Trial reportCritical care (London, England)2024
Novel subtypes of severe COVID-19 respiratory failure based on biological heterogeneity: a secondary analysis of a randomized controlled trial.
Trial report in Critical care (London, England), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 13 citations in OpenAlex.
- Efficacy and safety of imatinib in patients with COVID-19: a systematic review and meta-analysis.Wiener klinische Wochenschrift · 2025Pooled it
- Treatment with Allogeneic Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome: A Double-Blind, Placebo-controlled, Multicenter Phase 2b Clinical Trial (STAT).American journal of respiratory and critical care medicine · 2026Trial
- Research progress on biomarkers of blast lung injury: Transition from traditional indicators to novel molecular markers.iScience · 2026Review
- Unbiased characterization of COVID-19 endotypes leads to prognostication of high-risk individuals using routine blood tests.Communications medicine · 2026Article
- Current Insights into Clinical, Molecular, and Therapeutic Approaches to Acute Respiratory Distress Syndrome.Medical sciences (Basel, Switzerland) · 2026Review
- Endothelial-Epithelial Crosstalk Drives Alveolar-Capillary Barrier Dysfunction in ARDS.Journal of inflammation research · 2026Review
- Biomarkers trajectories in critically ill patients with COVID-19 acute respiratory distress syndrome: insights from latent class growth analysis.BMC pulmonary medicine · 2025Article
- TREM-1 Interacts with Rotavirus Proteins and Drives Inflammatory Responses: A Combined Experimental and Computational Approach.Pathogens (Basel, Switzerland) · 2025Article
- MICBG406A polymorphism reduces risk of mechanical ventilation and death during viral acute lung injury.JCI insight · 2025Article
- Plasma Proteomic Profiling Yields a High-Performance Biomarker Panel for Predicting a Poor Prognosis in Patients with COVID-19.Journal of proteome research · 2025Article
- Phosphatidylethanol measures in patients with severe COVID-19-associated respiratory failure identify a subset with alcohol misuse.Alcohol, clinical & experimental research · 2025Article
- Pulmonary redox imbalance drives early fibroproliferative response in moderate/severe coronavirus disease-19 acute respiratory distress syndrome and impacts long-term lung abnormalities.Annals of intensive care · 2024Article
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundDespite evidence associating inflammatory biomarkers with worse outcomes in hospitalized adults with COVID-19, trials of immunomodulatory therapies have met with mixed results, likely due in part to biological heterogeneity of participants. Latent class analysis (LCA) of clinical and protein biomarker data has identified two subtypes of non-COVID acute respiratory distress syndrome (ARDS) with different clinical outcomes and treatment responses. We studied biological heterogeneity and clinical outcomes in a multi-institutional platform randomized controlled trial of adults with severe COVID-19 hypoxemic respiratory failure (I-SPY COVID).
methodsClinical and plasma protein biomarker data were analyzed from 400 trial participants enrolled from September 2020 until October 2021 with severe COVID-19 requiring ≥ 6 L/min supplemental oxygen. Seventeen hypothesis-directed protein biomarkers were measured at enrollment using multiplex Luminex panels or single analyte enzyme linked immunoassay methods (ELISA). Biomarkers and clinical variables were used to test for latent subtypes and longitudinal biomarker changes by subtype were explored. A validated parsimonious model using interleukin-8, bicarbonate, and protein C was used for comparison with non-COVID hyper- and hypo-inflammatory ARDS subtypes.
resultsAverage participant age was 60 ± 14 years; 67% were male, and 28-day mortality was 25%. At trial enrollment, 85% of participants required high flow oxygen or non-invasive ventilation, and 97% were receiving dexamethasone. Several biomarkers of inflammation (IL-6, IL-8, IL-10, sTNFR-1, TREM-1), epithelial injury (sRAGE), and endothelial injury (Ang-1, thrombomodulin) were associated with 28- and 60-day mortality. Two latent subtypes were identified. Subtype 2 (27% of participants) was characterized by persistent derangements in biomarkers of inflammation, endothelial and epithelial injury, and disordered coagulation and had twice the mortality rate compared with Subtype 1. Only one person was classified as hyper-inflammatory using the previously validated non-COVID ARDS model.
conclusionsWe discovered evidence of two novel biological subtypes of severe COVID-19 with significantly different clinical outcomes. These subtypes differed from previously established hyper- and hypo-inflammatory non-COVID subtypes of ARDS. Biological heterogeneity may explain inconsistent findings from trials of hospitalized patients with COVID-19 and guide treatment approaches.
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