In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived ...from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea.
In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group.
A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval CI, -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed.
The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).
Emerging infectious diseases such as Ebola Virus Disease (EVD), Nipah Virus Encephalitis and Lassa fever pose significant epidemic threats. Responses to emerging infectious disease outbreaks ...frequently occur in resource-constrained regions and under high pressure to quickly contain the outbreak prior to potential spread. As seen in the 2020 EVD outbreaks in the Democratic Republic of Congo and the current COVID-19 pandemic, there is a continued need to evaluate and address the ethical challenges that arise in the high stakes environment of an emerging infectious disease outbreak response. The research presented here provides analysis of the ethical challenges with regard to allocation of limited resources, particularly experimental therapeutics, using the 2013-2016 EVD outbreak in West Africa as a case study. In-depth semi-structured interviews were conducted with senior healthcare personnel (n = 16) from international humanitarian aid organizations intimately engaged in the 2013-2016 EVD outbreak response in West Africa. Interviews were recorded in private setting, transcribed, and iteratively coded using grounded theory methodology. A majority of respondents indicated a clear propensity to adopt an ethical framework of guiding principles for international responses to emerging infectious disease outbreaks. Respondents agreed that prioritization of frontline workers' access to experimental therapeutics was warranted based on a principle of reciprocity. There was widespread acceptance of adaptive trial designs and greater trial transparency in providing access to experimental therapeutics. Many respondents also emphasized the importance of community engagement in limited resource allocation scheme design and culturally appropriate informed consent procedures. The study results inform a potential ethical framework of guiding principles based on the interview participants' insights to be adopted by international response organizations and their healthcare workers in the face of allocating limited resources such as experimental therapeutics in future emerging infectious disease outbreaks to ease the moral burden of individual healthcare providers.
This study explores factors associated with virological detectability, and viral re-suppression after enhanced adherence counselling, in adults and children on antiretroviral therapy (ART) in ...Swaziland.
This descriptive study used laboratory data from 7/5/2012 to 30/9/2013, which were linked with the national ART database to provide information on time on ART and CD4 count; information on enhanced adherence counselling was obtained from file review in health facilities. Multivariable logistic regression was used to explore the relationship between viral load, gender, age, time on ART, CD4 count and receiving (or not receiving) enhanced adherence counselling.
From 12,063 patients undergoing routine viral load monitoring, 1941 (16%) had detectable viral loads. Children were more likely to have detectable viral loads (AOR 2.6, 95%CI 1.5-4.5), as were adolescents (AOR 3.2, 95%CI 2.2-4.8), patients with last CD4<350 cells/µl (AOR 2.2, 95%CI 1.7-2.9) or WHO Stage 3/4 disease (AOR 1.3, 95%CI 1.1-1.6), and patients on ART for longer (AOR 1.1, 95%CI 1.1-1.2). At retesting, 450 (54% of those tested) showed viral re-suppression. Children were less likely to re-suppress (AOR 0.2, 95%CI 0.1-0.7), as were adolescents (AOR 0.3, 95%CI 0.2-0.8), those with initial viral load> 1000 copies/ml (AOR 0.3, 95%CI 0.1-0.7), and those with last CD4<350 cells/µl (AOR 0.4, 95%CI 0.2-0.7). Receiving (or not receiving) enhanced adherence counselling was not associated with likelihood of re-suppression.
Children, adolescents and those with advanced disease were most likely to have high viral loads and least likely to achieve viral suppression at retesting; receiving adherence counselling was not associated with higher likelihood of viral suppression. Although the level of viral resistance was not quantified, this study suggests the need for ART treatment support that addresses the adherence problems of younger people; and to define the elements of optimal enhanced adherence support for patients of all ages with detectable viral loads.
The nucleotide analogue brincidofovir was developed to prevent and treat infections caused by double-stranded DNA viruses. Based on in vitro data suggesting an antiviral effect against Ebola virus, ...brincidofovir was included in the World Health Organisation list of agents that should be prioritised for clinical evaluation in patients with Ebola virus disease (EVD) during the West African epidemic.
In this single-arm phase 2 trial conducted in Liberia, patients with laboratory-confirmed EVD (two months of age or older, enrolment bodyweight ≥50 kg) received oral brincidofovir 200 mg as a loading dose on day 0, followed by 100 mg brincidofovir on days 3, 7, 10, and 14. Bodyweight-adjusted dosing was used for patients weighing <50 kg at enrolment. The primary outcome was survival at Day 14 after the first dose of brincidofovir. Four patients were enrolled between 01 January 2015 and 31 January 2015. The trial was stopped following the decision by the manufacturer to terminate their program of development of brincidofovir for EVD. No Serious Adverse Reactions or Suspected Unexpected Serious Adverse Reactions were identified. All enrolled subjects died of an illness consistent with EVD.
Due to the small sample size it was not possible to determine the efficacy of brincidofovir for the treatment of EVD. The premature termination of the trial highlights the need to establish better practices for preclinical in-vitro and animal screening of therapeutics for potentially emerging epidemic infectious diseases prior to their use in patients.
Pan African Clinical Trials Registry PACTR201411000939962.
Maternal infection with cholera may negatively affect pregnancy outcomes. The objective of this research is to systematically review the literature and determine the risk of fetal, neonatal and ...maternal death associated with cholera during pregnancy.
Medline, Global Health Library, and Cochrane Library databases were searched using the key terms cholera and pregnancy for articles published in any language and at any time before August 2013 to quantitatively summarize estimates of fetal, maternal, and neonatal mortality. 95% confidence intervals (CIs) were calculated for each selected study. Random-effect non-linear logistic regression was used to calculate pooled rates and 95% CIs by time period. Studies from the recent period (1991-2013) were compared with studies from 1969-1990. Relative risk (RR) estimates and 95% CIs were obtained by comparing mortality of selected recent studies with published national normative data from the closest year.
The meta-analysis included seven studies that together involved 737 pregnant women with cholera from six countries. The pooled fetal death rate for 4 studies during 1991-2013 was 7.9% (95% CIs 5.3-10.4), significantly lower than that of 3 studies from 1969-1990 (31.0%, 95% CIs 25.2-36.8). There was no difference in fetal death rate by trimester. The pooled neonatal death rate for 1991-2013 studies was 0.8% (95% CIs 0.0-1.6), and 6.4% (95% CIs 0.0-20.8) for 1969-1990. The pooled maternal death rate for 1991-2013 studies was 0.2% (95% CIs 0.0-0.7), and 5.0% (95% CIs 0.0-16.0) for 1969-1990. Compared with published national mortality estimates, the RR for fetal death of 5.8 (95% CIs 2.9-11.3) was calculated for Haiti (2013), 1.8 (95% CIs 0.3-10.4) for Senegal (2007), and 2.6 (95% CIs 0.5-14.9) for Peru (1991); there were no significant differences in the RR for neonatal or maternal death.
Results are limited by the inconsistencies found across included studies but suggest that maternal cholera is associated with adverse pregnancy outcomes, particularly fetal death. These findings can inform a research agenda on cholera in pregnancy and guidance for the timely management of pregnant women with cholera.
Rapid diagnostic methods are essential in control of Ebola outbreaks and lead to timely isolation of cases and improved epidemiologic surveillance. Diagnosis during Ebola outbreaks in West Africa has ...relied on PCR performed in laboratories outside this region. Because time between sampling and PCR results can be considerable, we assessed the feasibility and added value of using the Xpert Ebola Assay in an Ebola control program in Guinea. A total of 218 samples were collected during diagnosis, treatment, and convalescence of patients. Median time for obtaining results was reduced from 334 min to 165 min. Twenty-six samples were positive for Ebola virus. Xpert cycle thresholds were consistently lower, and 8 (31%) samples were negative by routine PCR. Several logistic and safety issues were identified. We suggest that implementation of the Xpert Ebola Assay under programmatic conditions is feasible and represents a major advance in diagnosis of Ebola virus disease without apparent loss of assay sensitivity.
In Sierra Leone, maternal and under-five mortality rates are among the highest in the world. In 2010, the government adopted the Free Healthcare Initiative (FHCI) providing free healthcare for ...children aged under-five and pregnant and lactating women. However, the FHCI is seriously impeded by the limited availability of health staff, gaps in medication supply, and weak management. In this paper, we present experiences of the Gorama Mende and Wandor (GMW) chiefdom residents in Kenema district, Sierra Leone and how they navigate available options to seek care. We argue that the health-seeking behaviour (HSB) of the population is influenced by interrelated structural and social factors. This qualitative research was conducted in rural GMW chiefdoms in February 2020, using in-depth individual, paired, and group interviews. Contrary to the assumption that traditional healers influence HSB, data suggest that structural factors like proximity, affordability, previous experience, and reception at the health facility were the main determinants. Healthcare providers felt that people went to a traditional healer first; however, the population emphasised that their first choice was always the peripheral health unit (PHU) provided there were no barriers. These barriers include, living in hard-to-reach areas, transportation, unexpected payment for services, and fear of the health staff. The study reveals the complex reality people face in terms of access to healthcare and multiple factors that influence HSB. One community member noted that if people could not afford a PHU, they would turn to alternative forms of healthcare — ‘Where my pocket can afford is where I will take my child’.
Since 2004, Médecins Sans Frontières-Switzerland has provided treatment and care for people living with HIV in Dawei, Myanmar. Renal function is routinely monitored in patients on tenofovir ...(TDF)-based antiretroviral treatment (ART), and this provides an opportunity to measure incidence and risk factors for renal dysfunction.
We used routinely collected program data on all patients aged ≥15 years starting first-line TDF-based ART between January 2012 and December 2013. Creatinine clearance (CrCl) was assessed at base line and six-monthly, with renal dysfunction defined as CrCl < 50 ml/min/1.73 m2. We calculated incidence of renal dysfunction and used Cox regression analysis to identify associated risk factors.
There were 1391 patients, of whom 1372 had normal renal function at baseline. Of these, 86 (6.3%) developed renal dysfunction during a median time of follow-up 1.14 years with an incidence rate of 5.4 per 100 person-years: 78 had CrCl between 30-50 ml/min/1.73 m2 and were maintained on TDF-based ART, but 5 were changed to another regimen: 4 because of CrCl <30 ml/min/1.73 m2. Risk factors for renal dysfunction included age ≥45 years, diagnosed diabetes, underlying renal disease, underweight and CD4 count <200 cells/mm3. There were 19 patients with baseline renal dysfunction and all continued on TDF-based ART: CrCl stayed between 30-49 ml/min/1.73 m2 in five patients while the remainder regained normal renal function.
In a resource-poor country like Myanmar, the low incidence of renal toxicity in our patient cohort suggests that routine assessment of CrCl may not be needed and could be targeted to high risk groups if resources permit.
The association between cholera in pregnancy and negative fetal outcome has been described since the 19(th) century. However, there is limited published literature on the subject. We describe ...pregnancy outcomes from a specialized multidisciplinary hospital unit at the onset of a large cholera outbreak in Haiti in 2010 and 2011.
Pregnant women with cholera were hospitalized in a specialized unit within the MSF hospital compound in Léogâne and treated using standard cholera treatment guidelines but with earlier, more intense fluid replacement. All women had intravenous access established at admission regardless of their hydration status, and all received antibiotic treatment. Data were collected on patient demographics, pregnancy and cholera status, and pregnancy outcome. In this analysis we calculated risk ratios for fetal death and performed logistic regression analysis to control for confounding factors.
263 pregnant women with cholera were hospitalized between December 2010 and July 2011. None died during hospitalization, 226 (86%) were discharged with a preserved pregnancy and 16 (6%) had live fullterm singleton births, of whom 2 died within the first 5 days postpartum. The remaining 21 pregnancies (8%) resulted in intrauterine fetal death. The risk of fetal death was associated with factors reflecting severity of the cholera episode: after adjusting for confounding factors, the strongest risk factor for fetal death was severe maternal dehydration (adjusted risk ratio for severe vs. mild dehydration was 9.4, 95% CI 2.5-35.3, p = 0.005), followed by severe vomiting (adjusted risk ratio 5.1, 95% 1.1-23.8, p = 0.041).
This is the largest cohort of pregnant women with cholera described to date. The main risk factor identified for fetal death was severity of dehydration. Our experience suggests that establishing specialized multidisciplinary units which facilitate close follow-up of both pregnancy and dehydration status due to cholera could be beneficial for patients, especially in large epidemics.
Summary Despite great advances in the diagnosis and treatment of Buruli ulcer, it is one of the least studied major neglected tropical diseases. In Africa, major constraints in the management of ...Buruli ulcer relate to diagnosis and treatment, and accessibility, feasibility, and delivery of services. In this Personal View, we outline key areas for clinical, diagnostic, and operational research on this disease in Africa and propose a research agenda that aims to advance the management of Buruli ulcer in Africa. A model of care is needed to increase early case detection, to diagnose the disease accurately, to simplify and improve treatment, to reduce side-effects of treatment, to deal with populations with HIV and tuberculosis appropriately, to decentralise care, and to scale up coverage in populations at risk. This approach will require commitment and support to strategically implement research by national Buruli ulcer programmes and international technical and donor organisations, combined with adaptations in programme design and advocacy. A critical next step is to build consensus for a research agenda with WHO and relevant groups experienced in Buruli ulcer care or related diseases, and we call on on them to help to turn this agenda into reality.
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