Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization in Infantile Hydrocephalus: An Experience from Mali.

INTRODUCTION: Pediatric hydrocephalus is a common disease in sub-Saharan Africa. In Mali, 350-400 new cases are diagnosed in our center yearly. With a total land mass of 1,241,000 km2, patients in remote areas must travel up to 1,500 km to access neurosurgical care. Hence, treatment and follow-ups of "shunted" patients are difficult. In this context, endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) provides an opportunity for an affordable and less constraining treatment for hydrocephalus children under 12 months of age. METHODS: We performed a retrospective analysis of ETV/CPC performed on infants from July 2013 to January 2015. Patients were followed postoperatively on day 15, month 6, and month 12. Statistical analysis was conducted using Prism 9 GraphPad software. ETV successes were categorized according to the patient's age into 3 groups: ≤3 months, 3-6 months, and 6-12 months. Statistical significance was defined at p < 0.05. RESULTS: During the study period, 199 patients were included with 40% of patients aged between 0 and 6 months. The head circumference ranged from 35 cm to 79 cm. The etiology was congenital malformation in 55%. ETV/CPC was a success in 69% of 6- to 12-month-old patients, 54% in the 3- to 6-month-old patients, and 29% in ≤3-month-old patients. Overall, 94 (47%) patients were successfully treated without a shunt. The postoperative infection rate was 1% and mortality at 12 months was 8%. CONCLUSION: In a low-income environment such as Mali, ETV/CPC stands as a viable and alternative treatment option for pediatric hydrocephalus patients; our findings suggest that age is an important factor in predicting ETV success.

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

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.

Kinetics of Soluble Mediators of the Host Response in Ebola Virus Disease.

Background: The pathophysiology of Ebola virus disease (EVD) is still poorly understood. This study aimed at identifying soluble biomarkers that inform on disease mechanisms. Methods: Fifty-four soluble mediators of the immune, coagulation, and endothelial system were measured in baseline and follow-up samples from hospitalized patients with EVD, using Luminex technology. Cross-sectional expression levels and changes over time were correlated with outcome. Results: Levels of circulating proinflammatory cytokines and chemokines, as well as markers of endothelial dysfunction and coagulopathy, were elevated on admission to hospital in patients who died from EVD as compared to survivors. These markers further increased in patients who died and/or decreased over time in survivors. In contrast, markers of gut integrity and T-cell response were higher in survivors and increased until discharge. Conclusions: Inflammatory response, endothelial integrity, gastric tissue protection, and T cell immunity play a role in EVD pathophysiology.

Ebola Virus Persistence in Breast Milk After No Reported Illness: A Likely Source of Virus Transmission From Mother to Child.

A 9-month-old infant died from Ebola virus (EBOV) disease with unknown epidemiological link. While her parents did not report previous illness, laboratory investigations revealed persisting EBOV RNA in the mother's breast milk and the father's seminal fluid. Genomic analysis strongly suggests EBOV transmission to the child through breastfeeding.

Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days.

We report on an Ebola virus disease (EVD) survivor who showed Ebola virus in seminal fluid 531 days after onset of disease. The persisting virus was sexually transmitted in February 2016, about 470 days after onset of symptoms, and caused a new cluster of EVD in Guinea and Liberia.

Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.

[This corrects the article DOI: 10.1371/journal.pmed.1001967.].

Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.

BACKGROUND: Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies. METHODS AND FINDINGS: Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in "cycle threshold" [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A "target value" of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%-32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%-91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 µmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 µmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 µmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 µmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated. CONCLUSIONS: In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02329054.

High doses of favipiravir in two men survivors of Ebola virus disease carrying Ebola virus in semen in Guinea.

BACKGROUND: Persistence of Ebola virus (EBOV) in semen remains of deep concern, as sexual transmission of EBOV seems plausible up to 6 months after acute phase of Ebola virus disease (EVD). Favipiravir, a broad spectrum antiviral product, has been evaluated in reducing EVD mortality in Guinea in 2014-2015 in the JIKI trial, the pharmacokinetic results of which suggest that an increase of dose might be necessary to achieve a therapeutically relevant exposure. In FORCE trial, we aimed at evaluating the tolerance and activity of high doses of favipiravir in male EVD survivors with EBOV RNA detection in semen in Guinea. CASE: In 2016, we launched a phase IIa open-labeled multicenter dose escalation study. Male survivors of EVD with EBOV RT-PCR positive on semen received a loading dose of 2400 mg BID of favipiravir on day 1 then a maintenance dose of 1800 mg BID from day 2-14. The primary outcome was the tolerance, assessed daily during period treatment and up to day 90. Unfortunately only two participants were included and the trial was stopped for lack of recruitment. No clinical adverse event of grade 3/4 was reported for both patients. One patient experienced a grade 3 hypocalcemia at day 10 and 14. CONCLUSIONS: High doses of favipiravir were well tolerated in these two participants. Better characterized tolerance and pharmacokinetics of high doses of favipiravir are of utmost importance considering that favipiravir is a candidate treatment for a variety of emerging severe viral diseases with poor prognosis.

Field evaluation of clinical features during chikungunya outbreak in Mayotte, 2005-2006.

BACKGROUND: To record and assess the clinical features of chikungunya fever (CHIKF), with a view to enable diagnosis based on clinical criteria rather than costly laboratory procedures in field conditions. METHODS: As part of a cross-sectional serologic survey conducted in Mayotte after a massive chikungunya outbreak in 2006, we collected data on clinical features of chikungunya infection and assessed the performance and accuracy of clinical case definition criteria combining different symptoms. RESULTS: Of 1154 participants included, 440 (38.1%) had chikungunya-specific IgM or IgG antibodies by enzyme-linked immunosorbent assay (ELISA). Of symptomatic participants, 318 (72.3%) had confirmed chikungunya, the dominant symptoms reported were incapacitating polyarthralgia (98.7%), myalgia (93.1%), backache (86%), fever of abrupt onset (85%) and headache (81.4%). There was a strong linear association between symptomatic infection and age (chi(2) for trend = 9.85, P < 0.001). Only 52% of persons with presumptive chikungunya sought medical advice, principally at public primary health care facilities. The association of fever and polyarthralgia had a sensitivity of 84% (95% CI: 79-87) and a specificity of 89% (95% CI: 86-91). This association allowed to classify correctly 87% (95% CI: 85-89) of individuals with serologically confirmed chikungunya. CONCLUSIONS: Our results suggest that the pair fever and incapacitating polyarthralgia is an accurate and reliable tool for identifying presumptive CHIKF cases in the field. These criteria provide a useful evidence base to support operational syndromic surveillance in laboratory-confirmed chikungunya epidemic settings.

Rift Valley fever, Mayotte, 2007-2008.

After the 2006-2007 epidemic wave of Rift Valley fever (RVF) in East Africa and its circulation in the Comoros, laboratory case-finding of RVF was conducted in Mayotte from September 2007 through May 2008. Ten recent human RVF cases were detected, which confirms the indigenous transmission of RFV virus in Mayotte.

Outbreak of Chikungunya fever in Mayotte, Comoros archipelago, 2005-2006.

In 2005-2006, a large outbreak of Chikungunya (CHIK) fever occurred on the western Indian Ocean Islands. In Mayotte, concurrent with an enhanced passive case notification system, we carried out two surveys. A seroprevalence survey designed to document recent CHIK infection was conducted on serum samples collected from pregnant women in October 2005 (n=316) and in March-April 2006 (n=629). A cross-sectional clinical community survey carried out from 2 to 10 May 2006 among 2235 individuals was designed to determine the cumulative incidence of presumptive CHIK fever cases. The seroprevalence of recent infection among pregnant women was 1.6% in October 2005 and rose to 26% in April 2006. The clinical community survey showed that nearly 26% of respondents had experienced presumptive CHIK fever between January and May 2006. Extrapolated to the overall population of Mayotte, these figures lead to an estimated attack rate of 249.5 cases per 1000 population as of early May 2006. Nine patients with the maternofetal form and six subjects with the severe form were recorded. This first emergence of CHIK fever in Mayotte lead to a very large outbreak. Efforts to strengthen surveillance and prevention of arbovirus infection are needed at country and regional levels.

A major epidemic of chikungunya virus infection on Reunion Island, France, 2005-2006.

In January 2005, an epidemic of chikungunya fever broke out in the Comoro Islands and lasted until May 2005. In April, cases were also reported in Mayotte and Mauritius. On Réunion Island, the first cases were reported at the end of April. Surveillance of this epidemic required an adaptive system, which at first was based on active and retrospective case detection around the cases reported, then relied on a sentinel network when the incidence increased. Emerging and severe forms of infection were investigated. Death certificates were monitored. By April 2006, the surveillance estimate was 244,000 cases of chikungunya virus infection, including 123 severe cases and 41 of maternoneonatal transmission, with an overall attack rate of 35%. Chikungunya infection was mentioned on 203 death certificates and significant mortality was observed. This epidemic highlighted the need for a mutual strategy of providing information on arboviral diseases and their prevention and control between countries in the southwestern Indian Ocean.

[Integrating clinical research into epidemic response: the field perspective in the Ebola experience]. / Intégrer la recherche clinique dans la réponse aux épidémies - Les leçons de l'expérience d'Ebola.

During the 2013-2016 west African Ebola outbreak that affected West Africa, accelerated clinical trials, testing unproven but promising and potentially lifesaving experimental interventions emerged as a key component of the global outbreak. In 2017, no Ebola medical countermeasures had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried a list of potential drug candidates developed or repurposed with demonstrated antiviral efficacy in vitro or in animal models. Numerous therapeutics were considered or explored during the outbreak, including nucleoside and nucleotide analogues, nucleic acid-based drugs and immunotherapeutics. Drugs in clinical trials were tested within the framework of optimized supportive care with fluids and electrolytes and management of severe compromise of multiple organs resulting from viral cytopathology and immune-mediated cell damage. Assessment of those therapeutics with encouraging preliminary efficacy or safety profile, like the repurposed direct antiviral agent favipiravir or the combination of antibodies ZMapp requires further investigation to confirm their efficacy in humans, propose appropriate doses and evaluate the possibility of treatment combinations. During the lull before the next epidemic, major challenges for managing future Ebola epidemics include scientific, clinical and public health preparedness with establishment of innovative patient care and clinical research support in remote poor areas where Ebola and other deadly infectious diseases typically reemerge.

How to treat Ebola virus infections? A lesson from the field.

The reported case fatality ratios (CFR) of Ebola virus disease (EVD) have been as high as 90% in previous outbreaks. While the cumulative CFR among patients medically evacuated and treated in Western countries was inferior to 20%, it peaked to approximately 75% between September and December 2014 in West Africa, thereafter decreasing to less than 40% (May 2015) without current evidence of major virus mutations capable to alter virus pathogenicity over the course of the epidemic. Therefore, the observed diminution of CFR is likely to reflect improvement of EVD patient care. Here, we summarize major lessons learned, that is, progresses and knowledge gaps, about the clinical management of patients in West African settings during the 2014-2016 outbreak.

Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted.

BACKGROUND: In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. METHODS AND FINDINGS: Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient's individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient's characteristics (median value of 46.1 versus 54.3 µg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 µg/mL for observed and predicted concentrations, respectively, p<10-6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality. CONCLUSIONS: Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses. TRIAL REGISTRATION: ClinicalTrials.gov NCT02329054.

Challenges in preparing and implementing a clinical trial at field level in an Ebola emergency: A case study in Guinea, West Africa.

During the large Ebola outbreak that affected West Africa in 2014 and 2015, studies were launched to evaluate potential treatments for the disease. A clinical trial to evaluate the effectiveness of the antiviral drug favipiravir was conducted in Guinea. This paper describes the main challenges of the implementation of the trial in the Ebola treatment center of Guéckédou. Following the principles of the Good Clinical Research Practices, we explored the aspects of the community's communication and engagement, ethical conduct, trial protocol compliance, informed consent of participants, ongoing benefit/risk assessment, record keeping, confidentiality of patients and study data, and roles and responsibilities of the actors involved. We concluded that several challenges have to be addressed to successfully implement a clinical trial during an international medical emergency but that the potential for collaboration between research teams and humanitarian organizations needs to be highlighted.

Deep Sequencing of RNA from Blood and Oral Swab Samples Reveals the Presence of Nucleic Acid from a Number of Pathogens in Patients with Acute Ebola Virus Disease and Is Consistent with Bacterial Translocation across the Gut.

In this study, samples from the 2013-2016 West African Ebola virus outbreak from patients in Guinea with Ebola virus disease (EVD) were analyzed to discover and classify what other pathogens were present. Throat swabs were taken from deceased EVD patients, and peripheral blood samples were analyzed that had been taken from patients when they presented at the treatment center with acute illness. High-throughput RNA sequencing (RNA-seq) and bioinformatics were used to identify the potential microorganisms. This approach confirmed Ebola virus (EBOV) in all samples from patients diagnosed as acute positive for the virus by quantitative reverse transcription-PCR in deployed field laboratories. Nucleic acid mapping to Plasmodium was also used on the patient samples, confirming results obtained with an antigen-based rapid diagnostic test (RDT) conducted in the field laboratories. The data suggested that a high Plasmodium load, as determined by sequence read depth, was associated with mortality and influenced the host response, whereas a lower parasite load did not appear to affect outcome. The identifications of selected bacteria from throat swabs via RNA-seq were confirmed by culture. The data indicated that the potential pathogens identified in the blood samples were associated with translocation from the gut, suggesting the presence of bacteremia, which transcriptome data suggested may induce or aggravate the acute-phase response observed during EVD. Transcripts mapping to different viruses were also identified, including those indicative of lytic infections. The development of high-resolution analysis of samples from patients with EVD will help inform care pathways and the most appropriate general antimicrobial therapy to be used in a resource-poor setting. IMPORTANCE Our results highlight the identification of an array of pathogens in the blood of patients with Ebola virus disease (EVD). This has not been done before, and the data have important implications for the treatment of patients with EVD, particularly considering antibiotic stewardship. We show that EVD patients who were also infected with Plasmodium, particularly at higher loads, had more adverse outcomes than patients with lower levels of Plasmodium. However, the presence of Plasmodium did not influence the innate immune response, and it is likely that the presence of EBOV dominated this response. Several viruses other than EBOV were identified, and bacteria associated with sepsis were also identified. These findings were indicative of bacterial translocation across the gut during the acute phase of EVD.

Transcriptomic signatures differentiate survival from fatal outcomes in humans infected with Ebola virus.

BACKGROUND: In 2014, Western Africa experienced an unanticipated explosion of Ebola virus infections. What distinguishes fatal from non-fatal outcomes remains largely unknown, yet is key to optimising personalised treatment strategies. We used transcriptome data for peripheral blood taken from infected and convalescent recovering patients to identify early stage host factors that are associated with acute illness and those that differentiate patient survival from fatality. RESULTS: The data demonstrate that individuals who succumbed to the disease show stronger upregulation of interferon signalling and acute phase responses compared to survivors during the acute phase of infection. Particularly notable is the strong upregulation of albumin and fibrinogen genes, which suggest significant liver pathology. Cell subtype prediction using messenger RNA expression patterns indicated that NK-cell populations increase in patients who survive infection. By selecting genes whose expression properties discriminated between fatal cases and survivors, we identify a small panel of responding genes that act as strong predictors of patient outcome, independent of viral load. CONCLUSIONS: Transcriptomic analysis of the host response to pathogen infection using blood samples taken during an outbreak situation can provide multiple levels of information on both disease state and mechanisms of pathogenesis. Host biomarkers were identified that provide high predictive value under conditions where other predictors, such as viral load, are poor prognostic indicators. The data suggested that rapid analysis of the host response to infection in an outbreak situation can provide valuable information to guide an understanding of disease outcome and mechanisms of disease.