Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data

ObjectiveTo assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen.DesignComparative observational study using data collected from routine care.SettingFour French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020.Participants181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care.InterventionsHydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group).Main outcome measuresThe primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting.ResultsIn the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment.ConclusionsHydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.

An open-label randomized, controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19 – Final results from the DisCoVeRy trial (preprint)

Objectives We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in COVID-19 inpatients requiring oxygen and/or ventilatory support. While preliminary results were previously published, we present here the final results, following completion of the data monitoring. Methods We conducted a phase 3 multi-centre open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), add-on trial to Solidarity ( NCT04315948 , EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens, pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, which were stopped prematurely. Results The intention-to-treat population included 593 participants (lopinavir/ritonavir, n=147; lopinavir/ritonavir-IFN-β-1a, n=147; hydroxychloroquine, n=150; control, n=149), among whom 421 (71.0%) were male, the median age was 64 years (IQR, 54-71) and 214 (36.1%) had a severe disease. The day 15 clinical status was not improved with investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.82, (95% confidence interval [CI] 0.54-1.25, P=0.36); lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.05, P=0.08); hydroxychloroquine versus control, aOR 0.94 (95%CI 0.62-1.41, P=0.76). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of Serious Adverse Events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms. Conclusion In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-ß-1a and hydroxychloroquine did not improve the clinical status at day 15, nor SARS-CoV-2 clearance in respiratory tract specimens.

Innate immune deficiencies in patients with COVID-19 (preprint)

COVID-19 can cause acute respiratory distress syndrome (ARDS), leading to death in a significant number of individuals. Evidence of a strong role of the innate immune system is accumulating, but the precise cells and mechanism involved remain unclear. In this study, we investigated the links between circulating innate phagocyte phenotype and functions and severity in COVID-19 patients. Eighty-four consecutive patients were included, 44 of which were in intensive care units (ICU). We performed an in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, myeloid cell functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Resulting parameters were linked to disease severity and prognosis. Both ICU and non-ICU patients had circulating neutrophils and monocytes with an activated phenotype, as well as elevated concentrations of soluble activation markers (calprotectin, myeloperoxidase, neutrophil extracellular traps, MMP9, sCD14) in their plasma. ICU patients were characterized by increased CD10low CD13low immature neutrophils, LOX-1+ and CCR5+ immunosuppressive neutrophils, and HLA-DRlow CD14low downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity and poor outcome. Moreover, neutrophils and monocytes of ICU patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Our study reveals a marked dysregulation of innate immunity in COVID-19 patients, which was correlated with severity and prognosis. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options. One Sentence SummaryOur study reveals a marked dysregulation of innate immunity in COVID-19 patients, which correlates with severity and prognosis.

Sarilumab treatment of hospitalised patients with severe or critical COVID-19: a multinational, randomised, adaptive, phase 3, double-blind, placebo-controlled trial (preprint)

Background: Elevated proinflammatory cytokines have been associated with 2019 coronavirus disease (COVID-19) severity. We assessed efficacy and safety of sarilumab, an interleukin-6 receptor inhibitor, in severe (requiring supplemental oxygen by nasal canula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: This was a 60-day, randomised, double-blind, placebo-controlled, multinational trial in patients hospitalised with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomised 2:2:1 to intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. The primary endpoint was time to >=2-point clinical improvement (7-point scale; range: 1 [death] to 7 [not hospitalised]). The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This trial is registered with ClinicalTrials.gov (NCT04327388). Findings: Between March 28 and July 3, 2020, 420 patients were randomised; 416 received treatment (placebo, n=84; sarilumab 200 mg, n=159; sarilumab 400 mg, n=173). At day 29, there were no significant differences in median (95% CI) time to >=2-point improvement between placebo (12.0 [9.0-15.0] days) and sarilumab groups (200 mg: 10.0 [9.0-12.0] days, p=0.96, log-rank test; 400 mg: 10.0 [9.0-13.0] days, p=0.34) or in proportions of patients alive (placebo, 91.7%; sarilumab 200 mg, 89.9%, p=0.63; sarilumab 400 mg, 91.9%, p=0.85). At day 29, there were numerical, nonsignificant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +9%, 95% CI -7.7 to 25.5, p=0.25) for critical patients. There were no unexpected safety signals. Interpretation: This trial did not demonstrate efficacy of sarilumab in patients hospitalised with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals, Inc.

Pulmonary bacterial infections in patients hospitalized for COVID-19: a retrospective observational study (preprint)

Backround During the COVID-19 pandemic, antibiotics use was very common. However, bacterial co/secondary infections with coronaviruses remain largely unknown, especially outside of intensive care. The aim of this study was to investigate the pulmonary bacterial infections characteristics associated with COVID-19 in hospitalized patients.Methods A retrospective monocentric observational study was conducted in Bichat hospital in France, between February 26 and April 22, 2020. All patients hospitalized in standard wards with COVID-19 (positive nasopharyngeal PCR and/or typical aspect on CT scan) and diagnosed with a pulmonary bacterial infection (positive bacteriological samples) were included. Bacteriological and clinical data were collected from the microbiology laboratories and the patient's medical records.Results Twenty-three bacteriological samples from 22 patients were positive out of 2075 screened samples (1.1%) from 784 patients (2.8%). Bacterial infection occurred with a median of ten days after COVID-19 onset. Diagnosis of pulmonary bacterial infection was suspected on the increase of oxygen requirements (20/22), productive cough or modification of sputum (17/22), or fever (10/22). Positive samples included 13 sputum cultures, one Film Array® on sputum, one bronchoalveolar lavage, six blood cultures and two pneumococcal antigenuria. The most frequent bacteria were Pseudomonas aeruginosa (6/23), Staphylococcus aureus (5/23), Streptococcus pneumoniae (4/23), Enterococcus faecalis (3/23) and Klebsiella aerogenes (3/23). No Legionella antigenuria was positive. Four out of 496 nasopharyngeal PCR (0.8%) were positive for intracellular bacteria (two Bordetella pertussis and two Mycoplasma pneumonia).Conclusions Pulmonary bacterial secondary infections and co-infections with SARS-CoV-2 are uncommon. Antibiotic use should remain limited in the management of COVID-19.

Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial (preprint)

Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-beta-1a (44 micrograms of subcutaneous IFN-beta-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). Measurements: The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. Results: Adjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-beta-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing

Sociodemographic Characteristics and Transmission Risk Factors In Patients Hospitalized for COVID-19 Before And During The Lockdown In France (preprint)

Background: The efficacy of lockdown in containing the COVID-19 pandemic has been reported in different studies. However, the impact on sociodemographic characteristics of individuals infected with SARS-CoV-2 has not been evaluated. The aim of this study was to describe the changes in sociodemographic characteristics of patients hospitalized for COVID-19 and to compare the transmission risk factors of COVID-19 before and during lockdown in France. Methods: An observational retrospective study was conducted in a University Hospital in Paris, France. Data from patients hospitalized for COVID-19 in the Infectious Diseases Department between February 26 and May 11, 2020 were collected. The study population was divided into 2 groups: group A of patients infected before lockdown, and group B of patients infected during lockdown, considering a maximum incubation period of 14 days. Sociodemographic characteristics and transmission risk factors were compared between the 2 groups using Student's t-test for continuous variables and Chi-2 test or Fisher exact test for categorical variables.Results: Three hundred eighty-three patients were included in the study, 305 (79.6%) in group A and 78 (20.4%) in group B. Patients in group A were significantly younger (60.0 versus (vs) 66.5 years (p=0.03)). The professionally active population was larger in group A (44.3% vs 24.4%). There were significantly more non-French-speaking people in group B (16.7% vs 6.6%, p<0.01). Most patients from group A had individual accommodation (92.8% vs 74.4%, p<0.01). Contact with a relative was the main transmission risk factor in both groups (24.6% vs 33.3%, p=0.16). Recent travel and large gathering were found only in group A. The proportion of people living in disadvantaged conditions, such as homeless people or people living in social housing, was significantly higher in group B (11.5% vs 4.3%, p=0.03) as was the proportion of institutionalized individuals (14.1% vs 3.0%, p<0.01).Conclusions: In this study conducted in patients hospitalized for COVID-19 in Paris, France, the likelihood of being infected despite the lockdown was higher for people who do not speak French, live in social housing, are homeless or institutionalized. Targeted measures have to be implemented to protect these populations.

Airborne contamination of COVID-19 in hospitals: a scoping review of the current evidence. (preprint)

Introduction A controversy remains worldwide regarding the transmission routes of SARS-CoV-2 in hospital settings. We reviewed the current evidence on the air contamination with SARS-CoV-2 in hospital settings, and the factors associated to the contamination including the viral load and the particles size. Methods The MEDLINE, Embase, Web of Science databases were systematically interrogated for original English-language articles detailing COVID-19 air contamination in hospital settings between 1 December 2019 and 21 July 2020. This study was conducted in accordance with the PRISMA-ScR guidelines. The positivity rate of SARS-CoV-2 viral RNA and culture were described and compared according to the setting, clinical context, air ventilation system, and distance from patient. The SARS-CoV-2 RNA concentrations in copies per m3 of air were pooled and their distribution were described by hospital areas. Particle sizes and SARS-CoV-2 RNA concentrations in copies or TCID50 per m3 were analysed after categorization of sizes in <1 micrometers, 1-4 micrometers, and >4 micrometers. Results Among 2,034 records identified, 17 articles were included in the review. Overall, 27.5% (68/247) of air sampled from close patients environment were positive for SARS-CoV-2 RNA, without difference according to the setting (ICU: 27/97, 27.8%; non-ICU: 41/150, 27.3%; p=0.93), the distance from patients (<1 meter: 1/64, 1.5%; 1-5 meters: 4/67, 6%; p=0.4). In other areas, the positivity rate was 23.8% (5/21) in toilets, 9.5% (20/221) in clinical areas, 12.4% (15/121) in staff areas, and 34.1% (14/41) in public areas. A total of 78 viral cultures were performed in three studies, and 3 (4%) were positive, all from close patients environment. The median SARS-CoV-2 RNA concentrations varied from 1.103 copies per m3 (IQR: 0.4.103-9.103) in clinical areas to 9.7.103 (5.1.103-14.3.103) in the air of toilets or bathrooms. The protective equipment removal and patients rooms had high concentrations/titre of SARS-CoV-2 with aerosol size distributions that showed peaks in the <1 micrometers region, and staff offices in the >4 micrometers region. Conclusion In hospital, the air near and away from COVID-19 patients is frequently contaminated with SARS-CoV-2 RNA, with however, rare proofs of their viability. High viral loads found in toilet/bathrooms, staff and public hallways suggests to carefully consider these areas.

Repurposed prophylaxis strategies for COVID-19: a systematic review (preprint)

Introduction Efficient therapeutic strategies are needed to counter the COVID-19 pandemic, caused by the SARS- CoV-2 virus. In a context where specific vaccines are not yet available, the containment of the pandemic would be facilitated with efficient prophylaxis. Methods We screened several clinical trials repositories and platforms in search of the prophylactic strategies that are investigated against COVID-19 in late April 2020. Results Up to April 27, 2020, we found 68 clinical trials targeting medical workers (n=43, 63%), patients relatives (n=16, 24%) or individuals at risk of severe COVID-19 (n=5, 7%). (Hydroxy)chloroquine was the most frequently evaluated treatment (n=46, 68%), before BCG vaccine (n=5, 7%). Sixty-one (90%) clinical trials were randomized with a median of planned inclusions of 600 (IQR 255-1515). Conclusion The investigated prophylaxis strategies cover both pre- and post-exposure prophylaxis and study numerous immune enhancers and antivirals, although most research efforts are focused on (hydroxy)chloroquine.

Review and methodological analysis of trials currently testing treatment and prevention options for the novel coronavirus disease (COVID-19) globally. (preprint)

Background: As novel coronavirus disease (COVID-19) cases continue to steeply rise globally within an unprecedented short period of time, solid evidence from large randomised controlled trials is still lacking. Currently, numerous trials testing potential treatment and preventative options are undertaken globally. Objectives: We summarised all currently registered clinical trials examining treatment and prevention options for COVID-19 pneumonia. Additionally, we evaluated the quality of the retrieved interventional studies. Data sources: The ClinicalTrials.gov, the Chinese Clinical Trial Registry and the European Union Clinical Trials Register were systematically searched. Study eligibility criteria: Registered clinical trials examining treatment and/or prevention options for COVID-19 were included. No language, country or study design restrictions were applied. Withdrawn, cancelled studies and trials not reporting therapeutic or preventative strategies for COVID-19 were excluded. Participants and interventions: No restrictions in terms of participants' age and medical background or type of intervention were enforced. Methods: The registries were searched using the term "coronavirus" or "COVID-19" from their inception until 26th March 2020. Additional manual search of the registries was also performed. Eligible studies were summarised and tabulated. Interventional trials were methodologically analysed, excluding expanded access studies and trials testing Traditional Chinese Medicine. Results: In total, 309 trials evaluating therapeutic management options, 23 studies assessing preventive strategies and 3 studies examining both were retrieved. Interventional treatment studies were mostly randomised (n=150, 76%) and open-label (n=73, 37%) with a median number of planned inclusions of 90 (IQR 40-200). Major categories of interventions that are currently being investigated are discussed. Conclusion: Numerous clinical trials have been registered since the onset of the COVID-19 pandemic. Summarised data on these trials will assist physicians and researchers to promote patient care and guide future research efforts for COVID-19 pandemic containment. However, up to the end of March, 2020, significant information concerning reported trials was lacking.

A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19 (preprint)

Background: Although a number of antiviral agents have been evaluated for coronaviruses there are no approved drugs available. To provide an overview of the landscape of therapeutic research for COVID-19, we conducted a review of registered clinical trials. Methods: A review of currently registered clinical trials was performed on registries, including the Chinese (chictr.org.cn) and US (clinicaltrials.gov) databases to identify relevant studies up to March, 7th 2020. The search was conducted using the search terms "2019-nCoV", "COVID-19", "SARS-CoV-2", "Hcov-19", "new coronavirus", "novel coronavirus". We included interventional clinical trials focusing on patients with COVID-19 and assessing antiviral drugs or agents. Findings: Out of the 353 studies identified, 115 clinical trials were selected for data extraction. Phase IV trials were the most commonly reported study type (n=27, 23%). However, 62 trials (54%) did not describe the phase of the study. Eighty percent (n=92) of the trials were randomized with parallel assignment and the median number of planned inclusions was 63 (IQR, 36-120). Open-label studies were the most frequent (46%) followed by double-blind (13%) and single blind studies (10%). The most frequently assessed therapies were: stem cells therapy (n=23 trials), lopinavir/ritonavir (n=15), chloroquine (n=11), umifenovir (n=9), hydroxychloroquine (n=7), plasma treatment (n=7), favipiravir (n=7), methylprednisolone (n=5), and remdesivir (n=5). Remdesivir was tested in 5 trials with a median of 400 (IQR, 394-453) planned inclusions per trial, while stem cells therapy was tested in 23 trials, but had a median of 40 (IQR, 23-60) planned inclusions per trial. Lopinavir/ritonavir was associated with the highest total number of planned inclusions (2606) followed by remdesivir (2155). Only 52% of the clinical trials reported the treatment dose (n=60) and only 34% (n=39) the duration. The primary outcome was clinical in 76 studies (66%), virological in 27 (23%); radiological in 9 (8%) or immunological in three studies (3%). Interpretation: Numerous clinical trials have been registered since the beginning of the COVID-19 outbreak, however, a number of information regarding drugs or trial design were lacking. Funding: None