Armand Sprecher

Clinical presentation of patients with Ebola virus disease in Conakry, Guinea.

BACKGROUND In March 2014, the World Health Organization was notified of an outbreak of Zaire ebolavirus in a remote area of Guinea. The outbreak then spread to the capital, Conakry, and to neighboring countries and has subsequently become the largest epidemic of Ebola virus disease (EVD) to date. METHODS From March 25 to April 26, 2014, we performed a study of all patients with laboratory-confirmed EVD in Conakry. Mortality was the primary outcome. Secondary outcomes included patient characteristics, complications, treatments, and comparisons between survivors and nonsurvivors. RESULTS Of 80 patients who presented with symptoms, 37 had laboratory-confirmed EVD. Among confirmed cases, the median age was 38 years (interquartile range, 28 to 46), 24 patients (65%) were men, and 14 (38%) were health care workers; among the health care workers, nosocomial transmission was implicated in 12 patients (32%). Patients with confirmed EVD presented to the hospital a median of 5 days (interquartile range, 3 to 7) after the onset of symptoms, most commonly with fever (in 84% of the patients; mean temperature, 38.6°C), fatigue (in 65%), diarrhea (in 62%), and tachycardia (mean heart rate, >93 beats per minute). Of these patients, 28 (76%) were treated with intravenous fluids and 37 (100%) with antibiotics. Sixteen patients (43%) died, with a median time from symptom onset to death of 8 days (interquartile range, 7 to 11). Patients who were 40 years of age or older, as compared with those under the age of 40 years, had a relative risk of death of 3.49 (95% confidence interval, 1.42 to 8.59; P=0.007). CONCLUSIONS Patients with EVD presented with evidence of dehydration associated with vomiting and severe diarrhea. Despite attempts at volume repletion, antimicrobial therapy, and limited laboratory services, the rate of death was 43%.

Ebola Virus Disease in West Africa — Clinical Manifestations and Management

The cumulative clinical observations of physicians who cared for more than 700 patients with Ebola virus disease in Liberia between August and October of this year support a rational approach to EVD management in resource-limited settings.

Treatment of Marburg and Ebola hemorrhagic fevers: a strategy for testing new drugs and vaccines under outbreak conditions.

The filoviruses, Marburg and Ebola, have the dubious distinction of being associated with some of the highest case-fatality rates of any known infectious disease--approaching 90% in many outbreaks. In recent years, laboratory research on the filoviruses has produced treatments and vaccines that are effective in laboratory animals and that could potentially drastically reduce case-fatality rates and curtail outbreaks in humans. However, there are significant challenges in clinical testing of these products and eventual delivery to populations in need. Most cases of filovirus infection are recognized only in the setting of large outbreaks, often in the most remote and resource-poor areas of sub-Saharan Africa, with little infrastructure and few personnel experienced in clinical research. Significant political, legal, and socio-cultural barriers also exist. Here, we review the present research priorities and environment for field study of the filovirus hemorrhagic fevers and outline a strategy for future prospective clinical research on treatment and vaccine prevention.

Ebola viral load at diagnosis associates with patient outcome and outbreak evolution

BACKGROUND Ebola virus (EBOV) causes periodic outbreaks of life-threatening EBOV disease in Africa. Historically, these outbreaks have been relatively small and geographically contained; however, the magnitude of the EBOV outbreak that began in 2014 in West Africa has been unprecedented. The aim of this study was to describe the viral kinetics of EBOV during this outbreak and identify factors that contribute to outbreak progression. METHODS From July to December 2014, one laboratory in Sierra Leone processed over 2,700 patient samples for EBOV detection by quantitative PCR (qPCR). Viremia was measured following patient admission. Age, sex, and approximate time of symptom onset were also recorded for each patient. The data was analyzed using various mathematical models to find trends of potential interest. RESULTS The analysis revealed a significant difference (P = 2.7 × 10(-77)) between the initial viremia of survivors (4.02 log10 genome equivalents [GEQ]/ml) and nonsurvivors (6.18 log10 GEQ/ml). At the population level, patient viral loads were higher on average in July than in November, even when accounting for outcome and time since onset of symptoms. This decrease in viral loads temporally correlated with an increase in circulating EBOV-specific IgG antibodies among individuals who were suspected of being infected but shown to be negative for the virus by PCR. CONCLUSIONS Our results indicate that initial viremia is associated with outcome of the individual and outbreak duration; therefore, care must be taken in planning clinical trials and interventions. Additional research in virus adaptation and the impacts of host factors on EBOV transmission and pathogenesis is needed.

The Use of a Mobile Laboratory Unit in Support of Patient Management and Epidemiological Surveillance during the 2005 Marburg Outbreak in Angola

Background Marburg virus (MARV), a zoonotic pathogen causing severe hemorrhagic fever in man, has emerged in Angola resulting in the largest outbreak of Marburg hemorrhagic fever (MHF) with the highest case fatality rate to date. Methodology/Principal Findings A mobile laboratory unit (MLU) was deployed as part of the World Health Organization outbreak response. Utilizing quantitative real-time PCR assays, this laboratory provided specific MARV diagnostics in Uige, the epicentre of the outbreak. The MLU operated over a period of 88 days and tested 620 specimens from 388 individuals. Specimens included mainly oral swabs and EDTA blood. Following establishing on site, the MLU operation allowed a diagnostic response in <4 hours from sample receiving. Most cases were found among females in the child-bearing age and in children less than five years of age. The outbreak had a high number of paediatric cases and breastfeeding may have been a factor in MARV transmission as indicated by the epidemiology and MARV positive breast milk specimens. Oral swabs were a useful alternative specimen source to whole blood/serum allowing testing of patients in circumstances of resistance to invasive procedures but limited diagnostic testing to molecular approaches. There was a high concordance in test results between the MLU and the reference laboratory in Luanda operated by the US Centers for Disease Control and Prevention. Conclusions/Significance The MLU was an important outbreak response asset providing support in patient management and epidemiological surveillance. Field laboratory capacity should be expanded and made an essential part of any future outbreak investigation.

Unique human immune signature of Ebola virus disease in Guinea

Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD. In particular, very little is known about human immune responses to Ebola virus. Here we evaluate the physiology of the human T cell immune response in EVD patients at the time of admission to the Ebola Treatment Center in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we identify an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by a high percentage of CD4+ and CD8+ T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite comparable overall T cell activation. Concomitant with virus clearance, survivors mounted a robust Ebola-virus-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.

Transcriptomic Signatures Differentiate Survival from Fatal Outcomes in Humans Infected with Ebola Virus

BackgroundIn 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.ResultsThe 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.ConclusionsTranscriptomic 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.

First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease

Abstract A neonate born to an Ebola virus–positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months. This patient is the first neonate documented to have survived congenital infection with Ebola virus.

Personal Protective Equipment for Filovirus Epidemics: A Call for Better Evidence

Personal protective equipment (PPE) is an important part of worker protection during filovirus outbreaks. The need to protect against a highly virulent fluid-borne pathogen in the tropical environment imposes a heat stress on the wearer that is itself a safety risk. No evidence supports the choice of PPE employed in recent outbreaks, and standard testing procedures employed by the protective garment industry do not well simulate filovirus exposure. Further research is needed to determine the appropriate PPE for filoviruses and the heat stress that it imposes.

Flexibility of mobile laboratory unit in support of patient management during the 2007 Ebola-Zaire outbreak in the Democratic Republic of Congo.

The mobile laboratory provides a safe, rapid and flexible platform to provide effective diagnosis of Ebola virus as well as additional differential diagnostic agents in remote settings of equatorial Africa. During the 2007 Democratic Republic of Congo outbreak of Ebola‐Zaire, the mobile laboratory was set up in two different locations by two separate teams within a day of equipment arriving in each location. The first location was in Mweka where our laboratory took over the diagnostic laboratory space of the local hospital, whereas the second location, approximately 50 km south near Kampungu at the epicentre of the outbreak, required local labour to fabricate a tent structure as a suitable pre‐existing structure was not available. In both settings, the laboratory was able to quickly set up, providing accurate and efficient molecular diagnostics (within 3 h of receiving samples) for 67 individuals, including four cases of Ebola, seven cases of Shigella and 13 cases of malaria. This rapid turn‐around time provides an important role in the support of patient management and epidemiological surveillance.