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Biomarkers of innate immunity, coagulation, endothelial injury, and fibroproliferation have been studied as predictors. We aimed to examine whether trends in plasma biomarkers predict ICU mortality and to explore underlying biological processes through pathway analysis. Additionally, we explored whether HDS changes biomarker trajectories in COVID-19 ARDS. In this observational study, we included patients with COVID-19 ARDS admitted to the ICU of an academic hospital in Rotterdam between February 2020 and February 2022. In repeated plasma samples, 64 biomarkers were measured. Joint modeling assessed the association between biomarker changes and ICU mortality, adjusting for age, sex, BMI, and HDS. Protein\u2013protein interaction and gene ontology enrichment analyses were performed using STRING, Cytoscape, and DAVID EASE. Biomarker trajectories were compared between HDS-treated and non-treated patients, adjusting for timing, SOFA score, and tocilizumab. One hundred and sixty-two patients were included and 43 died during ICU stay. A doubling in the values of 26 biomarkers over the next day was predictive of ICU mortality (HRs 0.16\u20138.56; q\u2009&lt;\u20090.05). Gene ontology enrichment analysis identified 19 overrepresented biological processes (FDR\u2009\u2264\u20090.05), with highest fold enrichment for macrophage chemotaxis, negative regulation of bone resorption, and leukocyte cell\u2013cell adhesion. Forty-eight patients received HDS at a median of 6 ICU days. HDS significantly changed the trajectories of four mortality-associated biomarkers: Albumin and lactoferrin decreased, while CRP and VEGF increased. In COVID-19 ARDS, repeated biomarker measurements demonstrate a systemic inflammatory state associated with mortality. HDS changed trends of several biomarkers, but did not reduce those associated with fatal outcomes.\n                    <jats:italic>Trial registration<\/jats:italic>\n                    : ClinicalTrials.gov NCT05403359;\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT05403359\" ext-link-type=\"uri\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05403359<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1007\/s10238-025-01904-8","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T06:54:49Z","timestamp":1762844089000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Increasing inflammatory biomarkers are associated with mortality in critically ill COVID-19 patients despite anti-inflammatory treatment"],"prefix":"10.1007","volume":"25","clinical-trial-number":[{"clinical-trial-number":"nct05403359","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5664-5393","authenticated-orcid":false,"given":"Katrijn","family":"Daenen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris","family":"Rizopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virgil A. 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