Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital 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

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Multi-sectorial research is paramount for preventing and controlling emerging infectious diseases

International audienceThe social, economic and political consequences of emerging infectious disease (EID) may escape the sphere in which they first arise. In recent years, many EIDs have revealed the close links between human, animal and plant health, highlighting the need for multi-scale, multisectorial EID management. Human beings play a dual role in EID because they can promote their development through numerous human-environment interfaces and expanding international trade. On the other hand, their ability to analyze, interpret and act on the determinants of EID allows them to access the expertise necessary to control these EIDs. This expertise must be constantly adapted to remain relevant as the EID evolves, particularly in its virulence or transmission channels. Flexibility should become an inherent part of the expertise-based decision-making process even if it means going backwards. A certain degree of transparency and feedback to citizens is necessary for the acceptability of political decisions basing on expertise. A key step in the management of EID is the appropriate management of the early signal of infectious emergence. This step combines multidisciplinary skills allowing access to the best pathway for containing EID by implementing early countermeasures adapted to the situation. New digital technologies could significantly improve this early detection phase. Finally, experts have a fundamental role to play because they are located at the interface between operational actors and decision-makers, which allows multidirectional feedback, ideally in real time, between professional actors and decision makers. To combat current and future EIDs, expertise should be based on a multi-sectorial approach, promotion of collegiality and continuously adaptation to the evolving nature of EIDs

Emerging human infectious diseases of aquatic origin : a comparative biogeographic approach using Bayesian spatial modelling

BackgroundWith the increase in unprecedented and unpredictable disease outbreaks due to human-driven environmental changes in recent years, we need new analytical tools to map and predict the spatial distribution of emerging infectious diseases and identify the biogeographic drivers underpinning their emergence. The aim of the study was to identify and compare the local and global biogeographic predictors such as landscape and climate that determine the spatial structure of leptospirosis and Buruli Ulcer (BU).MethodsWe obtained 232 hospital-confirmed leptospirosis (2007-2017) cases and 236 BU cases (1969-2017) in French Guiana. We performed non-spatial and spatial Bayesian regression modeling with landscape and climate predictor variables to characterize the spatial structure and the environmental drivers influencing the distribution of the two diseases.ResultsOur results show that the distribution of both diseases is spatially dependent on environmental predictors such as elevation, topological wetness index, proximity to cropland and increasing minimum temperature at the month of potential infection. However, the spatial structure of the two diseases caused by bacterial pathogens occupying similar aquatic niche was different. Leptospirosis was widely distributed across the territory while BU was restricted to the coastal riverbeds.ConclusionsOur study shows that a biogeographic approach is an effective tool to identify, compare and predict the geographic distribution of emerging diseases at an ecological scale which are spatially dependent to environmental factors such as topography, land cover and climate

PADS 2-07 - La leptospirose en Guyane française : 1re étude transversale multicentrique 2007-2014.

National audienceIntroduction La leptospirose est une zoonose de répartition mondiale avec une incidence en augmentation. Elle représente un problème de santé publique en zone tropicale. L’objectif de notre étude était de faire un état des lieux de la leptospirose en Guyane Française afin d’en améliorer la prise en charge