Prone positioning of patients with moderate hypoxia due to COVID-19: A multicenter pragmatic randomized trial (preprint)

What is already known on this topic: Prone positioning is considered standard of care for mechanically ventilated patients who have severe acute respiratory distress syndrome. Recent data suggest prone positioning is beneficial for patients with COVID-19 who are requiring high flow oxygen. It is unknown of prone positioning is beneficial for patients not on high flow oxygen. What this study adds: Prone positioning is generally not well tolerated and innovative approaches are needed to improve adherence. Clinical and physiologic outcomes were not improved with prone positioning among hypoxic but not critically ill patients hospitalized with COVID-19. Objectives: To assess the effectiveness of prone positioning to reduce the risk of death or respiratory failure in non-critically ill patients hospitalized with COVID-19 Design: Pragmatic randomized clinical trial of prone positioning of patients hospitalized with COVID-19 across 15 hospitals in Canada and the United States from May 2020 until May 2021. Settings: Patients were eligible is they had a laboratory-confirmed or a clinically highly suspected diagnosis of COVID-19, required supplemental oxygen (up to 50% fraction of inspired oxygen [FiO2]), and were able to independently prone with verbal instruction. (NCT04383613). Main Outcome Measures: The primary outcome was a composite of in-hospital death, mechanical ventilation, or worsening respiratory failure defined as requiring at least 60% FiO2 for at least 24 hours. Secondary outcomes included the change in the ratio of oxygen saturation to FiO2 (S/F ratio). Results: A total of 248 patients were included. The trial was stopped early on the basis of futility for the pre-specified primary outcome. The median time from hospital admission until randomization was 1 day, the median age of patients was 56 years (interquartile range [IQR] 45,65), 36% were female, and 90% of patients were receiving oxygen via nasal prongs at the time of randomization. The median time spent prone in the first 72 hours was 6 hours total (IQR 1.5,12.8) for the prone arm compared to 0 hours (0,2) in the control arm. The risk of the primary outcome was similar between the prone group (18 [14.3%] events) and the standard care group (17 [13.9%] events), odds ratio 0.92 (95% CI 0.44 to 1.92). The change in the S/F ratio after 72 hours was similar for patients randomized to prone compared to standard of care. Conclusion: Among hypoxic but not critically patients with COVID-19 in hospital, a multifaceted intervention to increase prone positioning did not improve outcomes. Adherence to prone positioning was poor, despite multiple efforts. Subsequent trials of prone positioning should aim to develop strategies to improve adherence to awake prone positioning.

Heparin for Moderately Ill Patients with Covid-19 (preprint)

Background Heparin, in addition to its anticoagulant properties, has anti-inflammatory and potential anti-viral effects, and may improve endothelial function in patients with Covid-19. Early initiation of therapeutic heparin could decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. Methods We randomly assigned moderately ill hospitalized ward patients admitted for Covid-19 with elevated D-dimer level to therapeutic or prophylactic heparin. The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation or ICU admission. Safety outcomes included major bleeding. Analysis was by intention-to-treat. Results At 28 days, the primary composite outcome occurred in 37 of 228 patients (16.2%) assigned to therapeutic heparin, and 52 of 237 patients (21.9%) assigned to prophylactic heparin (odds ratio, 0.69; 95% confidence interval [CI], 0.43 to 1.10; p=0.12). Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65). The composite of all-cause mortality or any mechanical ventilation occurred in 23 (10.1%) in the therapeutic heparin group and 38 (16.0%) in the prophylactic heparin group (odds ratio, 0.59; 95%-CI, 0.34 to 1.02). Major bleeding occurred in 2 patients (0.9%) with therapeutic heparin and 4 patients (1.7%) with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85). Conclusions In moderately ill ward patients with Covid-19 and elevated D-dimer level, therapeutic heparin did not significantly reduce the primary outcome but decreased the odds of death at 28 days.

Assessing the utility of lymphocyte count to diagnose COVID-19 (preprint)

Background: COronaVirus Disease 2019 (COVID-19) can be challenging to diagnose, because symptoms are non-specific, clinical presentations are heterogeneous, and false negative tests can occur. Our objective was to assess the utility of lymphocyte count to differentiate COVID-19 from influenza or community-acquired pneumonia (CAP). Methods: We conducted a cohort study of adults hospitalized with COVID-19 or another respiratory infection (i.e., influenza, CAP) at seven hospitals in Ontario, Canada.The first available lymphocyte count during the hospitalization was used. Standard test characteristics for lymphocyte count (x109/L) were calculated (i.e., sensitivity, specificity, area under the receiver operating curve [AUC]). All analyses were conducting using R. Results: There were 869 hospitalizations for COVID-19, 669 for influenza, and 3009 for CAP. The mean age across the three groups was 67 and patients with pneumonia were older than those with influenza or COVID19, and approximately 46% were woman. The median lymphocyte count was nearly identical for the three groups of patients: 1.0 x109/L (interquartile range [IQR]:0.7,2.0) for COVID-19, 0.9 x109/L (IQR 0.6,1.0) for influenza, and 1.0 x109/L (IQR 0.6,2.0) for CAP. At a lymphocyte threshold of less than 2.0 x109/L, the sensitivity was 87% and the specificity was approximately 10%. As the lymphocyte threshold increased, the sensitivity of diagnosing COVID-19 increased while the specificity decreased. The AUC for lymphocyte count was approximately 50%. Interpretation: Lymphocyte count has poor diagnostic discrimination to differentiate between COVID-19 and other respiratory illnesses. The lymphopenia we consistently observed across the three illnesses in our study may reflect a non-specific sign of illness severity. However, lymphocyte count above 2.0 x109/L may be useful in ruling out COVID-19 (sensitivity = 87%).

Patient characteristics, clinical care, resource use, and outcomes associated with hospitalization for COVID-19 in the Toronto area (preprint)

Background: Patient characteristics, clinical care, resource use, and outcomes associated with hospitalization for coronavirus disease (COVID-19) in Canada are not well described. Methods: We described all adult discharges from inpatient medical services and medical-surgical intensive care units (ICU) between November 1, 2019 and June 30, 2020 at 7 hospitals in Toronto and Mississauga, Ontario. We compared patients hospitalized with COVID-19, influenza and all other conditions using multivariable regression models controlling for patient age, sex, comorbidity, and residence in long-term-care. Results: There were 43,462 discharges in the study period, including 1,027 (3.0%) with COVID-19 and 783 (2.3%) with influenza. Patients with COVID-19 had similar age to patients with influenza and other conditions (median age 65 years vs. 68 years and 68 years, respectively, SD<0.1). Patients with COVID-19 were more likely to be male (59.1%) and 11.7% were long-term care residents. Patients younger than 50 years accounted for 21.2% of all admissions for COVID-19 and 24.0% of ICU admissions. Compared to influenza, patients with COVID-19 had significantly greater mortality (unadjusted 19.9% vs 6.1%, aRR: 3.47, 95%CI: 2.57, 4.67), ICU use (unadjusted 26.4% vs 18.0%, aRR 1.52, 95%CI: 1.27, 1.83) and hospital length-of-stay (unadjusted median 8.7 days vs 4.8 days, aRR: 1.40, 95%CI: 1.20, 1.64), and not significantly different 30-day readmission (unadjusted 8.6% vs 8.2%, aRR: 1.01, 95%CI: 0.72, 1.42). Interpretation: Adults hospitalized with COVID-19 during the first wave of the pandemic used substantial hospital resources and suffered high mortality. COVID-19 was associated with significantly greater mortality, ICU use, and hospital length-of-stay than influenza.

Adjunctive Corticosteroids for COVID-19: A Retrospective Cohort Study (preprint)

Background: Coronavirus disease 2019 (COVID-19) is associated with severe pneumonia, respiratory failure and death. We aim to evaluate the efficacy of adjunctive corticosteroids in the management of COVID-19. Methods: This is a retrospective cohort study of hospitalized adults ([≥]18 years) who were diagnosed with COVID-19 and were given treatment. Treatment included hydroxycholoroquine and lopinavir-ritonavir. Corticosteroids were included as adjunctive therapy in mid-April, 2020. We compared composite outcomes of clinical progression and invasive mechanical ventilation (MV) or death between group that received treatment only (Group A) versus group that received adjunctive corticosteroids (Group B). Entropy balancing was used to generate stabilized weight for covariates between treatment groups. Unweighted Kaplan-Meir curves, weighted and adjusted Cox regression analysis were used to estimate effect of adjunctive corticosteroids on composite outcomes. Subgroup analysis was performed on those with pneumonia. Results: Of 1046 patients with COVID-19, 57 received treatment alone (Group A) and 35 received adjunctive corticosteroids in addition to treatment (Group B). Median day of illness at treatment initiation was 5 day. There were 44 patients with pneumonia; 68.9% of them were not requiring supplemental oxygen at treatment initiation. Overall, 17 (18.5%) of 92 patients had clinical progression including 13 (22.8%) of 57 patients in Group A versus 4 (11.4%) of 35 patients in Group B (p=0.172). Unweighted Kaplan-Meier estimates showed no significant difference in the proportion of patients who had clinical progression or invasive MV or death between the 2 treatment groups. However in those with pneumonia, there were lower proportions of patients in Group B with clinical progression (11.1% , 95% CI 0.0 - 22.2 versus 58.8%, 95% CI 27.3 - 76.7, log rank p<0.001 ); and invasive MV or death (11.3%, 95% CI 0.0 - 22.5 versus 41.2%, 95% CI 12.4. - 60.5, log rank p=0.016). In weighted and adjusted cox regression analysis, patients in Group B were less likely to have clinical progression, (adjusted HR [aHR] 0.08, 95% CI 0.01-0.99, p=0.049) but there was no statistical significant difference in risk of requiring invasive MV or death (aHR 0.22, 95%CI 0.02 - 2.54, p=0.22). In subgroup with pneumonia, patients in Group B were significantly at lower risk of clinical progression (aHR 0.15, 95% CI 0.06 - 0.39, p<0.001) and requiring invasive MV compared to Group A (aHR 0.30, 0.10-0.87, p=0.029). Conclusions: Use of adjunctive corticosteroids is associated with lower risk of clinical progression and invasive MV or death, especially in those with pneumonia. Concurrent use of antivirals and corticosteroids should be considered in the management of COVID-19 related pneumonia.