IMPORTANCE SARS-CoV-2 viral entry may disrupt angiotensin II (AII) homeostasis, contributing to COVID-19 induced lung injury. AII type 1 receptor blockade mitigates lung injury in preclinical models, although data in humans with COVID-19 remain mixed. OBJECTIVE To test the efficacy of losartan to reduce lung injury in hospitalized patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTS This blinded, placebo-controlled randomized clinical trial was conducted in 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already using a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible for participation. Data were analyzed from April 19 to August 24, 2021. INTERVENTIONS Losartan 50 mg orally twice daily vs equivalent placebo for 10 days or until hospital discharge. MAIN OUTCOMES AND MEASURES The primary outcome was the imputed arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 :FiO 2 ) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity; days without supplemental O 2 , ventilation, or vasopressors; and mortality. Losartan pharmacokinetics and RAAS components (AII, angiotensin-[1-7] and angiotensinconverting enzymes 1 and 2)] were measured in a subgroup of participants. RESULTS A total of 205 participants (mean [SD] age, 55.2 [15.7] years; 123 [60.0%] men) were randomized, with 101 participants assigned to losartan and 104 participants assigned to placebo.Compared with placebo, losartan did not significantly affect PaO 2 :FiO 2 ratio at 7 days (difference, −24.8 [95%, −55.6 to 6.1]; P = .12). Compared with placebo, losartan did not improve any secondary clinical outcomes and led to fewer vasopressor-free days than placebo (median [IQR], vasopressor-free days vs 8.7 [8.2-9.3] vasopressor-free days). CONCLUSIONS AND RELEVANCEThis randomized clinical trial found that initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury did not improve PaO 2 :FiO 2 ratio at 7 days. These data may have implications for ongoing clinical trials.

Objective Approximately one-third of sepsis patients experience poor outcomes including chronic critical illness (CCI, intensive care unit (ICU) stay > 14 days) or early death (in-hospital death within 14 days). We sought to characterize lipoprotein predictive ability for poor outcomes and contribution to sepsis heterogeneity. Design Prospective cohort study with independent replication cohort. Setting Emergency department and surgical ICU at two hospitals. Patients Sepsis patients presenting within 24 h. Methods Measures included cholesterol levels (total cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C]), triglycerides, paraoxonase-1 (PON-1), and apolipoprotein A-I (Apo A-I) in the first 24 h. Inflammatory and endothelial markers, and sequential organ failure assessment (SOFA) scores were also measured. LASSO selection assessed predictive ability for outcomes. Unsupervised clustering was used to investigate the contribution of lipid variation to sepsis heterogeneity. Measurements and main results 172 patients were enrolled. Most (~ 67%, 114/172) rapidly recovered, while ~ 23% (41/172) developed CCI, and ~ 10% (17/172) had early death. ApoA-I, LDL-C, mechanical ventilation, vasopressor use, and Charlson Comorbidity Score were significant predictors of CCI/early death in LASSO models. Unsupervised clustering yielded two discernible phenotypes. The Hypolipoprotein phenotype was characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1), higher SOFA scores, and worse clinical outcomes (45% rapid recovery, 40% CCI, 16% early death; 28-day mortality, 21%). The Normolipoprotein cluster patients had higher cholesterol levels, less endothelial dysfunction, lower SOFA scores and better outcomes (79% rapid recovery, 15% CCI, 6% early death; 28-day mortality, 15%). Phenotypes were validated in an independent replication cohort (N = 86) with greater sepsis severity, which similarly demonstrated lower HDL-C, ApoA-I, and higher ICAM-1 in the Hypolipoprotein cluster and worse outcomes (46% rapid recovery, 23% CCI, 31% early death; 28-day mortality, 42%). Normolipoprotein patients in the replication cohort had better outcomes (55% rapid recovery, 32% CCI, 13% early death; 28-day mortality, 28%) Top features for cluster discrimination were HDL-C, ApoA-I, total SOFA score, total cholesterol level, and ICAM-1. Conclusions Lipoproteins predicted poor sepsis outcomes. A Hypolipoprotein sepsis phenotype was identified and characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1) and organ failure, and worse clinical outcomes.

IntroductionSepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis.Methods and analysisThis is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours − enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function.Ethics and disseminationInvestigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial.Trial registration numberNCT03405870.