Rethinking the discharge policy for Ebola convalescents in an accelerating epidemic.

The outbreak of Ebola virus disease (EVD) in West Africa has outstripped available resources. Novel strategies are desperately needed to streamline operations. The present norm of requiring negative results on polymerase chain reaction for EVD convalescent patients to be discharged is not evidence-based and often results in asymptomatic patients competing for beds in dangerously crowded Ebola Treatment Units, posing risks to ward staff and patients and the community if infected persons are turned away. We summarize the relevant data and call for a change in discharge criteria for convalescent patients that can safely help reduce the strain on resources and direct energies where they are most needed. In the longer term, research is needed to assess the true infectivity of EVD convalescent patients to establish evidence-based criteria and guidelines for discharge

Using modelling to disentangle the relative contributions of zoonotic and anthroponotic transmission: the case of lassa fever.

BACKGROUND: Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. METHODOLOGY/PRINCIPAL FINDINGS: Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost [Formula: see text] of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals ('super-spreaders'), as we found only [Formula: see text] of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) [Formula: see text], with a maximum value up to [Formula: see text]. CONCLUSIONS/SIGNIFICANCE: This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection.This work for the Dynamic Drivers of Disease in Africa Consortium, NERC project no. NE-J001570-1, was funded with support from the Ecosystem Services for Poverty Alleviation (ESPA) programme. The ESPA programme is funded by the Department for International Development (DFID), the Economic and Social Research Council (ESRC) and the Natural Environment Research Council (NERC). See more at: http://www.espa.ac.uk/about/identity/acknowledging-espafunding# sthash.UivKPObf.dpuf. GL, JLNW, AAC, CTW and EFC also benefit from the support of the small mammal disease working group, funded by the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directorate, Department of Homeland Security, and Fogarty International Center, USA. JLNW and AC were also supported by the European Union FP7 project ANTIGONE (contract number 278976). AAC is supported by a Royal Society Wolfson Reearch Merit Award. JLNW is also supported by the Alborada Trust. JSS, LM, RG, and JGS were supported by the US National Institute of Health (JSS: NIH grant P20GM103501; LM, RG, JGS: NIH grant BAA-NIAID-DAIT-NIHQI2008031).This is the final published version. It first appeared at http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0003398

Lassa Fever in Post-Conflict Sierra Leone

Background: Lassa fever (LF), an often-fatal hemorrhagic disease caused by Lassa virus (LASV), is a major public health threat in West Africa. When the violent civil conflict in Sierra Leone (1991 to 2002) ended, an international consortium assisted in restoration of the LF program at Kenema Government Hospital (KGH) in an area with the world's highest incidence of the disease. Methodology/Principal Findings Clinical and laboratory records of patients presenting to the KGH Lassa Ward in the post-conflict period were organized electronically. Recombinant antigen-based LF immunoassays were used to assess LASV antigenemia and LASV-specific antibodies in patients who met criteria for suspected LF. KGH has been reestablished as a center for LF treatment and research, with over 500 suspected cases now presenting yearly. Higher case fatality rates (CFRs) in LF patients were observed compared to studies conducted prior to the civil conflict. Different criteria for defining LF stages and differences in sensitivity of assays likely account for these differences. The highest incidence of LF in Sierra Leone was observed during the dry season. LF cases were observed in ten of Sierra Leone's thirteen districts, with numerous cases from outside the traditional endemic zone. Deaths in patients presenting with LASV antigenemia were skewed towards individuals less than 29 years of age. Women self-reporting as pregnant were significantly overrepresented among LASV antigenemic patients. The CFR of ribavirin-treated patients presenting early in acute infection was lower than in untreated subjects. Conclusions/Significance: Lassa fever remains a major public health threat in Sierra Leone. Outreach activities should expand because LF may be more widespread in Sierra Leone than previously recognized. Enhanced case finding to ensure rapid diagnosis and treatment is imperative to reduce mortality. Even with ribavirin treatment, there was a high rate of fatalities underscoring the need to develop more effective and/or supplemental treatments for LF

Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone

Background Limited clinical and laboratory data are available on patients with Ebola virus disease (EVD). The Kenema Government Hospital in Sierra Leone, which had an existing infrastructure for research regarding viral hemorrhagic fever, has received and cared for patients with EVD since the beginning of the outbreak in Sierra Leone in May 2014. Methods We reviewed available epidemiologic, clinical, and laboratory records of patients in whom EVD was diagnosed between May 25 and June 18, 2014. We used quantitative reverse-transcriptase–polymerase-chain-reaction assays to assess the load of Ebola virus (EBOV, Zaire species) in a subgroup of patients. Results Of 106 patients in whom EVD was diagnosed, 87 had a known outcome, and 44 had detailed clinical information available. The incubation period was estimated to be 6 to 12 days, and the case fatality rate was 74%. Common findings at presentation included fever (in 89% of the patients), headache (in 80%), weakness (in 66%), dizziness (in 60%), diarrhea (in 51%), abdominal pain (in 40%), and vomiting (in 34%). Clinical and laboratory factors at presentation that were associated with a fatal outcome included fever, weakness, dizziness, diarrhea, and elevated levels of blood urea nitrogen, aspartate aminotransferase, and creatinine. Exploratory analyses indicated that patients under the age of 21 years had a lower case fatality rate than those over the age of 45 years (57% vs. 94%, P=0.03), and patients presenting with fewer than 100,000 EBOV copies per milliliter had a lower case fatality rate than those with 10 million EBOV copies per milliliter or more (33% vs. 94%, P=0.003). Bleeding occurred in only 1 patient. Conclusions The incubation period and case fatality rate among patients with EVD in Sierra Leone are similar to those observed elsewhere in the 2014 outbreak and in previous outbreaks. Although bleeding was an infrequent finding, diarrhea and other gastrointestinal manifestations were common. (Funded by the National Institutes of Health and others.

Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits

Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. The epitopes of the Lassa virus (LASV) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. Here we have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. One-half bind the GP2 fusion subunit, one-fourth recognize the GP1 receptor-binding subunit and the remaining fourth are specific for the assembled glycoprotein complex, requiring both GP1 and GP2 subunits for recognition. Notably, of the 16 mAbs that neutralize LASV, 13 require the assembled glycoprotein complex for binding, while the remaining 3 require GP1 only. Compared with non-neutralizing mAbs, neutralizing mAbs have higher binding affinities and greater divergence from germline progenitors. Some mAbs potently neutralize all four LASV lineages. These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design

Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis

Using Modelling to Disentangle the Relative Contributions of Zoonotic and Anthroponotic Transmission: The Case of Lassa Fever

Background Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. Methodology/Principal Findings Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals (‘super-spreaders’), as we found only of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) , with a maximum value up to . Conclusions/Significance This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection.</p

Epidemic curve.

<p>Daily number of referred/visiting patients at KGH (confirmed cases only) from the of April to the of January , <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003398#pntd.0003398-Shaffer1" target="_blank">[1]</a>.</p

Impact of super-spreaders I.

<p>A: Distribution of all individual for both nosocomial outbreaks, based on the permutations of the duration of illness. Mean value of the joint data: , median: , maximum: , proportion of cases when : , proportion of cases when : . B: Distribution of the effective reproduction number for cases of hospitalized patients in KGH for different values of the contribution of human-to-human transmission, , the corresponding data for the extra-nosocomial ( permutation based on , , , , cases in Jos) and all nosocomial outbreaks (based on all Jos and Zorzor cases) are also shown. C: Distribution of the total effective reproduction number, <i>i.e.</i> the average number of cases during the entire duration of the epidemic for different values the contribution of human-to-human transmission, .</p

Nosocomial outbreaks.

<p>A: Diagrammatic representation of LF cases admitted at Jos Hospital, Nigeria (total duration of the outbreak days), showing period of illness and interrelation among patients <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003398#pntd.0003398-Carey1" target="_blank">[2]</a>. The horizontal bars represent each patient. The x-axis is the time expressed in days from the start of the outbreak, when TS developed the illness (thus time in the calculation corresponds to December 1969). The grey portion of the bars are the period between the onset of the symptoms and admission to hospital; the black portion of the bars are the period between admission to hospital and discharge/death of the patients; the red thin lines are the period of exposure to the index case TS. The green bar represent the time when the patient was at the ward for unrelated illness. Note, the same diagram in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003398#pntd.0003398-Carey1" target="_blank">[2]</a> present an extra case, JT, which is not included here. This case refers to Dr. Jeanette M. Troup one of the first scientists working on Lassa Fever Virus, who contracted the disease from an autopsy accident incurred during examination of one of the fatal cases. B: Diagrammatic representation of LF cases admitted at Zorzor Hospital (total duration of the outbreak days), Liberia, showing period of illness and interrelation among patients <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003398#pntd.0003398-Monath1" target="_blank">[3]</a>. C: As in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0003398#pntd-0003398-g001" target="_blank">Fig. 1.A</a>, but the periods of illness (symptoms plus time at hospital) are randomly permuted. The contact network is kept the same. D: An example of how the time was calculated. In this particular case if and otherwise, where is the time when case is no longer exposed to case .</p