ABSTRACT
Background SARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed. Methods Multicenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1–7) (Ang-(1–7)), ACE, ACE2] were measured in a subgroup of participants. Findings From April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO 2 /FiO 2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. Interpretation Initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO 2 / FiO 2 ratio at 7 days. These data may have implications for ongoing clinical trials. Trial Registration Losartan for Patients With COVID-19 Requiring Hospitalization ( NCT04312009 ), https://clinicaltrials.gov/ct2/show/NCT04312009
Subject(s)
Lung Injury , Pneumonia, Viral , Acute Lung Injury , COVID-19ABSTRACT
Importance: An artificial intelligence (AI)-based model to predict COVID-19 likelihood from chest x-ray (CXR) findings can serve as an important adjunct to accelerate immediate clinical decision making and improve clinical decision making. Despite significant efforts, many limitations and biases exist in previously developed AI diagnostic models for COVID-19. Utilizing a large set of local and international CXR images, we developed an AI model with high performance on temporal and external validation. Conclusions and Relevance: AI-based diagnostic tools may serve as an adjunct, but not replacement, for clinical decision support of COVID-19 diagnosis, which largely hinges on exposure history, signs, and symptoms. While AI-based tools have not yet reached full diagnostic potential in COVID-19, they may still offer valuable information to clinicians taken into consideration along with clinical signs and symptoms.
Subject(s)
COVID-19ABSTRACT
Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex. Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNF-alpha inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983). Conclusions Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in Covid-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.