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BACKGROUND: Data on the presentation, management and outcomes of Lassa fever (LF) in children are limited. METHODS: Description of the clinical and biological features, treatment and outcomes of RT-PCR-confirmed LF in children aged under 15, enrolled in the LASCOPE prospective cohort study in Nigeria between April 2018 and February 2023. RESULTS: 124 children (aged under 12 months: 19; over 12 months: 105) were hospitalized with RT-PCR-confirmed LF. All received intravenous ribavirin. During follow-up, 99/124 (80%) had fever; 71/124 (57%) had digestive symptoms, vomiting (n = 56/122, 46%) and abdominal pain (n = 34/78 aged ≥ 5 years, 44%) more often than diarrhea (n = 19/124, 15%); 17/124 (14%) had hemorrhagic signs; 44/112 (39%) had a hematocrit lower than 25%, of whom 32/44 (73%) received transfusions; 44/88 (50%) developed hypotension; 18/112 (16.1%) developed KDIGO ≥ 2 acute kidney injury; 10/112 (8.9%) had KDIGO 3 acute kidney failure; 4/124 (3.2%) underwent renal replacement therapy. 7 children died, including 4 aged under 12 months (case fatality rate: under 12 months - 22%, 95% CI 7 - 48%; over 12 months - 2.9%, 95% CI 0.7 - 8.7%). In univariable analysis, age (p=0.003), impaired consciousness (p=0.026), and Lassa RT-PCR Ct value (p=0.006) were associated to Day 30 mortality. CONCLUSIONS: The fatality rate for children over 12 months hospitalized with LF was lower than that previously reported for adults. Hypotension and acute kidney injury were the most frequent organ dysfunctions. Bleeding was relatively infrequent. Anemia and the need for transfusion were common, the relative contribution of ribavirin-induced hemolysis being unknown.
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BACKGROUND: Dengue is a leading cause of febrile illness among international travellers. We aimed to describe the epidemiology and clinical characteristics of imported dengue in returning travellers evaluated at GeoSentinel sites from 2007-2022. METHODS: We retrieved GeoSentinel records of dengue among travellers residing in non-endemic countries. We considered dengue confirmed when diagnosed by a positive DENV-specific RT-PCR, positive NS-1 antigen, and/or anti-DENV IgG seroconversion, and probable when diagnosed by single anti-DENV IgM or high titre anti-DENV IgG detection. Severe dengue was defined as evidence of clinically significant plasma leakage or bleeding, organ failure, or shock, according to the 2009 WHO guidance. Complicated dengue was defined as either severe dengue or dengue with presence of any warning sign. Analyses were descriptive. RESULTS: This analysis included 5958 travellers with confirmed (n = 4859; 81.6%) or probable (n = 1099; 18.4%) dengue. The median age was 33 years (range: < 1-91); 3007 (50.5%) travellers were female. The median travel duration was 21 days (interquartile range [IQR]: 15-32). The median time between illness onset and GeoSentinel site visit was 7 days (IQR: 4-15). The most frequent reasons for travel were tourism (67.3%), visiting friends or relatives (12.2%), and business (11.0%). The most frequent regions of acquisition were Southeast Asia (50.4%), South-Central Asia (14.9%), the Caribbean (10.9%), and South America (9.2%). Ninety-five (1.6%) travellers had complicated dengue, of whom 27 (0.5%) had severe dengue, and one died. Of 2710 travellers with data available, 724 (26.7%) were hospitalized. The largest number of cases (n = 835) was reported in 2019. CONCLUSIONS: A broad range of international travellers should be aware of the risk of acquiring dengue and receive appropriate pretravel counselling regarding preventive measures. Prospective cohort studies are needed to further elucidate dengue risk by destination and over time, as well as severe outcomes and prolonged morbidity (long-dengue) due to travel-related dengue.
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BACKGROUND: Thrombo-inflammation and neutrophil extracellular traps (NETs) are exacerbated in severe cases of COVID-19, potentially contributing to disease exacerbation. However, the mechanisms underpinning this dysregulation remain elusive. We hypothesised that lower DNase activity may be associated with higher NETosis and clinical worsening in patients with COVID-19. METHODS: Biological samples were obtained from hospitalized patients (15 severe, 37 critical at sampling) and 93 non-severe ambulatory cases. Our aims were to compare NET biomarkers, functional DNase levels, and explore mechanisms driving any imbalance concerning disease severity. RESULTS: Functional DNase levels were diminished in the most severe patients, paralleling an imbalance between NET markers and DNase activity. DNase1 antigen levels were higher in ambulatory cases but lower in severe patients. DNase1L3 antigen levels remained consistent across subgroups, not rising alongside NET markers. DNASE1 polymorphisms correlated with reduced DNase1 antigen levels. Moreover, a quantitative deficiency in plasmacytoid dendritic cells (pDCs), which primarily express DNase1L3, was observed in critical patients. Analysis of public single-cell RNAseq data revealed reduced DNase1L3 expression in pDCs from severe COVID-19 patient. CONCLUSION: Severe and critical COVID-19 cases exhibited an imbalance between NET and DNase functional activity and quantity. Early identification of NETosis imbalance could guide targeted therapies against thrombo-inflammation in COVID-19-related sepsis, such as DNase administration, to avert clinical deterioration. TRIAL REGISTRATION: COVERAGE trial (NCT04356495) and COLCOV19-BX study (NCT04332016).
Subject(s)
COVID-19 , Extracellular Traps , Nervous System Diseases , Humans , Extracellular Traps/metabolism , Neutrophils/metabolism , Deoxyribonucleases/metabolism , Deoxyribonuclease I/metabolism , Inflammation/metabolismABSTRACT
BACKGROUND: Schistosomiasis affects approximately 230 million people worldwide. There is an increased incidence of schistosomiasis cases in France acquired from outside the country. This increases the risk of schistosomiasis outbreaks as observed in Corsica. Clinicians from non-endemic regions are not accustomed to diagnosing and managing this pathology. The objective of this study is to provide a better description of the clinical and paraclinical characteristics and disease evolution of affected children. METHODS: Through the French Pediatric Nephrology Society and the Pediatric Infectious Pathology Group, we contacted all French pediatric centers that may have treated children with urinary schistosomiasis between 2013 and 2019. Age, sex, comorbidities, and clinical, biological, and radiological data (at discovery and follow-up) were collected retrospectively. RESULTS: A total of 122 patients from 10 different centers were included. The median age was 14 years and the sex ratio M/F was 4:1. Hematuria was present in 82% of the patients while urinary tract abnormality was found in 36% of them. Fourteen patients (11%) displayed complicated forms of urinary schistosomiasis including 10 patients with chronic kidney disease. A total of 110 patients received treatment with praziquantel, which was well-tolerated and led to clinical resolution of symptoms in 98% of cases. CONCLUSION: Patients with schistosomiasis present frequent kidney, urinary, or genital involvement. Systematic screening of patients returning from endemic areas is therefore recommended, especially since treatment with antiparasitic drugs is effective and well-tolerated. Enhancing medical knowledge of this pathology among all practitioners is essential to improve care and outcomes.
Subject(s)
Schistosomiasis haematobia , Humans , Child , Adolescent , Animals , Schistosomiasis haematobia/diagnosis , Schistosomiasis haematobia/drug therapy , Schistosomiasis haematobia/epidemiology , Retrospective Studies , Praziquantel/therapeutic use , Hematuria , France/epidemiology , Schistosoma haematobiumABSTRACT
BACKGROUND: Prolonged diarrhoea is common amongst returning travellers and is often caused by intestinal protozoa. However, the epidemiology of travel-associated illness caused by protozoal pathogens is not well described. METHODS: We analysed records of returning international travellers with illness caused by Giardia duodenalis, Cryptosporidium spp., Cyclospora cayetanensis or Cystoisospora belli, reported to the GeoSentinel Network during January 2007-December 2019. We excluded records of travellers migrating, with an unascertainable exposure country, or from GeoSentinel sites that were not located in high-income countries. RESULTS: There were 2517 cases, 82.3% giardiasis (n = 2072), 11.4% cryptosporidiosis (n = 287), 6.0% cyclosporiasis (n = 150) and 0.3% cystoisosporiasis (n = 8). Overall, most travellers were tourists (64.4%) on long trips (median durations: 18-30 days). Cryptosporidiosis more frequently affected people < 18 years (13.9%) and cyclosporiasis affected people ≥ 40 years (59.4%). Giardiasis was most frequently acquired in South Central Asia (45.8%) and sub-Saharan Africa (22.6%), cryptosporidiosis in sub-Saharan Africa (24.7%) and South-Central Asia (19.5%), cyclosporiasis in South East Asia (31.3%) and Central America (27.3%), and cystoisosporiasis in sub-Saharan Africa (62.5%). Cyclosporiasis cases were reported from countries of uncertain endemicity (e.g. Cambodia) or in countries with no previous evidence of this parasite (e.g. French Guiana). The time from symptom onset to presentation at a GeoSentinel site was the longest amongst travellers with giardiasis (median: 30 days). Over 14% of travellers with cryptosporidiosis were hospitalized. CONCLUSIONS: This analysis provides new insights into the epidemiology and clinical significance of four intestinal protozoa that can cause morbidity in international travellers. These data might help optimize pretravel advice and post-travel management of patients with travel-associated prolonged gastrointestinal illnesses. This analysis reinforces the importance of international travel-related surveillance to identify sentinel cases and areas where protozoal infections might be undetected or underreported.
Subject(s)
Cryptosporidiosis , Cyclosporiasis , Giardiasis , Travel , Humans , Adult , Male , Female , Cryptosporidiosis/epidemiology , Cryptosporidiosis/diagnosis , Middle Aged , Adolescent , Travel/statistics & numerical data , Giardiasis/epidemiology , Giardiasis/diagnosis , Cyclosporiasis/epidemiology , Cyclosporiasis/diagnosis , Young Adult , Cryptosporidium/isolation & purification , Diarrhea/epidemiology , Diarrhea/parasitology , Cyclospora/isolation & purification , Child , Aged , Child, Preschool , Giardia lamblia/isolation & purification , Sentinel SurveillanceABSTRACT
In September 2023, a severe outbreak of type B botulism with fifteen cases was linked to consumption of canned sardines at a restaurant in Bordeaux, France, during the Rugby World Cup. The cases were from seven countries. One death was recorded. Outbreak investigation using credit card data, rapid communication between health authorities of the affected countries and broad media communication allowed identification of cases and exposed persons and prevented further severe outcomes.
Subject(s)
Botulism , Clostridium botulinum , Humans , Botulism/diagnosis , Botulism/epidemiology , Rugby , Disease Outbreaks , France/epidemiologyABSTRACT
Background: Since 2021, 3 variants of concern (VOC) have spread to France, causing successive epidemic waves. Objectives: To describe the features of Alpha, Delta and Omicron VOC circulation in the Nouvelle-Aquitaine region, France, between February 2021 and February 2022. Study design: Data from the three university hospitals (UH) of Nouvelle-Aquitaine were used to describe regional SARS-CoV-2 circulation (RT-PCR positive rates and identified VOC) as well as its consequences (total number of hospitalizations and admissions in intensive care unit). They were analyzed according to the predominant variant and compared with national data. Results: A total of 611,106 SARS-CoV-2 RT-PCR tests were performed in the 3 Nouvelle-Aquitaine UH during the study period. The 37,750 positive samples were analyzed by variant-specific RT-PCR or whole-genome sequencing. In 2021, Alpha VOC was detected from week 5 until week 35. Delta became the most prevalent variant (77.3%) in week 26, reaching 100% in week 35. It was replaced by Omicron, which was initially detected week 48, represented 77% of positive samples in week 52 and was still predominant in February 2022. The RT-PCR positive rates were 4.3, 4.2, and 21.9% during the Alpha, Delta and Omicron waves, respectively. The ratio between intensive care unit admissions and total hospitalizations was lower during the Omicron wave than during the two previous waves due to the Alpha and Delta variants. Conclusion: This study highlighted the need for strong regional cooperation to achieve effective SARS-CoV-2 epidemiological surveillance, in close association with the public health authorities.
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BACKGROUND: In endemic foci, the use of an aquaphilic cream containing paromomycin with/without gentamicin to treat cutaneous leishmaniasis (CL) is safe, painless and cures 78-82% of patients with New and Old World CL. Self-application in travelers requires evaluation. METHODS: Travelers with 1-10 lesions of confirmed CL were prospectively treated with the paromomycin-gentamicin formulation (WR279396, 2012-2017, Group 1) and carefully follow up, or treated with a locally produced paromomycin-only cream (2018-2022, Group 2). The cream was applied once under supervision, then self-applied daily for 20-30 days. A cured lesion was defined as 100% re-epithelialization at day 42 without relapse at three months. RESULTS: Medical features were similar in Group 1 (17 patients), and Group 2 (23 patients). Patients were infected with either Leishmania major, L. infantum, L. killicki, L. guyanensis, L. braziliensis, or L. naiffi. Intention-to-treat and per-protocol cure rates were 82% (95% confidence interval (CI) [64.23;100.00]) and 87% (95% CI [71,29;100.00]) in Group 1, and 69% (95% CI [50.76; 88.37]) and 76% (95% CI [57.97; 94.41]) in Group 2. In the pooled Group 1&2, 75% (95% CI [61.58;88.42]) (30/40) and 81% (95% CI [68,46;93.6]) (30/37) of patients were cured in intention-to-treat and per-protocol, respectively. There were no significant differences observed in the success rates between Old World and New World CL (83.3% vs. 60%, p = 0.14). Prospective observations in Group 1 showed that adverse events were mainly pruritus (24%) and pain (18%) on lesions (all mild or moderate). No mucosal involvement was observed in either group. DISCUSSION: In this representative population of travelers who acquired CL either in the Old or New World, the 81% per-protocol cure rate of a self-applied aminoglycoside cream was similar to that observed in clinical trials.
Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Humans , Paromomycin/therapeutic use , Antiprotozoal Agents/therapeutic use , Prospective Studies , Leishmaniasis, Cutaneous/drug therapy , Aminoglycosides/therapeutic use , Anti-Bacterial Agents/therapeutic use , GentamicinsABSTRACT
Patient experiences and perspectives on trial participation and follow-up may influence their compliance with research procedures or negatively impact their well-being. We aimed to explore the acceptability and feasibility of home-based and hospital-based follow-up modalities among COVID-19 patients enrolled in the ANTICOV ANRS COV33 Coverage-Africa trial in Burkina Faso and Guinea. The trial (2021-2022) evaluated the efficacy of treatments to prevent clinical worsening among COVID-19 patients with mild to moderate symptoms. Patients were either based at home or hospitalized, as per national recommendations, and followed-up through face-to-face visits and phone calls. We conducted a mixed-methods sub-study administering a questionnaire to all consenting participants and individually interviewing purposively selected participants. We performed descriptive analyses of Likert scale questions for the questionnaires and thematic analysis for the interviews. We conducted framework analysis and interpretation. Of the 400 trial patients, 220 completed the questionnaire (n = 182 in Burkina Faso, n = 38 in Guinea) and 24 were interviewed (n = 16 and n = 8, respectively). Participants were mostly followed-up at home in Burkina Faso; all patients from Guinea were first hospitalized, then followed-up at home. Over 90% of participants were satisfied with follow-up. Home follow-up was considered acceptable if (i) participants perceived they were not severely ill, (ii) it was combined with telemedicine, and (iii) the risk of stigma could be avoided. Hospital-based follow-up was viewed as a way to prevent contamination of family members, but could be badly experienced when mandatory and conflicting with family responsibilities and commitments. Phone calls were seen as reassuring and as a way to ensure continuity of care. These overall positive findings support the development of home-based follow-up for mildly ill patients in West-Africa, provided that both emotional and cognitive factors at individual, familial/inter-relational, healthcare and national levels be addressed when planning the implementation of a trial, or developing any public health strategy.
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Background: Earlier studies found characteristic haematological changes in African patients with active schistosomiasis. If consistently present, full blood counts (FBC) may be helpful to diagnose schistosomiasis also in migrants and returning travellers. Methods: A retrospective patient record review was conducted on data from seven European travel clinics, comparing FBC of Schistosoma egg-positive travellers and migrants to reference values. Sub-analyses were performed for children, returned travellers, migrants and different Schistosoma species. Results: Data analysis included 382 subjects (median age 21.0 years [range 2-73]). In returned travellers, decreases in means of haemoglobin particularly in females (ß = -0.82 g/dL, p = 0.005), MCV (ß = -1.6 fL, p = 0.009), basophils, neutrophils, lymphocytes and monocytes (ß = -0.07, p < 0.001; -0.57, p = 0.012; -0.57, p < 0.001 and -0.13 103/µL, p < 0.001, respectively) were observed. As expected, eosinophils were increased (ß = +0.45 103/µL, p < 0.001). In migrants, a similar FBC profile was observed, yet thrombocytes and leukocytes were significantly lower in migrants (ß = -48 103/µL p < 0.001 and ß = -2.35 103/µL, p < 0.001, respectively). Conclusions: Active egg-producing Schistosoma infections are associated with haematological alterations in returned travellers and migrants. However, these differences are discrete and seem to vary among disease stage and Schistosoma species. Therefore, the FBC is unsuitable as a surrogate diagnostic parameter to detect schistosomiasis.
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BACKGROUND: The emergency set-up and implementation of outpatient clinical trials on epidemic emerging infectious diseases such as COVID-19 raise many issues in terms of research structuration, regulations, and health systems organization. We aimed to describe the experience and points of view of different stakeholders involved in a French home-based outpatient trial on COVID-19 and to identify the early barriers and facilitators to the trial implementation. METHODS: We conducted a mixed-methods study in July 2020. A self-administered questionnaire was emailed to 213 clinical, operational and research stakeholders involved in the Coverage trial; individual semi-directed interviews were conducted among 14 stakeholders. Questionnaire data and written interview notes are presented together by key theme. RESULTS: One hundred fifty six stakeholders responded to the questionnaire. 53.4% did not have prior experience in clinical research. The motivation of most stakeholders to participate in the Coverage trial was to feel useful during the pandemic. 87.9% agreed that the trial had an unusual set-up timeframe, and many regretted a certain lack of regulatory flexibility. Mobile medical teams and specific professional skills were perceived as instrumental for outpatient research. CONCLUSIONS: The implementation of a home-based outpatient clinical trial on COVID-19 was perceived as relevant and innovative although requiring important adaptations of usual professional responsibilities and standard research procedures. Lessons learned from the Coverage trial underline the need for improved networks between hospital and community medicine, and call for a dedicated and reactive outpatient research platform on emerging or threatening infectious diseases.
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OBJECTIVES: To explore communities' perceptions about COVID-19 in the context of the ANRS COV33 Coverage-Africa clinical trial evaluating the efficacy of treatments in preventing clinical worsening of COVID-19. DESIGN: Descriptive qualitative study using semistructured in-depth individual interviews conducted by telephone in French and Soussou between May and September 2021. Data were transcribed, translated in French when applicable and analysed with the thematic analysis method. SETTING: The eight neighbourhoods most affected by COVID-19 in Conakry's urban context, capital of Guinea. PARTICIPANTS: 4 community leaders acting as key informants-providing insights regarding population's opinions-and six community members, who were exposed to an information session conducted as part of Coverage-Africa. RESULTS: According to participants, community members have heterogeneous viewpoints about COVID-19: it exists and is dangerous; it is benign ('bad cold'); or it is fictitious (eg, government conspiracy). The fear of stigmatisation and social isolation of those sick or cured of COVID-19 was largely reported by participants, with illustrations of distressing situations for the victims. To avoid stigma, many patients seem to adopt strategies of discretion (eg, lying/hiding about the disease). Although community attitudes were reported to have evolved since the beginning of the epidemic, stigma remained a pervasive concern for many people. CONCLUSIONS: Community perceptions about COVID-19 in Conakry may be partly explained by the Guinean context of Ebola history and of sociopolitical tensions. Stigmatisation of COVID+ people seems to be aimed at protecting others against contamination. However, social avoidance can greatly affect the morale of stigmatised people, especially in collectivist cultures like Guinea. Further investigating stigma, including its role on seeking COVID-19 screening and treatment services, and its consequences on mental health among affected/exposed people, would contribute to identifying improved prevention and care interventions in preparation for future health threats, and to promoting participation in health research. TRIAL REGISTRATION NUMBER: NCT04920838 (Pre-results stage).
Subject(s)
COVID-19 , Humans , Guinea/epidemiology , Qualitative Research , Social Stigma , AfricaABSTRACT
BACKGROUND: Viral hemorrhagic fevers (VHFs) are a group of diseases, which can be endemo-epidemic in some areas of the world. Most of them are characterized by outbreaks, which occur irregularly and are hard to predict. Innovative medical countermeasures are to be evaluated but due to the field specificities of emerging VHF, challenges arise when implementing clinical studies. To assess the state of the art around VHFs, we conducted a systematic review for all reports and clinical studies that included specific results on number of cases, mortality and treatment of VHFs. METHODS: The search was conducted in January 2020 based on PRISMA guidelines (PROSPERO CRD42020167306). We searched reports on the WHO and CDC websites, and publications in three international databases (MEDLINE, Embase and CENTRAL). Following the study selection process, qualitative and quantitative data were extracted from each included study. A narrative synthesis approach by each VHF was used. Descriptive statistics were conducted including world maps of cases number and case fatality rates (CFR); summary tables by VHF, country, time period and treatment studies. RESULTS: We identified 141 WHO/CDC reports and 126 articles meeting the inclusion criteria. Most of the studies were published after 2010 (n = 97 for WHO/CDC reports and n = 93 for publications) and reported number of cases and/or CFRs (n = 141 WHO/CDC reports and n = 88 publications). Results varied greatly depending on the outbreak or cluster and across countries within each VHF. A total of 90 studies focused on Ebola virus disease (EVD). EVD outbreaks were reported in Africa, where Sierra Leone (14,124 cases; CFR = 28%) and Liberia (10,678 cases; CFR = 45%) reported the highest cases numbers, mainly due to the 2014-2016 western Africa outbreak. Crimean-Congo hemorrhagic fever (CCHF) outbreaks were reported from 31 studies in Africa, Asia and Europe, where Turkey reported the highest cases number (6,538 cases; CFR = 5%) and Afghanistan the last outbreak in 2016/18 (293 cases; CFR = 43%). Regarding the 38 studies reporting results on treatments, most of them were non-randomized studies (mainly retrospective or non-randomized comparative studies), and only 10 studies were randomized controlled trials. For several VHFs, no specific investigational therapeutic option with strong proof of effectiveness on mortality was identified. CONCLUSION: We observed that number of cases and CFR varied greatly across VHFs as well as across countries within each VHF. The number of studies on VHF treatments was very limited with very few randomized trials and no strong proof of effectiveness of treatment against most of the VHFs. Therefore, there is a high need of methodologically strong clinical trials conducted in the context of VHF.
Subject(s)
Hemorrhagic Fever Virus, Crimean-Congo , Hemorrhagic Fever, Crimean , Hemorrhagic Fever, Ebola , Hemorrhagic Fevers, Viral , Humans , Hemorrhagic Fever, Ebola/epidemiology , Hemorrhagic Fever, Crimean/epidemiology , Retrospective Studies , Hemorrhagic Fevers, Viral/epidemiology , Hemorrhagic Fevers, Viral/therapy , Disease Outbreaks , LiberiaABSTRACT
Background: As mortality remains high for patients with Ebola virus disease (EVD) despite new treatment options, the ability to level up the provided supportive care and to predict the risk of death is of major importance. This analysis of the EVISTA cohort aims to describe advanced supportive care provided to EVD patients in the Democratic Republic of the Congo (DRC) and to develop a simple risk score for predicting in-hospital death, called PREDS. Methods: In this prospective cohort (NCT04815175), patients were recruited during the 10th EVD outbreak in the DRC across three Ebola Treatment Centers (ETCs). Demographic, clinical, biological, virological and treatment data were collected. We evaluated factors known to affect the risk of in-hospital death and applied univariate and multivariate Cox proportional-hazards analyses to derive the risk score in a training dataset. We validated the score in an internal-validation dataset, applying C-statistics as a measure of discrimination. Findings: Between August 1st 2018 and December 31th 2019, 711 patients were enrolled in the study. Regarding supportive care, patients received vasopressive drug (n = 111), blood transfusion (n = 101), oxygen therapy (n = 250) and cardio-pulmonary ultrasound (n = 15). Overall, 323 (45%) patients died before day 28. Six independent prognostic factors were identified (ALT, creatinine, modified NEWS2 score, viral load, age and symptom duration). The final score range from 0 to 13 points, with a good concordance (C = 86.24%) and calibration with the Hosmer-Lemeshow test (p = 0.12). Interpretation: The implementation of advanced supportive care is possible for EVD patients in emergency settings. PREDS is a simple, accurate tool that could help in orienting early advanced care for at-risk patients after external validation. Funding: This study was funded by ALIMA.
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The COVID-19 pandemic has exemplified that rigorous evaluation in large animal models is key for translation from promising in vitro results to successful clinical implementation. Among the drugs that have been largely tested in clinical trials but failed so far to bring clear evidence of clinical efficacy is favipiravir, a nucleoside analogue with large spectrum activity against several RNA viruses in vitro and in small animal models. Here, we evaluate the antiviral activity of favipiravir against Zika or SARS-CoV-2 virus in cynomolgus macaques. In both models, high doses of favipiravir are initiated before infection and viral kinetics are evaluated during 7 to 15 days after infection. Favipiravir leads to a statistically significant reduction in plasma Zika viral load compared to untreated animals. However, favipiravir has no effects on SARS-CoV-2 viral kinetics, and 4 treated animals have to be euthanized due to rapid clinical deterioration, suggesting a potential role of favipiravir in disease worsening in SARS-CoV-2 infected animals. To summarize, favipiravir has an antiviral activity against Zika virus but not against SARS-CoV-2 infection in the cynomolgus macaque model. Our results support the clinical evaluation of favipiravir against Zika virus but they advocate against its use against SARS-CoV-2 infection.
Subject(s)
COVID-19 Drug Treatment , Zika Virus Infection , Zika Virus , Amides , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Macaca fascicularis , Pandemics , Primates , Pyrazines , SARS-CoV-2 , Zika Virus Infection/drug therapyABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections initiate in the bronchi of the upper respiratory tract and are able to disseminate to the lower respiratory tract, where infections can cause an acute respiratory distress syndrome with a high degree of mortality in elderly patients. We used reconstituted primary bronchial epithelia from adult and child donors to follow the SARS-CoV-2 infection dynamics. We show that, in epithelia from adult donors, infections initiate in multiciliated cells and spread within 24 to 48 h throughout the whole epithelia. Syncytia formed of ciliated and basal cells appeared at the apical side of the epithelia within 3 to 4 d and were released into the apical lumen, where they contributed to the transmittable virus dose. A small number of reconstituted epithelia were intrinsically more resistant to virus infection, limiting virus spread to different degrees. This phenotype was more frequent in epithelia derived from children versus adults and correlated with an accelerated release of type III interferon. Treatment of permissive adult epithelia with exogenous type III interferon restricted infection, while type III interferon gene knockout promoted infection. Furthermore, a transcript analysis revealed that the inflammatory response was specifically attenuated in children. Taken together, our findings suggest that apical syncytia formation is an underappreciated source of virus propagation for tissue or environmental dissemination, whereas a robust type III interferon response such as commonly seen in young donors restricted SARS-CoV-2 infection. Thus, the combination of interferon restriction and attenuated inflammatory response in children might explain the epidemiological observation of age-related susceptibility to COVID-19.
Subject(s)
Bronchi , COVID-19 , Giant Cells , Interferons , Respiratory Mucosa , SARS-CoV-2 , Aged , Bronchi/immunology , Bronchi/virology , COVID-19/immunology , COVID-19/virology , Child , Disease Susceptibility , Giant Cells/immunology , Giant Cells/virology , Humans , Interferons/immunology , Respiratory Mucosa/immunology , Respiratory Mucosa/virology , SARS-CoV-2/immunology , Interferon LambdaABSTRACT
Introduction: Coronavirus disease 2019 (COVID-19) can cause life-threatening acute respiratory distress syndrome (ARDS). Recent data suggest a role for neutrophil extracellular traps (NETs) in COVID-19-related lung damage partly due to microthrombus formation. Besides, pulmonary embolism (PE) is frequent in severe COVID-19 patients, suggesting that immunothrombosis could also be responsible for increased PE occurrence in these patients. Here, we evaluate whether plasma levels of NET markers measured shorty after admission of hospitalized COVID-19 patients are associated with clinical outcomes in terms of clinical worsening, survival, and PE occurrence. Patients and Methods: Ninety-six hospitalized COVID-19 patients were included, 50 with ARDS (severe disease) and 46 with moderate disease. We collected plasma early after admission and measured 3 NET markers: total DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. Comparisons between survivors and non-survivors and patients developing PE and those not developing PE were assessed by Mann-Whitney test. Results: Analysis in the whole population of hospitalized COVID-19 patients revealed increased circulating biomarkers of NETs in patients who will die from COVID-19 and in patients who will subsequently develop PE. Restriction of our analysis in the most severe patients, i.e., the ones who enter the hospital for COVID-19-related ARDS, confirmed the link between NET biomarker levels and survival but not PE occurrence. Conclusion: Our results strongly reinforce the hypothesis that NETosis is an attractive therapeutic target to prevent COVID-19 progression but that it does not seem to be linked to PE occurrence in patients hospitalized with COVID-19.