Acute respiratory distress syndrome after SARS-CoV-2 infection on young adult population: international observational federated study based on electronic health records through the 4CE consortium ARDS after SARS-CoV-2 infection on young adult (preprint)

Purpose : In young adults (18 to 49 years old), investigation of the acute respiratory distress syndrome (ARDS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been limited. We evaluated the risk factors and outcomes of ARDS following infection with SARS-CoV-2 in a young adult population. Methods : A retrospective cohort study was conducted between January 1st, 2020 and February 28th, 2021 using patient-level electronic health records (EHR), across 241 United States hospitals and 43 European hospitals participating in the Consortium for Clinical Characterization of COVID-19 by EHR (4CE). To identify the risk factors associated with ARDS, we compared young patients with and without ARDS through a federated analysis. We further compared the outcomes between young and old patients with ARDS. Results : Among the 75,377 hospitalized patients with positive SARS-CoV-2 PCR, 1001 young adults presented with ARDS ( 7.8% of young hospitalized adults). Their mortality rate at 90 days was 16.2% and they presented with a similar complication rate for infection than older adults with ARDS. Peptic ulcer disease, paralysis, obesity, congestive heart failure, valvular disease, diabetes, chronic pulmonary disease and liver disease were associated with a higher risk of ARDS. We described a high prevalence of obesity (53%), hypertension (38%- although not significantly associated with ARDS), and diabetes (32%). Conclusion : Trough an innovative method, a large international cohort study of young adults developing ARDS after SARS-CoV-2 infection has been gather. It demonstrated the poor outcomes of this population and associated risk factor.

SurvMaximin: Robust Federated Approach to Transporting Survival Risk Prediction Models (preprint)

ObjectiveFor multi-center heterogeneous Real-World Data (RWD) with time-to-event outcomes and high-dimensional features, we propose the SurvMaximin algorithm to estimate Cox model feature coefficients for a target population by borrowing summary information from a set of health care centers without sharing patient-level information. Materials and MethodsFor each of the centers from which we want to borrow information to improve the prediction performance for the target population, a penalized Cox model is fitted to estimate feature coefficients for the center. Using estimated feature coefficients and the covariance matrix of the target population, we then obtain a SurvMaximin estimated set of feature coefficients for the target population. The target population can be an entire cohort comprised of all centers, corresponding to federated learning, or can be a single center, corresponding to transfer learning. ResultsSimulation studies and a real-world international electronic health records application study, with 15 participating health care centers across three countries (France, Germany, and the U.S.), show that the proposed SurvMaximin algorithm achieves comparable or higher accuracy compared with the estimator using only the information of the target site and other existing methods. The SurvMaximin estimator is robust to variations in sample sizes and estimated feature coefficients between centers, which amounts to significantly improved estimates for target sites with fewer observations. ConclusionsThe SurvMaximin method is well suited for both federated and transfer learning in the high-dimensional survival analysis setting. SurvMaximin only requires a one-time summary information exchange from participating centers. Estimated regression vectors can be very heterogeneous. SurvMaximin provides robust Cox feature coefficient estimates without outcome information in the target population and is privacy-preserving.

Association between Functional Inhibitors of Acid Sphingomyelinase and Reduced Risk of Intubation or Death in Individuals Hospitalized for Severe COVID-19: results from an observational multicenter study (preprint)

Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the (ASM)/ceramide system may be central to SARS-CoV-2 infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe COVID-19 in an observational multicenter retrospective study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking a FIASMA medication at the time of their hospital admission. The primary endpoint was a composite of intubation and/or death. We compared this endpoint between patients taking vs. not taking a FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD=12.5), the primary endpoint occurred in 104 patients (37.5%) who were taking a FIASMA medication, and 1,060 patients (41.4%) who were not. Taking a FIASMA medication was associated with reduced likelihood of intubation or death in both crude (HR=0.71; 95%CI=0.58-0.87; p<0.001) and the primary IPW (HR=0.58; 95%CI=0.46-0.72; p<0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one FIASMA class or medication. These results show the potential importance of the ASM/ceramide system as a treatment target in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.

Association between benzodiazepine receptor agonist use and increased mortality among patients hospitalized for COVID-19: results from an observational study (preprint)

ObjectiveTo examine the association between benzodiazepine receptor agonist (BZRA) use and mortality in patients hospitalized for COVID-19. MethodsWe conducted an observational multicenter retrospective cohort study at AP-HP Greater Paris University hospitals. The sample involved 14,381 adult patients hospitalized for COVID-19. 686 (4.8%) inpatients received a BZRA within at the time of hospital admission at a mean daily diazepam-equivalent dose of 19.7 mg (SD=25.4). The study baseline was the date of hospital admission and the primary endpoint was death. We compared this endpoint between patients who received BZRAs and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex, obesity and comorbidity) and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). ResultsOver a mean follow-up of 14.5 days (SD=18.1), the primary endpoint occurred in 186 patients (27.1%) who received a BZRA and in 1,134 patients (8.3%) who did not. There was a significant association between BZRA use and increased mortality both in the crude analysis (HR=3.20; 95% CI=2.74-3.74; p<0.01) and in the primary IPW analysis (HR=1.61; 95% CI=1.31-1.98, p<0.01), with a significant dose-dependent relationship (HR=1.55; 95% CI=1.08-2.22; p=0.02). This association remained significant in multiple sensitivity analyses. ConclusionsBZRA use was associated with increased mortality among patients hospitalized for COVID-19 with a dose-dependent relationship, suggesting a potential benefit of decreasing dose or tapering off these medications when possible in these patients.

Association between Psychotropic Medications Functionally Inhibiting Acid Sphingomyelinase and reduced risk of Intubation or Death among Individuals with Mental Disorder and Severe COVID-19: an Observational Study (preprint)

ABSTRACT Prior preclinical and clinical evidence suggests that the acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications with functional inhibition of acid sphingomyelinase, called FIASMA psychotropic medications, against COVID-19. We examined the potential usefulness of FIASMA psychotropic medication use among patients with mental disorder hospitalized for severe COVID-19, in an observational multicenter retrospective study conducted at AP-HP Greater Paris University hospitals. Of 545 adult patients with mental disorder hospitalized for severe COVID-19, 164 (30.1%) received a psychotropic FIASMA medication at study baseline, which was defined as the date of hospital admission for COVID-19. The primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and psychotropic and other medications. The primary analysis was a Cox regression model with inverse probability weighting (IPW). There was a significant association between FIASMA psychotropic medication use at baseline and reduced risk of intubation or death both in the crude analysis (HR=0.42; 95%CI=0.31-0.57; p<0.01) and in the primary IPW analysis (HR=0.50; 95%CI=0.37-0.67; p<0.01). This association remained significant in multiple sensitivity analyses. Exploratory analyses suggested that this association was not specific to one FIASMA psychotropic class or medication. These results suggest the usefulness of the ASM/ceramide system framework in COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.

International Comparisons of Harmonized Laboratory Value Trajectories to Predict Severe COVID-19: Leveraging the 4CE Collaborative Across 342 Hospitals and 6 Countries: A Retrospective Cohort Study (preprint)

Objectives: To perform an international comparison of the trajectory of laboratory values among hospitalized patients with COVID-19 who develop severe disease and identify optimal timing of laboratory value collection to predict severity across hospitals and regions. Design: Retrospective cohort study. Setting: The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), an international multi-site data-sharing collaborative of 342 hospitals in the US and in Europe. Participants: Patients hospitalized with COVID-19, admitted before or after PCR-confirmed result for SARS-CoV-2. Primary and secondary outcome measures: Patients were categorized as ''ever-severe'' or ''never-severe'' using the validated 4CE severity criteria. Eighteen laboratory tests associated with poor COVID-19-related outcomes were evaluated for predictive accuracy by area under the curve (AUC), compared between the severity categories. Subgroup analysis was performed to validate a subset of laboratory values as predictive of severity against a published algorithm. A subset of laboratory values (CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin) was compared between North American and European sites for severity prediction. Results: Of 36,447 patients with COVID-19, 19,953 (43.7%) were categorized as ever-severe. Most patients (78.7%) were 50 years of age or older and male (60.5%). Longitudinal trajectories of CRP, albumin, LDH, neutrophil count, D-dimer, and procalcitonin showed association with disease severity. Significant differences of laboratory values at admission were found between the two groups. With the exception of D-dimer, predictive discrimination of laboratory values did not improve after admission. Sub-group analysis using age, D-dimer, CRP, and lymphocyte count as predictive of severity at admission showed similar discrimination to a published algorithm (AUC=0.88 and 0.91, respectively). Both models deteriorated in predictive accuracy as the disease progressed. On average, no difference in severity prediction was found between North American and European sites. Conclusions: Laboratory test values at admission can be used to predict severity in patients with COVID-19. There is a need for prediction models that will perform well over the course of the disease in hospitalized patients.

Association of antihypertensive agents with the risk of in-hospital death in patients with Covid-19 (preprint)

In this retrospective multicenter cohort study, we aimed to investigate the association between antihypertensive agent exposure and in-hospital mortality in patients with Covid-19. Of 8,078 hospitalized patients for Covid-19, 3,686 (45.6%) had hypertension including 2043 (55.4%) patients exposed to a renin-angiotensin-aldosterone inhibitors (RAASi), 1624 (44.1%) to calcium channel blockers (CCB) and 1154 (37.7%) to beta-blockers. Overall in-hospital 30-day mortality was 23.1%. Compared to non-users, the risk of mortality was lower in CCB (aOR, 0.83 [0.70-0.99]) and beta-blockers users (aOR, 0.80 [0.67-0.95]), and not different in RAASi users. These findings support the continuation of antihypertensive agents in patients with Covid-19.

Association between Hydroxyzine Use and Reduced Mortality in Patients Hospitalized for Coronavirus Disease 2019: Results from a multicenter observational study (preprint)

Objective: To examine the association between hydroxyzine use and mortality in patients hospitalized for COVID-19, based on its anti-inflammatory and antiviral properties. Design: Multicenter observational retrospective cohort study. Setting: Greater Paris University hospitals, France. Participants: 7,345 adults hospitalized for COVID-19 between 24 January and 1 April 2020, including 138 patients (1.9%) who received hydroxyzine during the visit at a mean dose of 49.8 mg (SD=51.5) for an average of 22.4 days (SD=25.9). Data source: Assistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measures: The study endpoint was death. We compared this endpoint between patients who received hydroxyzine and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), clinical and biological markers of disease severity, and use of other medications. The primary analysis was a multivariable Cox model with inverse probability weighting. Sensitivity analyses included a multivariable Cox model and a univariate Cox regression model in a 1:1 ratio matched analytic sample. Results: Over a mean follow-up of 20.3 days (SD=27.5), 994 patients (13.5%) had a primary end-point event. The primary multivariable analysis with inverse probability weighting showed a significant association between hydroxyzine use and reduced mortality (HR, 0.42; 95% CI, 0.25 to 0.71; p=0.001) with a significant dose-effect relationship (HR, 0.10; 95% CI, 0.02 to 0.45; p=0.003). This association was similar in sensitivity analyses. In secondary analyses conducted among subsamples of patients, we found a significant association between hydroxyzine use and a faster decrease in biological inflammatory markers associated with COVID-19-related mortality, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-C-reactive protein ratio (LCRP), and circulating interleukin 6 levels (IL-6) (all p<0.016), with a significant dose-effect relationship for NLR and LCRP (both p<0.037). Conclusions: In this retrospective observational study, hydroxyzine use was associated with reduced mortality in patients hospitalized for COVID-19. This association may be partially mediated by specific anti-inflammatory properties of H1 antihistamines. Double-blind controlled randomized clinical trials of hydroxyzine for COVID-19 are needed to confirm these results.

Dexamethasone use and Mortality in Hospitalized Patients with Coronavirus Disease 2019: a Multicenter Retrospective Observational Study (preprint)

Objective: To examine the association between dexamethasone use and mortality among hospitalized patients for COVID-19. Design: Multicenter observational retrospective cohort study. Setting: Greater Paris University hospitals, France. Participants: 12,217 adults hospitalized with COVID-19 between 24 January and 20 May 2020, including 171 patients (1.4%) who received dexamethasone orally or by intravenous perfusion during the visit. Data source: Assistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measures: The primary endpoint was time to death. We compared this endpoint between patients who received dexamethasone and those who did not in time-to-event analyses adjusting for sex, age, obesity, current smoking status, any medical condition associated with increased COVID-19-related mortality, and clinical and biological severity of COVID-19 at admission, while stratifying by the need of respiratory support (i.e., oxygen or intubation). The primary analysis was a multivariable Cox model and the secondary analysis used a univariate Cox regression in a matched analytic sample. Results: Among patients who required respiratory support, the end-point event of death occurred in 10 patients (15.9%) who received dexamethasone and 298 patients (26.4%) who did not. In this group of patients, there was a significant association between dexamethasone use and reduced mortality in both the crude, unadjusted analysis (hazard ratio (HR), 0.40; 95% CI, 0.18 to 0.87, p=0.021) and the adjusted multivariable analysis (HR, 0.46; 95% CI, 0.22 to 0.96, p=0.039). In the sensitivity analysis, the univariate Cox regression model in the matched analytic sample yielded a same tendency, albeit non-significant (HR, 0.31; 95% CI, 0.08 to 1.14, p=0.077). Among patients without respiratory support, the end-point event of death occurred in 14 patients (13.0%) who received dexamethasone and 1,086 patients (10.0%) who did not. In this group of patients, there was no significant association between dexamethasone use and the endpoint. When examining the association between the cumulative dose of dexamethasone received during the visit and the endpoint, we found that the administration of a cumulative dose between 60 mg to 150 mg among patients who required respiratory support was significantly associated with a lower risk of death in the crude, unadjusted analysis (HR, 0.28; SE, 0.58, p=0.028), the adjusted multivariable analysis (HR, 0.24; SE, 0.65, p=0.030), and in the univariate Cox regression model in the matched analytic sample (HR, 0.32; SE, 0.58, p=0.048), whereas no significant association was observed with a different dose. Among patients without respiratory support, there was no significant association between the cumulative dose of dexamethasone and the endpoint in the crude and in the adjusted multivariable analyses. Conclusions: In this observational study involving patients with Covid-19 who had been admitted to the hospital, dexamethasone use administered either orally or by intravenous injection at a cumulative dose between 60 mg and 150 mg was associated with decreased mortality among those requiring respiratory support.

Observational Study of Haloperidol in Hospitalized Patients with Covid-19 (preprint)

Background: Haloperidol, a widely used antipsychotic, has been suggested as potential effective treatment for Covid-19 on the grounds of its in-vitro antiviral effects against SARS-CoV-2. Methods: We examined the association between haloperidol use and respiratory failure at AP-HP Greater Paris University hospitals. Data were obtained regarding all adult patients hospitalized with Covid-19 since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death and the secondary endpoint was discharge home among survivors in time-to-event analyses. We compared outcomes between patients who were exposed to haloperidol and those who were not, using a multivariable Cox regression model with inverse probability weighting according to the propensity score. Results: Of the 13,279 hospitalized adult patients with positive Covid-19 RT-PCR test, 667 patients (5.0%) were excluded because of missing data. Of the remaining 12,612 patients, 104 (0.8%) were exposed to haloperidol. Over a mean follow-up of 20.8 days, the primary endpoint of respiratory failure respectively occurred in 27 patients (26.0%) exposed to haloperidol and 1,700 patients (13.6%) who were not. Among survivors, the secondary endpoint of discharge home occurred in 26 patients (32.1%) who received haloperidol and 6,110 patients (55.3%) who did not. In the main analysis, there were no significant associations between haloperidol use and the primary (HR, 1.09; 95% CI, 0.60 to 1.97, p=0.772) and secondary (HR, 0.88; 95% CI, 0.50 to 1.53, p=0.643) endpoints. Results were similar in multiple sensitivity analyses. Conclusion: In this observational study involving patients with Covid-19 who had been admitted to the hospital, haloperidol use was not associated with risk of intubation or death, or with time to hospital discharge home. These results suggest that haloperidol is unlikely to have a clinical efficacy for Covid-19.

Observational Study of Chlorpromazine in Hospitalized Patients with Covid-19 (preprint)

On the grounds of its anti-inflammatory and potential antiviral effects, chlorpromazine has been suggested to be effective treatment for Covid-19. We examined the association between chlorpromazine use and respiratory failure among all hospitalized adults with Covid-19 at the 39 Greater Paris University hospitals since the beginning of the epidemic. Study baseline was defined as the date of hospital admission. The primary endpoint was a composite of intubation or death in a time-to-event analysis adjusting for numerous potential confounders. We used a multivariable Cox model with inverse probability weighting according to the propensity score. Of the 12,217 adult inpatients with a positive Covid-19 RT-PCR test included in the analyses, 57 (0.47%) received chlorpromazine. Over a mean follow-up of 20.8 days, the primary endpoint occurred in 29 patients (50.9%) exposed to chlorpromazine and 1,899 patients (15.6%) who were not. In the main analysis, there was a positive significant association between chlorpromazine use and the outcome (HR, 1.67; 95% CI, 1.09 to 2.56, p=0.019), while a Cox regression in a matched analytic sample yielded non-significant association (1.38; 95% CI, 0.91 to 2.09, p=0.123). These findings suggest that chlorpromazine is unlikely to have a clinical efficacy for Covid-19.

SSRIs and SNRIs and Risk of Death or Intubation in COVID-19: Results from an Observational Study (preprint)

ObjectiveTo examine the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19. DesignMulticenter observational retrospective cohort study. SettingGreater Paris University hospitals, France. Participants7,345 adults hospitalized with COVID-19 between 24 January and 1 April 2020, including 460 patients (6.3%) who received an antidepressant during the visit. Data sourceAssistance Publique-Hopitaux de Paris Health Data Warehouse. Main outcome measuresThe primary endpoint was a composite of intubation or death. We compared this endpoint between patients who received antidepressants and those who did not in time-to-event analyses adjusting for patient characteristics (such as age, sex, and comorbidities), disease severity and other psychotropic medications. The primary analyses were multivariable Cox models with inverse probability weighting. ResultsOver a mean follow-up of 18.5 days (SD=27.1), 1,331 patients (18.1%) had a primary end-point event. Unadjusted hazard ratio estimates of the association between antidepressant use and the primary outcome stratified by age (i.e., 18-50, 51-70, 71-80, and 81+) were non-significant (all p>0.072), except in the group of patients aged 71-80 years (HR, 0.66; 95% CI, 0.45 to 0.98; p=0.041). Following adjustments, the primary analyses showed a significant association between use of any antidepressant (HR, 0.64; 95% CI, 0.51 to 0.80; p<0.001), SSRI (HR, 0.56; 95% CI, 0.42 to 0.75; p<0.001), and SNRI (HR, 0.57; 95% CI, 0.34 to 0.96; p=0.034), and reduced risk of intubation or death. Specifically, exposures to escitalopram, fluoxetine, and venlafaxine were significantly associated with lower risk of intubation or death (all p<0.05). These associations remain significant in multiple sensitivity analyses, except for the association between SNRI use and the outcome. ConclusionsSSRI use could be associated with lower risk of death or intubation in hospitalized patients with COVID-19. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed. What is already known on this topicO_LIA prior meta-analysis, mainly including studies on selective serotonin reuptake inhibitors (SSRIs), showed that antidepressant use in major depressive disorder was associated with reduced levels of several pro-inflammatory cytokines, including IL-6, TNF-, and CCL-2, which have been suggested to be associated with severe COVID-19. C_LIO_LIA recent in-vitro study supports antiviral effects of the SSRI fluoxetine on SARS-CoV-2. C_LIO_LITo our knowledge, no study has examined the efficacy of antidepressants in patients with COVID-19. C_LI What this study addsO_LIIn a multicenter observational retrospective study, we examined the association between antidepressant use and the risk of intubation or death in hospitalized patients with COVID-19, adjusting for patient characteristics, disease severity and other psychotropic medications. C_LIO_LIAntidepressant use was significantly and substantially associated with reduced risk of intubation or death. C_LIO_LIAt the level of antidepressant classes, SSRI use was significantly and substantially associated with reduced risk of intubation or death, but not other antidepressant classes. C_LIO_LIAt the level of antidepressant medications, exposures to the SSRIs fluoxetine and escitalopram, and the SNRI venlafaxine were significantly associated with lower risk of intubation or death. C_LIO_LIDouble-blind controlled randomized clinical trials of these medications for COVID-19 are needed. C_LI

Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France (preprint)

Objective To assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. Design Retrospective cohort study. Setting An analysis of data from electronic medical records and administrative claim data from the French Assistance Publique - Hopitaux de Paris (AP-HP) data warehouse, in 39 public hospitals, Ile-de-France, France. Participants All adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 2020 were eligible for analysis. The study population was restricted to patients who did not receive COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive drugs. End of follow-up was defined as the date of death, discharge home, day 28 after admission, whichever occurred first, or administrative censoring on May 4, 2020. Intervention Patients were further classified into 3 groups: (i) receiving HCQ alone, (ii) receiving HCQ together with AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the 2 treatments (more or less one day). Main outcome measures The primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect (ATE) were computed to account for confounding. Results A total of 4,642 patients (mean age: 66.1 +/- 18; males: 2,738 (59%)) were included, of whom 623 (13.4%) received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. Patients receiving "HCQ alone" or "HCQ plus AZI" were more likely younger, males, current smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any chronic pulmonary diseases, liver diseases), while no major difference was apparent in biological parameters. After accounting for confounding, no statistically significant difference was observed between the "HCQ" and "Neither drug" groups for 28-day mortality: AIPTW absolute difference in ATE was +1.24% (-5.63 to 8.12), ratio in ATE 1.05 (0.77 to 1.33). 28-day discharge rates were statistically significantly higher in the "HCQ" group: AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). As for the "HCQ+AZI" vs neither drug, trends for significant differences and ratios in AIPTW ATE were found suggesting higher mortality rates in the former group (difference in ATE +9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to 1.81];p=0.062). Conclusions Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials.