME\u2009=\u2009\u22120.006, 95% CI\u2009=\u2009\u22120.011, \u22120.002; %\u2010mediation\u2009=\u2009\u221282.0%),\n                      <jats:sc>d<\/jats:sc>\n                      \u2010dimer (AME\u2009=\u2009\u22120.002, 95% CI\u2009=\u2009\u22120.005, \u22120.001; %\u2010mediation\u2009=\u2009\u221233.1%), and IL\u20106 (AME\u2009=\u2009\u22120.002, 95% CI\u2009=\u2009\u22120.004, \u22120.001; %\u2010mediation\u2009=\u2009\u221225.5%). There was no evidence of mediation for other biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      CRP,\n                      <jats:sc>d<\/jats:sc>\n                      \u2010dimer, and IL\u20106 mediated the association between high\u2010dose corticosteroids and mortality. When inflammation was reduced, the deleterious effect of high\u2010dose corticosteroids was eliminated.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/iid3.70427","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T06:01:11Z","timestamp":1777269671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inflammatory Biomarkers as Mediators of the Effect Between High\u2010Dose Corticosteroid Therapy and Mortality in COVID\u201019\u2010Related ARDS: A Causal Mediation Analysis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5664-5393","authenticated-orcid":false,"given":"Katrijn","family":"Daenen","sequence":"first","affiliation":[{"name":"Department of Intensive Care Erasmus University Medical Center Rotterdam the Netherlands"},{"name":"Department of Viroscience Erasmus University Medical Center Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9512-8928","authenticated-orcid":false,"given":"Anders","family":"Boyd","sequence":"additional","affiliation":[{"name":"Stichting HIV Monitoring Amsterdam the Netherlands"},{"name":"Infectious Diseases, Amsterdam University Medical Centers, Amsterdam Medical Center, University of Amsterdam Amsterdam the Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity Infectious Diseases Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virgil A. S. H.","family":"Dalm","sequence":"additional","affiliation":[{"name":"Department of Immunology Erasmus University Medical Center Rotterdam Rotterdam the Netherlands"},{"name":"Department of Internal Medicine, Division of Allergy &amp; Clinical Immunology Erasmus University Medical Center Rotterdam Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilske A.","family":"Huijben","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Erasmus University Medical Center Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0774-1496","authenticated-orcid":false,"given":"Sara C. M.","family":"Stoof","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Erasmus University Medical Center Rotterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lieuwe D. 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