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

Serologic evidence of human orthopoxvirus infections in Sierra Leone

<p>Abstract</p> <p>Background</p> <p>Orthopoxviruses, including variola virus, vaccinia virus, and monkeypox virus, have previously been documented in humans in West Africa, however, no cases of human orthopoxvirus infection have been reported in the region since 1986. We conducted a serosurvey to determine whether human exposure to orthopoxviruses continues to occur in eastern Sierra Leone.</p> <p>Findings</p> <p>To examine evidence of exposure to orthopoxviruses in the Kenema District of Sierra Leone, we collected and tested sera from 1596 persons by IgG ELISA and a subset of 313 by IgM capture ELISA. Eleven persons born after the cessation of smallpox vaccination had high orthopoxvirus-specific IgG values, and an additional 6 persons had positive IgM responses. No geographic clustering was noted.</p> <p>Conclusions</p> <p>These data suggest that orthopoxviruses continue to circulate in Sierra Leone. Studies aimed at obtaining orthopoxvirus isolates and/or genetic sequences from rodents and symptomatic humans in the area are indicated.</p

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

CFRs in suspected LF cases presenting to the KGH Lassa Ward by serostatus, 2008–12.

<p>Panel A: CFR by serostatus. The presence of LASV Ag and anti-LASV IgM in serum of patients with verifiable outcomes was assessed by recombinant Ag− and IgM− capture ELISA, respectively. Panel B: Alternative calculation of CFRs. Ag+/IgM± plus Ag−/IgM+ compared to Ag−/IgM−. Statistical significance was determined using a logistic regression model predicting CFR (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002748#pntd.0002748.s004" target="_blank">Table S3</a>). NS = not significant.</p

Geographic distribution of patients presenting to the KGH with LASV antigenemia and anti-LASV IgM serpositivity, 2008–12.

<p>Confirmed cases of LF as assessed by LASV Ag in serum or cases anti-LASV IgM are shown by year of presentation, district of residence and frequency of cases. Panel A: Patients presenting in 2008–9. Panel B: Patients presenting in 2010. Panel C: Patients presenting in 2011. Panel D: Patients presenting in 2012.</p

Age distribution of cases presenting to the KGH Lassa Ward, 2008–12.

<p>Panel A: Age distributions of patients presenting while antigenemic (Ag+/IgM±). Panel B: Age distributions of nonantigenemic patients presenting with serum anti-LASV IgM (Ag−/IgM+). Panel C: Age distributions of nonantigenemic patients presenting without anti-LASV IgM seropositivity (Ag−/IgM−). In Panels A–C yellow portion of bars represent patients who were discharged and black portion of bars represent patients who died. Panel D: Age demographic for the population of Sierra Leone (2010 estimate). Among patients who died, the age distributions differed significantly between the Ag+/IgM± and Ag−/IgM− groups (p = .005). Distributional comparisons were carried out using the Kolmogorov-Smirnov technique (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002748#pntd.0002748.s006" target="_blank">Table S5</a>).</p

Case fatality rates for suspected LF cases by ribavirin treatment status and serostatus.

<p>The presence of LASV Ag in serum of patients with observed survival outcomes and verified treatment status was assessed by recombinant Ag− and IgM-capture ELISA. Statistical significance for within and between group comparisons was determined using a multivariate logistic regression model (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002748#pntd.0002748.s010" target="_blank">Table S9</a>). NS = not significant.</p

Monthly distribution of suspected LF cases presenting to the KGH Lassa Ward by serostatus, 2008–2012.

<p>Panel A: antigenemic Lassa fever cases (Ag+/IgM±). Panel B: Patients with serum anti-LASV IgM (Ag−/IgM+). Panel C: Patients with no Lassa virus seropositivity (Ag−/IgM−). The monthly frequency distributions differed between each of the serostatus group comparisons as assessed using a Poisson regression model (p<.001 for all serostatus comparisons; data not shown).</p