Publications by authors named "Denis Malvy"

194 Publications

Accuracy of COVID-19 rapid antigenic tests compared to RT-PCR in a student population: The StudyCov study.

J Clin Virol 2021 Jun 5;141:104878. Epub 2021 Jun 5.

Bordeaux Population Health Research Center, Inserm U1219, Université de Bordeaux, 146 rue Léo Saignat, 33076, F-33000, Bordeaux, France; Agence régionale de santé Nouvelle-Aquitaine, 103 bis rue de Belleville, F-33000 Bordeaux, France; CHU de Bordeaux, Place Amélie Raba Léon, F-33000 Bordeaux, France. Electronic address:

Objective: There is a lack of data evaluating performance of antigenic test (AT) for SARS-CoV-2 diagnosis (Ag-RDT) in clinical practice, especially in asymptomatic subjects. The main objective of this study was to evaluate the diagnostic performance of AT compared to Reverse Transcription Polymerase Chain Reaction (RT-PCR) for SARS-CoV-2 diagnosis.

Methods: StudyCov is a monocentric cross-sectional study. A SARS-CoV-2 screening facility was set up in the Bordeaux University health campus from October 28th to November 20th 2020. Students willing to have a RT-PCR test (ARGENE SARS-CoV-2 R-GENE, BioMérieux, France) for SARS-CoV-2 diagnosis were also offered the Abbott Panbio™ SARS-CoV-2 antigenic rapid test. All participants attending the screening facility with an AT in addition to RT-PCR and having signed an informed consent were included in the study. The main objective was to assess performance of AT as compared with RT-PCR in the recruited population. Secondary objectives dealt with the analysis of the main objective stratified by current symptoms and risk exposure. A sensitivity analysis with different RT-PCR cycle thresholds was included.

Results: RT-PCR and AT results were available for 692 subjects. Overall sensitivity and specificity of AT tests were respectively 63.5% (95% confidence interval (CI): 49.0 - 76.4) and 100% (95% CI: 99.4 - 100). In the asymptomatic sub-group, they were respectively 35.0% (95% CI: 15.4% - 59.2%) and 100% (95% CI: 99.3 - 100).

Conclusions: This study shows the poor sensitivity of AT in asymptomatic subjects, specificity being however excellent. The performance results fall below the World Health Organization recommendation of 80% sensitivity and question using AT in general population, especially when asymptomatic.
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http://dx.doi.org/10.1016/j.jcv.2021.104878DOI Listing
June 2021

Clinical presentation, outcomes and factors associated with mortality: A prospective study from three COVID-19 referral care centres in West Africa.

Int J Infect Dis 2021 May 14;108:45-52. Epub 2021 May 14.

Inserm 1219, Univ. Bordeaux, IRD, Bordeaux, France; Department of Infectious Diseases and Tropical Medicine, CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France. Electronic address:

Objectives: The overall death toll from COVID-19 in Africa is reported to be low but there is little individual-level evidence on the severity of the disease. This study examined the clinical spectrum and outcome of patients monitored in COVID-19 care centres (CCCs) in two West-African countries.

Methods: Burkina Faso and Guinea set up referral CCCs to hospitalise all symptomatic SARS-CoV-2 carriers, regardless of the severity of their symptoms. Data collected from hospitalised patients by November 2020 are presented.

Result: A total of 1,805 patients (64% men, median age 41 years) were admitted with COVID-19. Symptoms lasted for a median of 7 days (IQR 4-11). During hospitalisation, 443 (25%) had a SpO2 < 94% at least once, 237 (13%) received oxygen and 266 (15%) took corticosteroids. Mortality was 5% overall, and 1%, 5% and 14% in patients aged <40, 40-59 and ≥60 years, respectively. In multivariable analysis, the risk of death was higher in men (aOR 2.0, 95% CI 1.1; 3.6), people aged ≥60 years (aOR 2.9, 95% CI 1.7; 4.8) and those with chronic hypertension (aOR 2.1, 95% CI 1.2; 3.4).

Conclusion: COVID-19 is as severe in Africa as elsewhere, and there must be more vigilance for common risk factors such as older age and hypertension.
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http://dx.doi.org/10.1016/j.ijid.2021.05.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120805PMC
May 2021

Incidental infiltrated gallbladder in a migrant from Ivory Coast: A diagnostic challenge.

Travel Med Infect Dis 2021 May-Jun;41:102061. Epub 2021 Apr 11.

Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, CHU de Bordeaux, Hôpital Pellegrin, Place Amélie Raba Léon, 33076, Bordeaux, France; Inserm 1219, Univ. Bordeaux, IRD, 33076, Bordeaux, France. Electronic address:

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http://dx.doi.org/10.1016/j.tmaid.2021.102061DOI Listing
April 2021

Lassa fever outcomes and prognostic factors in Nigeria (LASCOPE): a prospective cohort study.

Lancet Glob Health 2021 04;9(4):e469-e478

Inserm 1219, University of Bordeaux, and French National Research Institute for Sustainable Development, Bordeaux, France; Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, University Hospital Centre of Bordeaux, Hôpital Pellegrin, Bordeaux, France; Programme PAC-CI/ANRS Research Site, University Hospital Centre of Treichville, Abidjan, Côte d'Ivoire.

Background: Lassa fever is a viral haemorrhagic fever endemic in parts of west Africa. New treatments are needed to decrease mortality, but pretrial reference data on the disease characteristics are scarce. We aimed to document baseline characteristics and outcomes for patients hospitalised with Lassa fever in Nigeria.

Methods: We did a prospective cohort study (LASCOPE) at the Federal Medical Centre in Owo, Nigeria. All patients admitted with confirmed Lassa fever were invited to participate and asked to give informed consent. Patients of all ages, including newborn infants, were eligible for inclusion, as were pregnant women. All participants received standard supportive care and intravenous ribavirin according to Nigeria Centre for Disease Control guidelines and underwent systematic biological monitoring for 30 days. Patients' characteristics, care received, mortality, and associated factors were recorded using standard WHO forms. We used univariable and multivariable logistic regression models to investigate an association between baseline characteristics and mortality at day 30.

Findings: Between April 5, 2018, and March 15, 2020, 534 patients with confirmed Lassa fever were admitted to hospital, of whom 510 (96%) gave consent and were included in the analysis. The cohort included 258 (51%) male patients, 252 (49%) female patients, 426 (84%) adults, and 84 (16%) children (younger than 18 years). The median time between first symptoms and hospital admission was 8 days (IQR 7-13). At baseline, 176 (38%) of 466 patients had a Lassa fever RT-PCR cycle threshold (Ct) lower than 30. From admission to end of follow-up, 120 (25%) of 484 reached a National Early Warning Score (second version; NEWS2) of 7 or higher, 67 (14%) of 495 reached a Kidney Disease-Improving Global Outcome (KDIGO) stage of 2 or higher, and 41 (8%) of 510 underwent dialysis. All patients received ribavirin for a median of 10 days (IQR 9-13). 62 (12%) patients died (57 [13%] adults and five [6%] children). The median time to death was 3 days (1-6). The baseline factors independently associated with mortality were the following: age 45 years or older (adjusted odds ratio 16·30, 95% CI 5·31-50·30), NEWS2 of 7 or higher (4·79, 1·75-13·10), KDIGO grade 2 or higher (7·52, 2·66-21·20), plasma alanine aminotransferase 3 or more times the upper limit of normal (4·96, 1·69-14·60), and Lassa fever RT-PCR Ct value lower than 30 (4·65, 1·50-14·50).

Interpretation: Our findings comprehensively document clinical and biological characteristics of patients with Lassa fever and their relationship with mortality, providing prospective estimates that could be useful for designing future therapeutic trials. Such trials comparing new Lassa fever treatments to a standard of care should take no more than 15% as the reference mortality rate and consider adopting a combination of mortality and need for dialysis as the primary endpoint.

Funding: Institut National de la Santé et de la Recherche Médicale, University of Oxford, EU, UK Department for International Development, Wellcome Trust, French Ministry of Foreign Affairs, Agence Nationale de Recherches sur le SIDA et les hépatites virales, French National Research Institute for Sustainable Development.
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http://dx.doi.org/10.1016/S2214-109X(20)30518-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970450PMC
April 2021

Maternal Infection and Adverse Pregnancy Outcomes among Pregnant Travellers: Results of the International Zika Virus in Pregnancy Registry.

Viruses 2021 02 22;13(2). Epub 2021 Feb 22.

School of Pharmaceutical Sciences, Geneva University and Service of Pharmacy, Lausanne University Hospital, 1011 Lausanne, Switzerland.

In this multicentre cohort study, we evaluated the risks of maternal ZIKV infections and adverse pregnancy outcomes among exposed travellers compared to women living in areas with ZIKV circulation (residents). The risk of maternal infection was lower among travellers compared to residents: 25.0% ( = 36/144) versus 42.9% ( = 309/721); aRR 0.6; 95% CI 0.5-0.8. Risk factors associated with maternal infection among travellers were travelling during the epidemic period (i.e., June 2015 to December 2016) (aOR 29.4; 95% CI 3.7-228.1), travelling to the Caribbean Islands (aOR 3.2; 95% CI 1.2-8.7) and stay duration >2 weeks (aOR 8.7; 95% CI 1.1-71.5). Adverse pregnancy outcomes were observed in 8.3% ( = 3/36) of infected travellers and 12.7% ( = 39/309) of infected residents. Overall, the risk of maternal infections is lower among travellers compared to residents and related to the presence of ongoing outbreaks and stay duration, with stays <2 weeks associated with minimal risk in the absence of ongoing outbreaks.
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http://dx.doi.org/10.3390/v13020341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926842PMC
February 2021

Immune evasion means we need a new COVID-19 social contract.

Lancet Public Health 2021 04 18;6(4):e199-e200. Epub 2021 Feb 18.

Inserm 1219, University of Bordeaux, Bordeaux, France.

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http://dx.doi.org/10.1016/S2468-2667(21)00036-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891047PMC
April 2021

Home Treatment of Older People with Symptomatic SARS-CoV-2 Infection (COVID-19): A structured Summary of a Study Protocol for a Multi-Arm Multi-Stage (MAMS) Randomized Trial to Evaluate the Efficacy and Tolerability of Several Experimental Treatments to Reduce the Risk of Hospitalisation or Death in outpatients aged 65 years or older (COVERAGE trial).

Trials 2020 Oct 13;21(1):846. Epub 2020 Oct 13.

CHU Bordeaux, Department of Infectious Diseases and Tropical Medicine, Division of Tropical Medicine and Clinical International Health, F-33000, Bordeaux, France.

Objectives: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation.

Trial Design: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial.

Participants: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate <50/min; Kalaemia >5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations.

Intervention And Comparator: The four experimental treatments planned in protocol version 1.2 (April 8, 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan.

Main Outcome: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm.

Randomisation: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home).

Blinding (masking): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment.

Numbers To Be Randomised (sample Size): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively.

Trial Status: This describes the Version 1.2 (April 8, 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15, 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15, 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites.

Trial Registration: The trial was registered on Clinical Trials.gov on April 22, 2020 (Identifier: NCT04356495): and on EudraCT on April 10, 2020 (Identifier: 2020-001435-27).

Full Protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
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http://dx.doi.org/10.1186/s13063-020-04619-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552584PMC
October 2020

COVID-19: France grapples with the pragmatics of isolation.

Lancet Public Health 2020 11 10;5(11):e573-e574. Epub 2020 Oct 10.

National Ethical Consultative Committee for Life Sciences and Health, Paris, France.

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http://dx.doi.org/10.1016/S2468-2667(20)30235-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547370PMC
November 2020

Chikungunya resurgence in the Maldives and risk for importation via tourists to Europe in 2019-2020: A GeoSentinel case series.

Travel Med Infect Dis 2020 Jul - Aug;36:101814. Epub 2020 Jun 30.

IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France; Laveran Military Teaching Hospital, Marseille, France. Electronic address:

Background: Chikungunya virus (CHIKV) is an arthropod-borne virus mainly transmitted in tropical areas by Aedes spp. mosquitoes. It has been responsible for small-to-large outbreaks in temperate areas including southern Europe and North America. Past outbreaks in 2006 on the islands of Maldives, as well as on other islands in the Indian Ocean and in Southeast Asia, demonstrated for the first time the capacity of CHIKV to disseminate through travel and transcontinental commerce, and revealed the major socio-economic impact of CHIKV epidemics. Recently, CHIKV has been circulating in highly touristic areas including the Maldives, where 1736 cases were notified by the Health Protection Agency during 2019.

Case Series: Among EuroTravNet/GeoSentinel patient records, eight CHIKV-confirmed cases imported the Maldives to France, Germany, Denmark, Italy and Spain were identified between February 2019 and February 2020; exceeding the total number of CHIKV infections travel-acquired in Maldives reported to this surveillance network during the previous 10 years.

Conclusions: The prevention and control of CHIKV introduction into naïve areas colonised by competent vectors is crucial. CHIKV outbreaks must be detected and reported in a timely manner. This must lead to adapted health information for international travellers and to prompt management of suspected imported cases. Conversely, travellers make for excellent sentinels and increased reports of imported cases might reflect a change in the level of endemicity or even herald an outbreak. Feedback to the local health authorities and matching this with local epidemiological surveillance data may lead to health benefits for the local population.
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http://dx.doi.org/10.1016/j.tmaid.2020.101814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324928PMC
June 2020

The safety profile of favipiravir should not be the first argument to suspend its evaluation in viral hemorrhagic fevers.

PLoS Negl Trop Dis 2020 06 25;14(6):e0008259. Epub 2020 Jun 25.

CNMR, Maladies Cardiaques Héréditaires Rares & Department of Cardiology, AP-HP, Université de Paris, Paris, France.

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http://dx.doi.org/10.1371/journal.pntd.0008259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316222PMC
June 2020

Timing of Antiviral Treatment Initiation is Critical to Reduce SARS-CoV-2 Viral Load.

CPT Pharmacometrics Syst Pharmacol 2020 09 7;9(9):509-514. Epub 2020 Aug 7.

Université de Paris, IAME, INSERM, Paris, France.

We modeled the viral dynamics of 13 untreated patients infected with severe acute respiratory syndrome-coronavirus 2 to infer viral growth parameters and predict the effects of antiviral treatments. In order to reduce peak viral load by more than two logs, drug efficacy needs to be > 90% if treatment is administered after symptom onset; an efficacy of 60% could be sufficient if treatment is initiated before symptom onset. Given their pharmacokinetic/pharmacodynamic properties, current investigated drugs may be in a range of 6-87% efficacy. They may help control virus if administered very early, but may not have a major effect in severely ill patients.
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http://dx.doi.org/10.1002/psp4.12543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323384PMC
September 2020

Timing of antiviral treatment initiation is critical to reduce SARS-Cov-2 viral load.

medRxiv 2020 Apr 7. Epub 2020 Apr 7.

We modeled the viral dynamics of 13 untreated patients infected with SARS-CoV-2 to infer viral growth parameters and predict the effects of antiviral treatments. In order to reduce peak viral load by more than 2 logs, drug efficacy needs to be greater than 80% if treatment is administered after symptom onset; an efficacy of 50% could be sufficient if treatment is initiated before symptom onset. Given their pharmacokinetic/pharmacodynamic properties, current investigated drugs may be in a range of 20-70% efficacy. They may help control virus if administered very early, but may not have a major effect in severe patients.
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http://dx.doi.org/10.1101/2020.04.04.20047886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276997PMC
April 2020

Dose Rationale for Favipiravir Use in Patients Infected With SARS-CoV-2.

Clin Pharmacol Ther 2020 08 21;108(2):188. Epub 2020 May 21.

IAME, Inserm, University of Paris, Paris, France.

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http://dx.doi.org/10.1002/cpt.1877DOI Listing
August 2020

Zika among international travellers presenting to GeoSentinel sites, 2012-2019: implications for clinical practice.

J Travel Med 2020 Jul;27(4)

Department of Epidemiology and Global Health, University of Umea, Petrus Laestadius Väg, 901 87, Umeå, Sweden.

Introduction: International travellers contribute to the rapid spread of Zika virus (ZIKV) and its sentinel identification globally. We describe ZIKV infections among international travellers seen at GeoSentinel sites with a focus on ZIKV acquired in the Americas and the Caribbean, describe countries of exposure and traveller characteristics, and assess ZIKV diagnostic testing by site.

Methods: Records with an international travel-related diagnosis of confirmed or probable ZIKV from January 2012 through December 2019 reported to GeoSentinel with a recorded illness onset date were included to show reported cases over time. Records from March 2016 through December 2019 with an exposure region of the Americas or the Caribbean were included in the descriptive analysis. A survey was conducted to assess the availability, accessibility and utilization of ZIKV diagnostic tests at GeoSentinel sites.

Results: GeoSentinel sites reported 525 ZIKV cases from 2012 through 2019. Between 2012 and 2014, eight cases were reported, and all were acquired in Asia or Oceania. After 2014, most cases were acquired in the Americas or the Caribbean, a large decline in ZIKV cases occurred in 2018-19.Between March 2016 and December 2019, 423 patients acquired ZIKV in the Americas or the Caribbean, peak reporting to these regions occurred in 2016 [330 cases (78%)]. The median age was 36 years (range: 3-92); 63% were female. The most frequent region of exposure was the Caribbean (60%). Thirteen travellers were pregnant during or after travel; one had a sexually acquired ZIKV infection. There was one case of fetal anomaly and two travellers with Guillain-Barré syndrome. GeoSentinel sites reported various challenges to diagnose ZIKV effectively.

Conclusion: ZIKV should remain a consideration for travellers returning from areas with risk of ZIKV transmission. Travellers should discuss their travel plans with their healthcare providers to ensure ZIKV prevention measures are taken.
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http://dx.doi.org/10.1093/jtm/taaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604850PMC
July 2020

Clinical Management of Argentine Hemorrhagic Fever using Ribavirin and Favipiravir, Belgium, 2020.

Emerg Infect Dis 2020 07 21;26(7):1562-1566. Epub 2020 Jun 21.

We report a case of Argentine hemorrhagic fever diagnosed in a woman in Belgium who traveled from a disease-endemic area. Patient management included supportive care and combination therapy with ribavirin and favipiravir. Of 137 potential contacts, including friends, relatives, and healthcare and laboratory workers, none showed development of clinical symptoms of this disease.
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http://dx.doi.org/10.3201/eid2607.200275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323566PMC
July 2020

Clinical and virological data of the first cases of COVID-19 in Europe: a case series.

Lancet Infect Dis 2020 06 27;20(6):697-706. Epub 2020 Mar 27.

Department of Infectious and Tropical Diseases, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France. Electronic address:

Background: On Dec 31, 2019, China reported a cluster of cases of pneumonia in people at Wuhan, Hubei Province. The responsible pathogen is a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the relevant features of the first cases in Europe of confirmed infection, named coronavirus disease 2019 (COVID-19), with the first patient diagnosed with the disease on Jan 24, 2020.

Methods: In this case series, we followed five patients admitted to Bichat-Claude Bernard University Hospital (Paris, France) and Pellegrin University Hospital (Bordeaux, France) and diagnosed with COVID-19 by semi-quantitative RT-PCR on nasopharyngeal swabs. We assessed patterns of clinical disease and viral load from different samples (nasopharyngeal and blood, urine, and stool samples), which were obtained once daily for 3 days from hospital admission, and once every 2 or 3 days until patient discharge. All samples were refrigerated and shipped to laboratories in the National Reference Center for Respiratory Viruses (The Institut Pasteur, Paris, and Hospices Civils de Lyon, Lyon, France), where RNA extraction, real-time RT-PCR, and virus isolation and titration procedures were done.

Findings: The patients were three men (aged 31 years, 48 years, and 80 years) and two women (aged 30 years and 46 years), all of Chinese origin, who had travelled to France from China around mid-January, 2020. Three different clinical evolutions are described: (1) two paucisymptomatic women diagnosed within a day of exhibiting symptoms, with high nasopharyngeal titres of SARS-CoV-2 within the first 24 h of the illness onset (5·2 and 7·4 log copies per 1000 cells, respectively) and viral RNA detection in stools; (2) a two-step disease progression in two young men, with a secondary worsening around 10 days after disease onset despite a decreasing viral load in nasopharyngeal samples; and (3) an 80-year-old man with a rapid evolution towards multiple organ failure and a persistent high viral load in lower and upper respiratory tract with systemic virus dissemination and virus detection in plasma. The 80-year-old patient died on day 14 of illness (Feb 14, 2020); all other patients had recovered and been discharged by Feb 19, 2020.

Interpretation: We illustrated three different clinical and biological types of evolution in five patients infected with SARS-CoV-2 with detailed and comprehensive viral sampling strategy. We believe that these findings will contribute to a better understanding of the natural history of the disease and will contribute to advances in the implementation of more efficient infection control strategies.

Funding: REACTing (Research & Action Emerging Infectious Diseases).
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http://dx.doi.org/10.1016/S1473-3099(20)30200-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156120PMC
June 2020

Modeling Favipiravir Antiviral Efficacy Against Emerging Viruses: From Animal Studies to Clinical Trials.

CPT Pharmacometrics Syst Pharmacol 2020 05 28;9(5):258-271. Epub 2020 Apr 28.

Université de Paris, IAME, INSERM, Paris, France.

In 2014, our research network was involved in the evaluation of favipiravir, an anti-influenza polymerase inhibitor, against Ebola virus. In this review, we discuss how mathematical modeling was used, first to propose a relevant dosing regimen in humans, and then to optimize its antiviral efficacy in a nonhuman primate (NHP) model. The data collected in NHPs were finally used to develop a model of Ebola pathogenesis integrating the interactions among the virus, the innate and adaptive immune response, and the action of favipiravir. We conclude the review of this work by discussing how these results are of relevance for future human studies in the context of Ebola virus, but also for other emerging viral diseases for which no therapeutics are available.
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http://dx.doi.org/10.1002/psp4.12510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239338PMC
May 2020

First cases of coronavirus disease 2019 (COVID-19) in France: surveillance, investigations and control measures, January 2020.

Euro Surveill 2020 02;25(6)

The members of the investigation team are listed at the end of the article.

A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) causing a cluster of respiratory infections (coronavirus disease 2019, COVID-19) in Wuhan, China, was identified on 7 January 2020. The epidemic quickly disseminated from Wuhan and as at 12 February 2020, 45,179 cases have been confirmed in 25 countries, including 1,116 deaths. Strengthened surveillance was implemented in France on 10 January 2020 in order to identify imported cases early and prevent secondary transmission. Three categories of risk exposure and follow-up procedure were defined for contacts. Three cases of COVID-19 were confirmed on 24 January, the first cases in Europe. Contact tracing was immediately initiated. Five contacts were evaluated as at low risk of exposure and 18 at moderate/high risk. As at 12 February 2020, two cases have been discharged and the third one remains symptomatic with a persistent cough, and no secondary transmission has been identified. Effective collaboration between all parties involved in the surveillance and response to emerging threats is required to detect imported cases early and to implement adequate control measures.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.6.2000094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029452PMC
February 2020

Detection of Zika Virus Replication in Human Semen by Reverse-Transcription Polymerase Chain Reaction Targeting of Antisense Ribonucleic Acid.

J Infect Dis 2020 06;222(2):319-323

Institute of Tropical Medicine, Department of Clinical Sciences, Antwerp, Belgium.

Background: Persistence of Zika virus (ZIKV) ribonucleic acid (RNA) in semen is common after infection.

Methods: We designed a reverse-transcription polymerase chain reaction assay that targets antisense ZIKV RNA (asRNA) to assess ZIKV replication competence in ZIKV RNA-positive semen samples.

Results: We detected ZIKV asRNA in semen of 9 of 19 men (47.4%) diagnosed with ZIKV infection. All asRNA-positive samples had high ZIKV loads (cycle threshold values <26) and were obtained within 21 days of symptom onset.

Conclusions: The sensitivity of the asRNA assay for detection of ZIKV replication was higher than that of conventional virus isolation methods (47.4% vs 21.1%, P = .032).
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http://dx.doi.org/10.1093/infdis/jiaa070DOI Listing
June 2020

Changes in the Transmission Dynamic of Chikungunya Virus in Southeastern Senegal.

Viruses 2020 02 10;12(2). Epub 2020 Feb 10.

Inserm U1219 University of Bordeaux, 33063 Bordeaux, France.

In Senegal, chikungunya virus (CHIKV) is maintained in a sylvatic cycle and causes sporadic cases or small outbreaks in rural areas. However, little is known about the influence of the environment on its transmission. To address the question, 120 villages were randomly selected in the Kedougou region of southeastern Senegal. In each selected village, 10 persons by randomly selected household were sampled and tested for specific anti-CHIKV IgG antibodies by ELISA. We investigated the association of CHIKV seroprevalence with environmental variables using logistic regression analysis and the spatial correlation of village seroprevalence based on semivariogram analysis. Fifty-four percent (51%-57%) of individuals sampled during the survey tested positive for CHIKV-specific IgG. CHIKV seroprevalence was significantly higher in populations living close to forested areas (Normalized Difference Vegetation Index (NDVI), Odds Ratio (OR) = 1.90 (1.42-2.57)), and was negatively associated with population density (OR = 0.76 (0.69-0.84)). In contrast, in gold mining sites where population density was >400 people per km, seroprevalence peaked significantly among adults (46% (27%-67%)) compared to all other individuals (20% (12%-31%)). However, traditional gold mining activities significantly modify the transmission dynamic of CHIKV, leading to a potential increase of the risk of human exposition in the region.
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http://dx.doi.org/10.3390/v12020196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077306PMC
February 2020

Lassa fever clinical course and setting a standard of care for future randomized trials: A protocol for a cohort study of Lassa-infected patients in Nigeria (LASCOPE).

Travel Med Infect Dis 2020 Jul - Aug;36:101557. Epub 2020 Jan 21.

Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford, OX3 7FZ, United Kingdom. Electronic address:

Background: Lassa Fever (LF), is a severe viral disease prevalent in Western Africa. It is classified as a priority disease by the World Health Organization (WHO). Ribavirin is the recommended therapy despite weak evidence of its efficacy. Promising therapeutic agents are becoming available for evaluation in human. Before launching therapeutic trials, we need data on the evolution of the disease under the best possible conditions of care.

Methods: We have initiated a prospective study in Nigeria to better understand the clinical course and prognostic factors of LF while implementing high quality standardized care. Inclusion criteria are: suspected or confirmed LF and informed consent. Participants are followed 60 days from admission and receive free of charge standardized supportive care and biological monitoring, as well as intravenous ribavirin for those with confirmed LF. Data are collected using standardized case report forms (CRF). Primary and secondary outcomes are fatality and severe morbidity, with special focus on acute kidney dysfunction and pregnancy complications. Factors associated with outcomes will be investigated.

Results: The cohort is planned for 3 years. Inclusions started in April 2018 at the Federal Medical Center Owo in Ondo State. A second site will open in Nigeria in 2020 and discussions are underway to open a site in Benin. 150 to 200 new participants are expected per year.

Conclusions: This cohort will: provide evidence to standardize LF case management; provide key inputs to design future clinical trials of novel therapeutics; and establish clinical research teams capable of conducting such trials in LF-endemic areas.

Study Registration: The LASCOPE study was registered on ClinicalTrial.gov (NCT03655561).
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http://dx.doi.org/10.1016/j.tmaid.2020.101557DOI Listing
January 2020

Travel-associated chikungunya acquired in Myanmar in 2019.

Euro Surveill 2020 01;25(1)

Department of Global Health and Boston University School of Public Health and Section of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA, United States.

Eighteen cases of chikungunya virus infection in travellers returning from Myanmar were reported to the GeoSentinel Surveillance Network, its subnetwork EuroTravNet and TropNet in 2019, reflecting an ongoing local outbreak. This report reinforces the importance of travellers as sentinels of emerging arboviral outbreaks and highlights the importance of vigilance for imported cases, due to the potential for dissemination of the virus into areas with competent local vectors and conducive environmental conditions.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.1.1900721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961262PMC
January 2020

[Epidemic and emerging prone-infectious diseases: Lessons learned and ways forward].

Presse Med 2019 Dec 26;48(12):1536-1550. Epub 2019 Nov 26.

Université de Bordeaux, centre René Labusquière, département universitaire de médecine tropicale et santé internationale clinique, 33000Bordeaux, France. Electronic address:

Africa along side with south-east Asia are the epicentres of emerging and epidemic prone-infectious diseases and megacity biosecurity threat scenarios. Massive mobility and reluctance in the populations exposed to epidemic and emerging prone-infectious diseases coupled by a weak health system made disease alert and control measures difficult to implement. The investigation of virus detection and persistence in semen across a range of emerging viruses is useful for clinical and public health reasons, in particular for viruses that lead to high mortality or morbidity rates or to epidemics. Innovating built facility to safely treat patients with highly pathogenic infectious diseases is urgently need, not only to prevent the spread of infection from patients to healthcare workers but also to offer provision of relatively invasive organ support, whenever considered appropriate, without posing additional risk to staff. Despite multiple challenges, the need to conduct research during epidemics is inevitable, and candidate products must continue undergoing rigorous trials. Preparedness including management of complex humanitarian crises with community distrust is a cornerstone in response to high consequence emerging infectious disease outbreaks and imposes strengthening of the public health response infrastructure and emergency outbreak systems in high-risk regions.
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http://dx.doi.org/10.1016/j.lpm.2019.09.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127531PMC
December 2019

A meta-analysis of clinical studies conducted during the West Africa Ebola virus disease outbreak confirms the need for randomized control groups.

Sci Transl Med 2019 11;11(520)

Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Recent Ebola virus disease outbreaks affirm the dire need for treatments with proven efficacy. Randomized controlled clinical trials remain the gold standard but, during disease outbreaks, may be difficult to conduct due to ethical concerns and challenging field conditions. In the absence of a randomized control group, statistical modeling to create a control group could be a possibility. Such a model-based reference control would only be credible if it had the same mortality risk as that of the experimental group in the absence of treatment. One way to test this counterfactual assumption is to evaluate whether reasonable similarity exists across nonrandomized control groups from different clinical studies, which might suggest that a future control group would be similarly homogeneous. We evaluated similarity across six clinical studies conducted during the 2013-2016 West Africa outbreak of Ebola virus disease. These studies evaluated favipiravir, the biologic ZMapp, the antimalarial drug amodiaquine, or administration of convalescent plasma or convalescent whole blood. We compared the nonrandomized control groups of these six studies comprising 1147 individuals infected with Ebola virus. We found considerable heterogeneity, which did not disappear after statistical modeling to adjust for prognostic variables. Mortality risk varied widely (31 to 66%) across the nonrandomized control arms of these six studies. Models adjusting for baseline covariates (age, sex, and cycle threshold, a proxy for viral load) failed to sufficiently recalibrate these studies and showed that heterogeneity remained. Our findings highlight concerns about making invalid conclusions when comparing nonrandomized control groups to cohorts receiving experimental treatments.
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http://dx.doi.org/10.1126/scitranslmed.aaw1049DOI Listing
November 2019

Severe toxoplasmosis imported from tropical Africa in immunocompetent patients: A case series.

Travel Med Infect Dis 2020 May - Jun;35:101509. Epub 2019 Nov 9.

Department for Infectious and Tropical Diseases, University Hospital Centre of Bordeaux, Inserm 1219, University of Bordeaux, Bordeaux, France.

Background: Toxoplasmosis is a zoonosis caused by the protozoan Toxoplasma gondii. In immunocompetent patients the infection is usually benign. However, cases of severe and even lethal primo-infections are regularly reported in South America. In contrast, data from tropical Africa are fragmentary.

Methods: Data for French cases of severe toxoplasmosis acquired between 2013 and 2018, in tropical Africa and among immunocompetent patients were collected retrospectively in 2018.

Results: Four male patients with a mean age of 34-years were identified. All infections originated in West or Central Africa. The clinical presentations were heterogeneous: two patients had severe disseminated toxoplasmosis, of which one presented with chorioretinitis associated with myositis and the other with febrile pneumopathy; one patient presented with post-infectious acute cerebellar ataxia and the final case had general symptoms and skin manifestations. The diagnosis of acute toxoplasmosis was confirmed by serology in four patients. Molecular diagnosis confirmed T. gondii infection in three patients with Africa 1 as the dominant genotype. The infection was cured with anti-infective treatment in all four patients. Ocular sequelae were reported in the two patients with chorioretinitis.

Conclusions: Imported cases of severe toxoplasmosis in immunocompetent patients are rare in France. However, this aetiology should be evoked rapidly in a patient with a severe infectious syndrome who has recently visited or originated from tropical Africa.
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http://dx.doi.org/10.1016/j.tmaid.2019.101509DOI Listing
June 2021

The exacerbation of Ebola outbreaks by conflict in the Democratic Republic of the Congo.

Proc Natl Acad Sci U S A 2019 11 21;116(48):24366-24372. Epub 2019 Oct 21.

Center for Infectious Disease Modeling and Analysis, Yale School of Public Health, New Haven, CT 06520.

The interplay between civil unrest and disease transmission is not well understood. Violence targeting healthcare workers and Ebola treatment centers in the Democratic Republic of the Congo (DRC) has been thwarting the case isolation, treatment, and vaccination efforts. The extent to which conflict impedes public health response and contributes to incidence has not previously been evaluated. We construct a timeline of conflict events throughout the course of the epidemic and provide an ethnographic appraisal of the local conditions that preceded and followed conflict events. Informed by temporal incidence and conflict data as well as the ethnographic evidence, we developed a model of Ebola transmission and control to assess the impact of conflict on the epidemic in the eastern DRC from April 30, 2018, to June 23, 2019. We found that both the rapidity of case isolation and the population-level effectiveness of vaccination varied notably as a result of preceding unrest and subsequent impact of conflict events. Furthermore, conflict events were found to reverse an otherwise declining phase of the epidemic trajectory. Our model framework can be extended to other infectious diseases in the same and other regions of the world experiencing conflict and violence.
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http://dx.doi.org/10.1073/pnas.1913980116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883813PMC
November 2019

Positive direct antiglobulin test in post-artesunate delayed haemolysis: more than a coincidence?

Malar J 2019 Apr 8;18(1):123. Epub 2019 Apr 8.

ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.

Background: Delayed haemolysis is a frequent adverse event after treatment with artesunate (AS). Removing once-infected "pitted" erythrocytes by the spleen is the most accepted mechanism of haemolysis in these cases. However, an increasing number of cases with positive direct antiglobulin test (DAT) haemolysis after AS have been reported.

Methods: All malaria cases seen at Hospital Clinic of Barcelona between 2015 and 2017 were retrospectively reviewed. Clinical, parasitological and laboratory data from patients treated with intravenous artesunate-specifically looking for delayed haemolysis and DAT-was collected.

Results: Among the 36 severe malaria patients treated with artesunate at the hospital, 10 (27.8%) developed post-artesunate delayed haemolysis. Out of these, DAT was performed in six, being positive in four of them (at least 40%). DAT was positive only for complement-without IgG-suggesting drug-dependent immune-haemolytic anaemia of the immune-complex type. Three of the four patients were treated with corticosteroids and two also received blood transfusion, with a complete recovery.

Conclusions: Drug-induced auto-immune phenomena in post-artesunate delayed haemolysis may be underreported and must be considered. The role of corticosteroids should be reassessed.
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http://dx.doi.org/10.1186/s12936-019-2762-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454619PMC
April 2019

Travel-related health events and their risk factors in HIV-infected sub-Saharan migrants living in France and visiting their native country: The ANRS VIHVO cohort study.

Travel Med Infect Dis 2019 May - Jun;29:40-47. Epub 2019 Apr 2.

AP-HP, Hôpital Antoine Béclère, Clamart, France; Inserm U1018, Centre de recherche en Epidémiologie et Santé des Populations (CESP), Le Kremlin-Bicêtre Cedex, Université Paris Sud University, Paris Saclay University, France. Electronic address:

Background: Literature on health events in HIV-infected travellers is scarce, particularly in sub-Saharan African (SSA) migrants.

Methods: We investigated health events in HIV-infected SSA migrants living in France during and after travel to their native country. All had a pre-travel plasma viral load (pVL) below 200 copies/mL and were on stable combined antiretroviral therapy (cART). Logistic regression models were used to assess the risk factors for at least one adverse health event or febrile event.

Results: Among 264 HIV migrants, pre-travel median CD4 count was 439/mm3 and 27 migrants (6%) experienced a low-level viremia between 50 and 200 copies/mL. One hundred (38%) experienced at least one event (13 experienced two events). The most common events were gastrointestinal, including diarrhoea (n = 29, 26%), respiratory events (n = 20, 18%), and malaria (n = 17, 15%; 1 death). In multivariable analysis, a pre-travel low-level viremia and a lack of pre-travel medical advice significantly increased the risk for any event (OR 4.31, 95% CI, 1.41-13.1; and OR 3.62, 95% CI, 1.38-9.47; respectively). A lack of pre-travel advice significantly increased the risk for febrile event.

Conclusions: Early and tailored counselling on pre-travel medical advice regarding diarrhoea and vector-borne diseases prophylactic measures in HIV-infected SSA migrants should be emphasised before travel to Africa.
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http://dx.doi.org/10.1016/j.tmaid.2019.03.010DOI Listing
July 2019

Laboratory Findings, Compassionate Use of Favipiravir, and Outcome in Patients With Ebola Virus Disease, Guinea, 2015-A Retrospective Observational Study.

J Infect Dis 2019 06;220(2):195-202

European Mobile Laboratory Consortium, Hamburg.

Background: In 2015, the laboratory at the Ebola treatment center in Coyah, Guinea, confirmed Ebola virus disease (EVD) in 286 patients. The cycle threshold (Ct) of an Ebola virus-specific reverse transcription-polymerase chain reaction assay and 13 blood chemistry parameters were measured on admission and during hospitalization. Favipiravir treatment was offered to patients with EVD on a compassionate-use basis.

Methods: To reduce biases in the raw field data, we carefully selected 163 of 286 patients with EVD for a retrospective study to assess associations between potential risk factors, alterations in blood chemistry findings, favipiravir treatment, and outcome.

Results: The case-fatality rate in favipiravir-treated patients was lower than in untreated patients (42.5% [31 of 73] vs 57.8% [52 of 90]; P = .053 by univariate analysis). In multivariate regression analysis, a higher Ct and a younger age were associated with survival (P < .001), while favipiravir treatment showed no statistically significant effect (P = .11). However, Kaplan-Meier analysis indicated a longer survival time in the favipiravir-treated group (P = .015). The study also showed characteristic changes in blood chemistry findings in patients who died, compared with survivors.

Conclusions: Consistent with the JIKI trial, this retrospective study revealed a trend toward improved survival in favipiravir- treated patients; however, the effect of treatment was not statistically significant, except for its influence on survival time.
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http://dx.doi.org/10.1093/infdis/jiz078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581890PMC
June 2019