Causal Bayesian machine learning to assess treatment effect heterogeneity by dexamethasone dose for patients with COVID-19 and severe hypoxemia.

The currently recommended dose of dexamethasone for patients with severe or critical COVID-19 is 6 mg per day (mg/d) regardless of patient features and variation. However, patients with severe or critical COVID-19 are heterogenous in many ways (e.g., age, weight, comorbidities, disease severity, and immune features). Thus, it is conceivable that a standardized dosing protocol may not be optimal. We assessed treatment effect heterogeneity in the COVID STEROID 2 trial, which compared 6 mg/d to 12 mg/d, using a causal inference framework with Bayesian Additive Regression Trees, a flexible modeling method that detects interactive effects and nonlinear relationships among multiple patient characteristics simultaneously. We found that 12 mg/d of dexamethasone, relative to 6 mg/d, was probably associated with better long-term outcomes (days alive without life support and mortality after 90 days) among the entire trial population (i.e., no signals of harm), and probably more beneficial among those without diabetes mellitus, that were older, were not using IL-6 inhibitors at baseline, weighed less, or had higher level respiratory support at baseline. This adds more evidence supporting the use of 12 mg/d in practice for most patients not receiving other immunosuppressants and that additional study of dosing could potentially optimize clinical outcomes.

Association between days alive without life support/out of hospital and health-related quality of life.

BACKGROUND: Trials in critically ill patients increasingly focus on days alive without life support (DAWOLS) or days alive out of hospital (DAOOH) and health-related quality of life (HRQoL). DAWOLS and DAOOH convey more information than mortality and are simpler and faster to collect than HRQoL. However, whether these outcomes are associated with HRQoL is uncertain. We thus aimed to assess the associations between DAWOLS and DAOOH and long-term HRQoL. METHODS: Secondary analysis of the COVID STEROID 2 trial including adults with COVID-19 and severe hypoxaemia and the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial including adult intensive care unit patients with acute hypoxaemic respiratory failure. Associations between DAWOLS and DAOOH at day 28 and 90 and long-term HRQoL (after 6 or 12 months) using the EuroQol 5-dimension 5-level survey (EQ VAS and EQ-5D-5L index values) were assessed using flexible models and evaluated using measures of fit and prediction adequacy in both datasets (comprising internal performance and external validation), non-parametric correlation coefficients and graphical presentations. RESULTS: We found no strong associations between DAWOLS or DAOOH and HRQoL in survivors at HRQoL-follow-up (615 and 1476 patients, respectively). There was substantial variability in outcomes, and predictions from the best fitted models were poor both internally and externally in the other trial dataset, which also showed inadequate calibration. Moderate associations were found when including non-survivors, although predictions remained uncertain and calibration inadequate. CONCLUSION: DAWOLS and DAOOH were poorly associated with HRQoL in adult survivors of severe or critical illness included in the COVID STEROID 2 and HOT-ICU trials.

Atrial Fibrillation (AFIB) in the ICU: Incidence, Risk Factors, and Outcomes: The International AFIB-ICU Cohort Study.

OBJECTIVES: To assess the incidence, risk factors, and outcomes of atrial fibrillation (AF) in the ICU and to describe current practice in the management of AF. DESIGN: Multicenter, prospective, inception cohort study. SETTING: Forty-four ICUs in 12 countries in four geographical regions. SUBJECTS: Adult, acutely admitted ICU patients without a history of persistent/permanent AF or recent cardiac surgery were enrolled; inception periods were from October 2020 to June 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We included 1,423 ICU patients and analyzed 1,415 (99.4%), among whom 221 patients had 539 episodes of AF. Most (59%) episodes were diagnosed with continuous electrocardiogram monitoring. The incidence of AF was 15.6% (95% CI, 13.8-17.6), of which newly developed AF was 13.3% (11.5-15.1). A history of arterial hypertension, paroxysmal AF, sepsis, or high disease severity at ICU admission was associated with AF. Used interventions to manage AF were fluid bolus 19% (95% CI 16-23), magnesium 16% (13-20), potassium 15% (12-19), amiodarone 51% (47-55), beta-1 selective blockers 34% (30-38), calcium channel blockers 4% (2-6), digoxin 16% (12-19), and direct current cardioversion in 4% (2-6). Patients with AF had more ischemic, thromboembolic (13.6% vs 7.9%), and severe bleeding events (5.9% vs 2.1%), and higher mortality (41.2% vs 25.2%) than those without AF. The adjusted cause-specific hazard ratio for 90-day mortality by AF was 1.38 (95% CI, 0.95-1.99). CONCLUSIONS: In ICU patients, AF occurred in one of six and was associated with different conditions. AF was associated with worse outcomes while not statistically significantly associated with 90-day mortality in the adjusted analyses. We observed variations in the diagnostic and management strategies for AF.

Stringency of COVID-19 Containment Response Policies and Air Quality Changes: A Global Analysis across 1851 Cities.

The COVID-19 containment response policies (CRPs) had a major impact on air quality (AQ). These CRPs have been time-varying and location-specific. So far, despite having numerous studies on the effect of COVID-19 lockdown on AQ, a knowledge gap remains on the association between stringency of CRPs and AQ changes across the world, regions, nations, and cities. Here, we show that globally across 1851 cities (each more than 300 000 people) in 149 countries, after controlling for the impacts of relevant covariates (e.g., meteorology), Sentinel-5P satellite-observed nitrogen dioxide (NO2) levels decreased by 4.9% (95% CI: 2.2, 7.6%) during lockdowns following stringent CRPs compared to pre-CRPs. The NO2 levels did not change significantly during moderate CRPs and even increased during mild CRPs by 2.3% (95% CI: 0.7, 4.0%), which was 6.8% (95% CI: 2.0, 12.0%) across Europe and Central Asia, possibly due to population avoidance of public transportation in favor of private transportation. Among 1768 cities implementing stringent CRPs, we observed the most NO2 reduction in more populated and polluted cities. Our results demonstrate that AQ improved when and where stringent COVID-19 CRPs were implemented, changed less under moderate CRPs, and even deteriorated under mild CRPs. These changes were location-, region-, and CRP-specific.

Transmission dynamics model and the coronavirus disease 2019 epidemic: applications and challenges.

Since late 2019, the beginning of coronavirus disease 2019 (COVID-19) pandemic, transmission dynamics models have achieved great development and were widely used in predicting and policy making. Here, we provided an introduction to the history of disease transmission, summarized transmission dynamics models into three main types: compartment extension, parameter extension and population-stratified extension models, highlight the key contribution of transmission dynamics models in COVID-19 pandemic: estimating epidemiological parameters, predicting the future trend, evaluating the effectiveness of control measures and exploring different possibilities/scenarios. Finally, we pointed out the limitations and challenges lie ahead of transmission dynamics models.

Incidence of Positive Severe Acute Respiratory Syndrome Coronavirus Polymerase Chain Reaction After Coronavirus Disease 2019 Vaccination With up to 8 Months of Follow-up: Real-life Data From the Capital Region of Denmark.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccines are implemented worldwide in efforts to curb the pandemic. This study investigates the risk of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction (RT-PCR) test following BNT162b2 vaccination in a large real-life population in Denmark. METHODS: Vaccination status and positive SARS-CoV-2 RT-PCR results from adults in the Capital Region of Denmark (n = 1 549 488) were obtained from national registries. PCR testing was free and widely available. The number of positive PCR tests per individual at risk was calculated as weekly rates. Time to positive PCR test was modelled using Kaplan-Meier methods and hazard ratios (HRs) were calculated using Cox regression. RESULTS: A total of 1 119 574 individuals received the first dose of BNT162b2 and 1 088 879 received a second dose of BNT162b2. Individuals were followed up to 8.7 months after first dose (median: 5.5 months; interquartile ratio: 4.1-8.7). Rates of PCR-confirmed SARS-CoV-2 infection 2-4 months after the second dose were 0.21, 0.33, and 0.36 per 1000 individuals per week at risk for July, August, and September, respectively. Four or more months after the second dose, the rates were 0.56, 0.76, and 0.53 per 1000 individuals per week at risk for July, August, and September, respectively. HR of SARS-CoV-2 infection after the second dose was 0.2 (95% confidence interval, .05-.48; P = .001) for individuals with 8 months' follow-up. CONCLUSIONS: Individuals who received 2 doses of the BNT162b2 COVID-19 vaccine had a low risk of breakthrough infection after up to 8 months of follow-up. However, there was a tendency toward higher rates with longer follow-up.

The effect of prostacyclin infusion on markers of endothelial activation and damage in mechanically ventilated patients with SARS-CoV-2 infection.

BACKGROUND: In a pilot study, we found a significant reduction in mean daily sequential organ failure assessment score in mechanically ventilated patients with COVID-19 who received prostacyclin, compared to placebo. We here investigate the effect on biomarkers of endothelial activation and damage. METHODS: Post-hoc study of a randomized controlled trial in adult patients with confirmed SARS-CoV-2 infection, mechanically ventilated, with soluble thrombomodulin (sTM) plasma levels >4 ng/mL. Patients received prostacyclin infusion (1 ng/kg/min) or placebo. Blood samples were collected at baseline and 24 h. RESULTS: Eighty patients were randomized (41 prostacyclin, 39 placebo). The median changes in syndecan-1 plasma levels at 24 h were -3.95 (IQR: -21.1 to 2.71) ng/mL in the prostacyclin group vs. 3.06 (IQR: -8.73 to 20.5) ng/mL in the placebo group (difference of the medians: -7.01 [95% CI: -22.3 to -0.231] ng/mL, corresponding to -3% [95% CI: -11% to 0%], p = 0.04). Changes in plasma levels of sTM, PECAM-1, p-selectin, and CD40L did not differ significantly between groups. CONCLUSIONS: Prostacyclin infusion, compared to placebo, resulted in a measurable decrease in endothelial glycocalyx shedding (syndecan-1) at 24 h, suggesting a protective effect on the endothelium, which may be related to the observed reduction in organ failure.

Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial.

Rationale: The mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who require mechanical ventilation remains high, and endotheliopathy has been implicated. Objectives: To determine the effect of prostacyclin infusion in mechanically ventilated patients infected with SARS-CoV-2 with severe endotheliopathy. Methods: We conducted a multicenter, randomized clinical trial in adults infected with coronavirus disease (COVID-19) who required mechanical ventilation and had a plasma level of thrombomodulin >4 ng/ml; patients were randomized to 72-hour infusion of prostacyclin 1 ng/kg/min or placebo. Measurements and Main Results: The main outcome was the number of days alive and without mechanical ventilation within 28 days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Eighty patients were randomized (41 prostacyclin and 39 placebo). The median number of days alive without mechanical ventilation at 28 days was 16.0 days (SD, 12) versus 5.0 days (SD, 10) (difference of the medians, 10.96 days; 95% confidence interval [CI], -5 to 21; P = 0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio, 0.50; 95% CI, 0.24 to 0.96; P = 0.06). The incidence of serious adverse events within 7 days was 2.4% versus 12.8% (risk ratio, 0.19; 95% CI, 0.001 to 1.11; P = 0.10) in the prostacyclin and the placebo groups, respectively. Conclusions: Prostacyclin was not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28 days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials. Clinical trial registered with www.clinicaltrials.gov (NCT04420741); EudraCT Identifier: 2020-001296-33.

Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial.

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.

Higher versus lower oxygenation targets in COVID-19 patients with severe hypoxaemia (HOT-COVID) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Respiratory failure is the main cause of mortality and morbidity among ICU patients with coronavirus disease 2019 (COVID-19). In these patients, supplemental oxygen therapy is essential, but there is limited evidence the optimal target. To address this, the ongoing handling oxygenation targets in COVID-19 (HOT-COVID) trial was initiated to investigate the effect of a lower oxygenation target (partial pressure of arterial oxygen (PaO2 ) of 8 kPa) versus a higher oxygenation target (PaO2 of 12 kPa) in the ICU on clinical outcome in patients with COVID-19 and hypoxaemia. METHODS: The HOT-COVID is planned to enrol 780 patients. This paper presents the protocol and statistical analysis plan for the conduct of a secondary Bayesian analysis of the primary outcome of HOT-COVID being days alive without life-support at 90 days and the secondary outcome 90-day all-cause mortality. Furthermore, both outcomes will be investigated for the presence heterogeneity of treatment effects based on four baseline parameters being sequential organ failure assessment score, PaO2 /fraction of inspired oxygen ratio, highest dose of norepinephrine during the 24 h before randomisation, and plasma concentration of lactate at randomisation. CONCLUSION: The results of this pre-planned secondary Bayesian analysis will complement the primary frequentist analysis of the HOT-COVID trial and may facilitate a more nuanced interpretation of the trial results.

Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial.

Importance: A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. Objective: To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. Interventions: Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. Main Outcomes and Measures: The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and ≥1 serious adverse reactions at 28 days). Results: Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). Conclusions and Relevance: Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT04509973 and ctri.nic.in Identifier: CTRI/2020/10/028731.

Anti-SARS-CoV-2 Seropositivity Among Medical Students in Copenhagen.

BACKGROUND: Health care workers are at a higher risk of getting infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population. Knowledge about medical students' exposure to SARS-CoV-2 is lacking. Thus, we measured the prevalence of SARS-CoV-2 antibodies in a cohort of Danish medical students. METHODS: We invited all medical students at the University of Copenhagen (UCPH) to participate. Students underwent venous blood sampling and a questionnaire about work-life behaviors possibly associated with SARS-CoV-2 exposure and coronavirus disease 2019 (COVID-19) symptoms. Samples were analyzed for total immunoglobulin G (IgG) antibodies against SARS-CoV-2, and seropositive samples were screened for IgG, immunoglobulin M, and immunoglobulin A antibodies. We determined associations between seropositivity and clinical and social activities and self-reported symptoms. RESULTS: Between October 19 and 26, 1120 students participated in the questionnaire and 1096 were included. Of all included, 379 (34.58%) were seropositive. Seropositivity was associated with attendance at 2 parties at UCPH, on February 29 and March 6, 2020 (odds ratio [OR], 5.96; 95% CI, 4.34-8.24; P < .001). Four hundred sixty-one students (42.06%) worked with COVID-19 patients, which was significantly associated with seropositivity (OR, 1.38; 95% CI, 1.03-1.85; P = .033). The symptom most associated with seropositivity was loss of smell and/or taste (n = 183 of all, 31.35%; OR, 24.48; 95% CI, 15.49-40.60; P < .001). Bachelor's students were significantly more likely to be seropositive than Master's students (42.28% vs 16.87%; P < .001). CONCLUSIONS: Medical students have the highest reported seropositivity in the Danish health care system. In this cohort of students at UCPH, seropositivity was associated with social behavior markers and, to a lesser extent, with self-reported contact with SARS-CoV-2-infected patients.

Oxygenation targets in ICU patients with COVID-19: A post hoc subgroup analysis of the HOT-ICU trial.

BACKGROUND: Supplemental oxygen is the key intervention for severe and critical COVID-19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage. METHODS: In spring 2020, 110 COVID-19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT-ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO2 ) of 8 kPa (lower oxygenation group) or a PaO2 of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID-19 patients. RESULTS: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58-1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end-expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant. CONCLUSIONS: Targeting a PaO2 of 8 kPa may be beneficial in ICU patients with COVID-19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.

Handling oxygenation targets in ICU patients with COVID-19-Protocol and statistical analysis plan in the HOT-COVID trial.

BACKGROUND: Coronavirus disease (COVID-19) primarily affects the lungs and lower airways and may present as hypoxaemic respiratory failure requiring admission to an intensive care unit (ICU) for supportive treatment. Here, supplemental oxygen remains essential for COVID-19 patient management, but the optimal dosage is not defined. We hypothesize that targeting an arterial partial pressure of oxygen of 8 kPa throughout ICU admission is superior to targeting 12 kPa. METHODS: The Handling Oxygenation Targets in ICU patients with COVID-19 (HOT-COVID) trial, is an investigator-initiated, pragmatic, multicentre, randomized, parallel-group trial comparing a lower oxygenation target versus a higher oxygenation target in adult ICU patients with COVID-19. The primary outcome is days alive without life-support (use of mechanical ventilation, renal replacement therapy or vasoactive therapy) at day 90. Secondary outcomes are 90-day and 1-year mortality, serious adverse events in the ICU and days alive and out of hospital in the 90-day period, health-related quality-of-life at 1 year, and health economic analyses. One-year follow-up of cognitive and pulmonary function is planned in a subgroup of Danish patients. We will include 780 patients to detect or reject an absolute increase in days alive without life-support of 7 days with an α of 5% and a ß of 20%. An interim analysis is planned after 90-day follow-up of 390 patients. CONCLUSIONS: The HOT-COVID trial will provide patient-important data on the effect of two oxygenation targets in ICU patients with COVID-19 and hypoxia. This protocol paper describes the background, design and statistical analysis plan for the trial.

A predictive paradigm for COVID-19 prognosis based on the longitudinal measure of biomarkers.

Novel coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving crisis, and the ability to predict prognosis for individual COVID-19 patient is important for guiding treatment. Laboratory examinations were repeatedly measured during hospitalization for COVID-19 patients, which provide the possibility for the individualized early prediction of prognosis. However, previous studies mainly focused on risk prediction based on laboratory measurements at one time point, ignoring disease progression and changes of biomarkers over time. By using historical regression trees (HTREEs), a novel machine learning method, and joint modeling technique, we modeled the longitudinal trajectories of laboratory biomarkers and made dynamically predictions on individual prognosis for 1997 COVID-19 patients. In the discovery phase, based on 358 COVID-19 patients admitted between 10 January and 18 February 2020 from Tongji Hospital, HTREE model identified a set of important variables including 14 prognostic biomarkers. With the trajectories of those biomarkers through 5-day, 10-day and 15-day, the joint model had a good performance in discriminating the survived and deceased COVID-19 patients (mean AUCs of 88.81, 84.81 and 85.62% for the discovery set). The predictive model was successfully validated in two independent datasets (mean AUCs of 87.61, 87.55 and 87.03% for validation the first dataset including 112 patients, 94.97, 95.78 and 94.63% for the second validation dataset including 1527 patients, respectively). In conclusion, our study identified important biomarkers associated with the prognosis of COVID-19 patients, characterized the time-to-event process and obtained dynamic predictions at the individual level.

Estimates of mortality attributable to COVID-19: a statistical model for monitoring COVID-19 and seasonal influenza, Denmark, spring 2020.

BackgroundTimely monitoring of COVID-19 impact on mortality is critical for rapid risk assessment and public health action.AimBuilding upon well-established models to estimate influenza-related mortality, we propose a new statistical Attributable Mortality Model (AttMOMO), which estimates mortality attributable to one or more pathogens simultaneously (e.g. SARS-CoV-2 and seasonal influenza viruses), while adjusting for seasonality and excess temperatures.MethodsData from Nationwide Danish registers from 2014-week(W)W27 to 2020-W22 were used to exemplify utilities of the model, and to estimate COVID-19 and influenza attributable mortality from 2019-W40 to 2020-W20.ResultsSARS-CoV-2 was registered in Denmark from 2020-W09. Mortality attributable to COVID-19 in Denmark increased steeply, and peaked in 2020-W14. As preventive measures and national lockdown were implemented from 2020-W12, the attributable mortality started declining within a few weeks. Mortality attributable to COVID-19 from 2020-W09 to 2020-W20 was estimated to 16.2 (95% confidence interval (CI): 12.0 to 20.4) per 100,000 person-years. The 2019/20 influenza season was mild with few deaths attributable to influenza, 3.2 (95% CI: 1.1 to 5.4) per 100,000 person-years.ConclusionAttMOMO estimates mortality attributable to several pathogens simultaneously, providing a fuller picture of mortality by COVID-19 during the pandemic in the context of other seasonal diseases and mortality patterns. Using Danish data, we show that the model accurately estimates mortality attributable to COVID-19 and influenza, respectively. We propose using standardised indicators for pathogen circulation in the population, to make estimates comparable between countries and applicable for timely monitoring.

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Higher vs Lower Doses of Dexamethasone in Patients with COVID-19 and Severe Hypoxia (COVID STEROID 2) trial: Protocol for a secondary Bayesian analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial-Protocol and statistical analysis plan.

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists. METHODS: The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals. DISCUSSION: The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.