The Coronavirus infectious disease 2019 (COVID-19) pandemic has disproportionally impacted historically disadvantaged populations, with infection and mortality rates among Black and Latinx Americans far exceeding the proportion of the population that these groups represent. We, as researchers, educators, and critical care and pulmonary providers on the frontline of care for all individuals, believe it is important to reflect on the root causes for these striking disparities. Moreover, recent incidences of structural violence highlight the need to recognize the critical role of racism in causing and perpetuating health disparities. Without attention to the underlying causes, it is difficult to enact equitable action. Applying the World Health Organization Conceptual Framework for Action, we examine the social and structural determinants of health (SDOH) that contributed to disparities in the care and outcomes of patients with COVID-19. Applying this lens, we identify three potential critical targets for action: 1) increased exposure due to occupation and/or living circumstances that make social distancing and self-isolation more difficult, 2) limited access to accurate, up to date information regarding the health risks of COVID-19, and 3) limited and differential access to healthcare services, including coronavirus testing and care. In this perspective, we focus on action steps that we, as members of the American Thoracic Society, should take to actively change the status quo and influence policies that address root causes. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A₂ (sPLA₂) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA₂ group IIA (sPLA₂-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA₂-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA₂-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator–based (LASSO-based) regression analysis additionally identified sPLA₂-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA₂-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index–based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA₂-IIA as a therapeutic target to reduce COVID-19 mortality.

Background: Well-designed clinical research needs to obtain information that is applicable to the general population. However, most current studies fail to include substantial cohorts of racial/ethnic minority populations. Such underrepresentation may lead to delayed diagnosis or misdiagnosis of disease, wide application of approved interventions without appropriate knowledge of their usefulness in certain populations, and development of recommendations that are not broadly applicable. Goals: To develop best practices for recruitment and retention of racial/ethnic minorities for clinical research in pulmonary, critical care, and sleep medicine. Methods: The American Thoracic Society convened a workshop in May of 2019. This included an international interprofessional group from academia, industry, the NIH, and the U.S. Food and Drug Administration, with expertise ranging from clinical and biomedical research to community-based participatory research methods and patient advocacy. Workshop participants addressed historical and current mistrust of scientific research, systemic bias, and social and structural barriers to minority participation in clinical research. A literature search of PubMed and Google Scholar was performed to support conclusions. The search was not a systematic review of the literature. Results: Barriers at the individual, interpersonal, institutional, and federal/policy levels were identified as limiting to minority participation in clinical research. Through the use of a multilevel framework, workshop participants proposed evidence-based solutions to the identified barriers. Conclusions: To date, minority participation in clinical research is not representative of the U.S. and global populations. This American Thoracic Society research statement identifies potential evidence-based solutions by applying a multilevel framework that is anchored in community engagement methods and patient advocacy.

Rationale: Racial disparities in health and healthcare in the United States are well documented and are increasingly recognized in acute critical illnesses such as sepsis and acute respiratory failure. Objectives: Using a large, representative, U.S. nationwide database, we examined the hypothesis that black and Hispanic patients with severe acute respiratory failure have higher mortality rates when compared with non-Hispanic whites. Methods: This retrospective analysis used discharge data from the Agency for Healthcare Research and Quality, Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, for the years 2008–2012. We identified hospitalizations with acute respiratory failure using a combination of International Classification of Diseases, Ninth Revision, Clinical Modification, codes. A logistic regression model was fitted to compare in-hospital mortality rates by race. Measurements and Main Results: After adjusting for sex, age, race, disease severity, type of hospital, and median household income for patient ZIP code, blacks had a greater odds ratio of in-hospital death when compared with non-Hispanic whites (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.11–1.14; P < 0.001), and Hispanics also had a greater odds ratio of in-hospital death when compared with non-Hispanic whites (OR, 1.17; 95% CI, 1.15–1.19; P < 0.001), and so did Asian and Pacific Islanders (OR, 1.15; 95% CI, 1.12–1.18; P < 0.001) and Native Americans (OR, 1.08; 95% CI, 1.00–1.15; P < 0.001) when compared with non-Hispanic whites (OR, 1.0). Conclusions: Blacks, Hispanics, and other racial minorities in the United States were observed to exhibit significantly higher in-hospital sepsis-related respiratory failure associated mortality when compared with non-Hispanic whites.

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.Registration: NCT05172024.

Background: There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome. Methods: This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality. Results: From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p = 0.04). Conclusions: An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.