Prognostic Value of Lung Injury Biomarkers in Patients Hospitalized With COVID-19 Without Respiratory Failure at Admission

Objectives: – The COVID-19 pandemic highlighted an urgent need to more efficiently identify patients at highest risk for developing respiratory failure. We investigated whether plasma levels of lung injury biomarkers are associated with progression to respiratory failure among adults hospitalized with COVID-19 pneumonia without respiratory failure at admission. Design: – This was a nested case-control study of COVID-19 patients enrolled in the Accelerating COVID-19 Therapeutic Interventions and Vaccines-3 (ACTIV-3)/Therapeutics for Inpatients with COVID-19 (TICO) platform trial who were on less than 20 L/min supplemental oxygen at enrollment. We compared baseline measurements of lung injury biomarkers between participants who progressed to respiratory failure or died by study day 10 (cases) and matched controls who did not progress to respiratory failure or death. Cases and controls were matched 1:1 on age, baseline oxygen requirement, immunomodulator use, and study arm. Setting: – Hospitals enrolling in the ACTIV-3/TICO trials. Patients: – Four hundred five cases and 405 matched controls. Interventions: – None. Measurements and Main Results: – Baseline levels of plasma interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor receptor, angiopoietin-2, soluble receptor for advanced glycation end-products (sRAGE), C-reactive protein (CRP), and surfactant protein D (SPD) were compared between cases and controls using matched logistic regression. Forward variable selection was used to identify biomarkers that were independently associated with progression to respiratory failure or death in a multivariate model. All lung injury biomarkers with the exception of SPD were significantly associated with progression to respiratory failure or death, with sRAGE demonstrating the highest odds ratio (OR) for each doubling of biomarker level (OR, 1.85; 95% CI, 1.61–2.12). In multivariate regression analysis, sRAGE, IL-6, and CRP were independently associated with progression, with sRAGE as the biomarker with the strongest association. Conclusions: – Baseline levels of plasma lung injury biomarkers are significantly associated with progression to respiratory failure or death among hospitalized COVID-19 patients without respiratory failure at admission. These findings support the potential utility of measuring lung injury biomarkers in patients hospitalized without respiratory failure and should be tested in more heterogeneous patient groups including non-COVID-19 cohorts.