Study protocol for a national cohort of adults focused on respiratory health: the American Lung Association Lung Health Cohort (ALA-LHC) Study.

INTRODUCTION: The current framework for investigating respiratory diseases is based on defining lung health as the absence of lung disease. In order to develop a comprehensive approach to prevent the development of lung disease, there is a need to evaluate the full spectrum of lung health spanning from ideal to impaired lung health. The American Lung Association (ALA) Lung Health Cohort is a new, population-based, cohort study focused primarily on characterising lung health in members of the millennial generation without diagnosed severe respiratory disease. Participants will be enrolled for the baseline study visit starting in 2021, and funding will be sought to support future study exams as part of a longitudinal cohort study. This study will be crucial for developing a novel paradigm of lung health throughout the adult life course. METHODS AND ANALYSIS: This study will leverage the existing infrastructure of the ALA Airways Clinical Research Centers network to enrol 4000 participants between ages 25 and 35 years old at 39 sites across the USA between April 2021 and December 2024. Study procedures will include physical assessment, spirometry, chest CT scan, accelerometry and collection of nasal epithelial lining fluid, nasal epithelial cells, blood and urine. Participants will complete questionnaires about their sociodemographic characteristics, home address histories and exposures, work history and exposure, medical histories, lung health and health behaviours and activity. ETHICS AND DISSEMINATION: The study was approved by the Johns Hopkins Medicine Institutional Review Board. Findings will be disseminated to the scientific community through peer-reviewed journals and at professional conferences. The lay public will receive scientific findings directly through the ALA infrastructure including the official public website. Deidentified datasets will be deposited to BioLINCC, and deidentified biospecimens may be made available to qualified investigators along with a limited-use datasets.

Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure.

OBJECTIVES: Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019-associated respiratory failure. DESIGN: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of Pao2 over the corresponding Fio2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability-weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up. SETTING: ICUs at 68 U.S. sites. PATIENTS: Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of Pao2 over the corresponding Fio2 less than or equal to 200 mm Hg. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73-0.97). CONCLUSIONS: In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.

Hyperglycemia Is Associated With Increased Mortality in Critically Ill Patients With COVID-19

Objective: To explore the relationship between diabetes mellitus (DM), hyperglycemia, and adverse outcomes in critically ill patients with coronavirus disease 2019 (COVID-19).

Hyperglycemia is Associated With Increased Mortality in Critically Ill Patients With COVID-19.

OBJECTIVE: To explore the relationship between hyperglycemia in the presence and absence of diabetes mellitus (DM) and adverse outcomes in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: The study included 133 patients with COVID-19 admitted to an intensive care unit (ICU) at an urban academic quaternary-care center between March 10 and April 8, 2020. Patients were categorized based on the presence or absence of DM and early-onset hyperglycemia (EHG), defined as a blood glucose >180 mg/dL during the first 2 days after ICU admission. The primary outcome was 14-day all-cause in-hospital mortality; also examined were 60-day all-cause in-hospital mortality and the levels of C-reactive protein, interleukin 6, procalcitonin, and lactate. RESULTS: Compared to non-DM patients without EHG, non-DM patients with EHG exhibited higher adjusted hazard ratios (HRs) for mortality at 14 days (HR 7.51, CI 1.70-33.24) and 60 days (HR 6.97, CI 1.86-26.13). Non-DM patients with EHG also featured higher levels of median C-reactive protein (306.3 mg/L, P = .036), procalcitonin (1.26 ng/mL, P = .028), and lactate (2.2 mmol/L, P = .023). CONCLUSION: Among critically ill COVID-19 patients, those without DM with EHG were at greatest risk of 14-day and 60-day in-hospital mortality. Our study was limited by its retrospective design and relatively small cohort. However, our results suggest the combination of elevated glucose and lactate may identify a specific cohort of individuals at high risk for mortality from COVID-19. Glucose testing and control are important in individuals with COVID-19, even those without preexisting diabetes.

Impact of corticosteroids in hospitalised COVID-19 patients.

BACKGROUND: Corticosteroids are a potential therapeutic agent for patients with COVID-19 pneumonia. The RECOVERY (Randomised Trials in COVID-19 Therapy) trial provided data on the mortality benefits of corticosteroids. The study aimed to determine the association between corticosteroid use on mortality and infection rates and to define subgroups who may benefit from corticosteroids in a real-world setting. METHODS: Clinical data were extracted that included demographic, laboratory data and details of the therapy, including the administration of corticosteroids, azithromycin, hydroxychloroquine, tocilizumab and anticoagulation. The primary outcome was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) admission and invasive mechanical ventilation. Outcomes were compared in patients who did and did not receive corticosteroids using the multivariate Cox regression model. RESULTS: 4313 patients were hospitalised with COVID-19 during the study period, of whom 1270 died (29.4%). When administered within the first 7 days after admission, corticosteroids were associated with reduced mortality (OR 0.73, 95% CI 0.55 to 0.97, p=0.03) and decreased transfers to the ICU (OR 0.72, 95% CI 0.47 to 1.11, p=0.02). This mortality benefit was particularly impressive in younger patients (<65 years of age), females and those with elevated inflammatory markers, defined as C reactive protein ≥150 mg/L (p≤0.05), interleukin-6 ≥20 pg/mL (p≤0.05) or D-dimer ≥2.0 µg/L (p≤0.05). Therapy was safe with similar rates of bacteraemia and fungaemia in corticosteroid-treated and non-corticosteroid-treated patients. CONCLUSION: In patients hospitalised with COVID-19 pneumonia, corticosteroid use within the first 7 days of admission decreased mortality and ICU admissions with no associated increase in bacteraemia or fungaemia.

Cardiovascular Disease and Severe Hypoxemia Are Associated With Higher Rates of Noninvasive Respiratory Support Failure in Coronavirus Disease 2019 Pneumonia.

Acute hypoxemic respiratory failure is the major complication of coronavirus disease 2019, yet optimal respiratory support strategies are uncertain. We aimed to describe outcomes with high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation in coronavirus disease 2019 acute hypoxemic respiratory failure and identify individual factors associated with noninvasive respiratory support failure. DESIGN: Retrospective cohort study to describe rates of high-flow oxygen delivered through nasal cannula and/or noninvasive positive pressure ventilation success (live discharge without endotracheal intubation). Fine-Gray subdistribution hazard models were used to identify patient characteristics associated with high-flow oxygen delivered through nasal cannula and/or noninvasive positive pressure ventilation failure (endotracheal intubation and/or in-hospital mortality). SETTING: One large academic health system, including five hospitals (one quaternary referral center, a tertiary hospital, and three community hospitals), in New York City. PATIENTS: All hospitalized adults 18-100 years old with coronavirus disease 2019 admitted between March 1, 2020, and April 28, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 331 and 747 patients received high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation as the highest level of noninvasive respiratory support, respectively; 154 (46.5%) in the high-flow oxygen delivered through nasal cannula cohort and 167 (22.4%) in the noninvasive positive pressure ventilation cohort were successfully discharged without requiring endotracheal intubation. In adjusted models, significantly increased risk of high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation failure was seen among patients with cardiovascular disease (subdistribution hazard ratio, 1.82; 95% CI, 1.17-2.83 and subdistribution hazard ratio, 1.40; 95% CI, 1.06-1.84, respectively). Conversely, a higher peripheral blood oxygen saturation to Fio2 ratio at high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation initiation was associated with reduced risk of failure (subdistribution hazard ratio, 0.32; 95% CI, 0.19-0.54, and subdistribution hazard ratio 0.34; 95% CI, 0.21-0.55, respectively). CONCLUSIONS: A significant proportion of patients receiving noninvasive respiratory modalities for coronavirus disease 2019 acute hypoxemic respiratory failure achieved successful hospital discharge without requiring endotracheal intubation, with lower success rates among those with comorbid cardiovascular disease or more severe hypoxemia. The role of high-flow oxygen delivered through nasal cannula and noninvasive positive pressure ventilation in coronavirus disease 2019-related acute hypoxemic respiratory failure warrants further consideration.

Anticoagulation, Bleeding, Mortality, and Pathology in Hospitalized Patients With COVID-19.

BACKGROUND: Thromboembolic disease is common in coronavirus disease-2019 (COVID-19). There is limited evidence on the association of in-hospital anticoagulation (AC) with outcomes and postmortem findings. OBJECTIVES: The purpose of this study was to examine association of AC with in-hospital outcomes and describe thromboembolic findings on autopsies. METHODS: This retrospective analysis examined the association of AC with mortality, intubation, and major bleeding. Subanalyses were also conducted on the association of therapeutic versus prophylactic AC initiated ≤48 h from admission. Thromboembolic disease was contextualized by premortem AC among consecutive autopsies. RESULTS: Among 4,389 patients, median age was 65 years with 44% women. Compared with no AC (n = 1,530; 34.9%), therapeutic AC (n = 900; 20.5%) and prophylactic AC (n = 1,959; 44.6%) were associated with lower in-hospital mortality (adjusted hazard ratio [aHR]: 0.53; 95% confidence interval [CI]: 0.45 to 0.62 and aHR: 0.50; 95% CI: 0.45 to 0.57, respectively), and intubation (aHR: 0.69; 95% CI: 0.51 to 0.94 and aHR: 0.72; 95% CI: 0.58 to 0.89, respectively). When initiated ≤48 h from admission, there was no statistically significant difference between therapeutic (n = 766) versus prophylactic AC (n = 1,860) (aHR: 0.86; 95% CI: 0.73 to 1.02; p = 0.08). Overall, 89 patients (2%) had major bleeding adjudicated by clinician review, with 27 of 900 (3.0%) on therapeutic, 33 of 1,959 (1.7%) on prophylactic, and 29 of 1,530 (1.9%) on no AC. Of 26 autopsies, 11 (42%) had thromboembolic disease not clinically suspected and 3 of 11 (27%) were on therapeutic AC. CONCLUSIONS: AC was associated with lower mortality and intubation among hospitalized COVID-19 patients. Compared with prophylactic AC, therapeutic AC was associated with lower mortality, although not statistically significant. Autopsies revealed frequent thromboembolic disease. These data may inform trials to determine optimal AC regimens.

Clinical features of COVID-19 mortality: development and validation of a clinical prediction model.

Background: The COVID-19 pandemic has affected millions of individuals and caused hundreds of thousands of deaths worldwide. Predicting mortality among patients with COVID-19 who present with a spectrum of complications is very difficult, hindering the prognostication and management of the disease. We aimed to develop an accurate prediction model of COVID-19 mortality using unbiased computational methods, and identify the clinical features most predictive of this outcome. Methods: In this prediction model development and validation study, we applied machine learning techniques to clinical data from a large cohort of patients with COVID-19 treated at the Mount Sinai Health System in New York City, NY, USA, to predict mortality. We analysed patient-level data captured in the Mount Sinai Data Warehouse database for individuals with a confirmed diagnosis of COVID-19 who had a health system encounter between March 9 and April 6, 2020. For initial analyses, we used patient data from March 9 to April 5, and randomly assigned (80:20) the patients to the development dataset or test dataset 1 (retrospective). Patient data for those with encounters on April 6, 2020, were used in test dataset 2 (prospective). We designed prediction models based on clinical features and patient characteristics during health system encounters to predict mortality using the development dataset. We assessed the resultant models in terms of the area under the receiver operating characteristic curve (AUC) score in the test datasets. Findings: Using the development dataset (n=3841) and a systematic machine learning framework, we developed a COVID-19 mortality prediction model that showed high accuracy (AUC=0·91) when applied to test datasets of retrospective (n=961) and prospective (n=249) patients. This model was based on three clinical features: patient's age, minimum oxygen saturation over the course of their medical encounter, and type of patient encounter (inpatient vs outpatient and telehealth visits). Interpretation: An accurate and parsimonious COVID-19 mortality prediction model based on three features might have utility in clinical settings to guide the management and prognostication of patients affected by this disease. External validation of this prediction model in other populations is needed. Funding: National Institutes of Health.