Clinical characterization of Lassa fever: A systematic review of clinical reports and research to inform clinical trial design

Abstract

Background Research is urgently needed to reduce the morbidity and mortality of Lassa fever (LF), including clinical trials to test new therapies and to verify the efficacy and safety of the only current treatment recommendation, ribavirin, which has a weak clinical evidence base. To help establish a basis for the development of an adaptable, standardised clinical trial methodology, we conducted a systematic review to identify the clinical characteristics and outcomes of LF and describe how LF has historically been defined and assessed in the scientific literature. Methodology Primary clinical studies and reports of patients with suspected and confirmed diagnosis of LF published in the peer-reviewed literature before 15 April 2021 were included. Publications were selected following a two-stage screening of abstracts, then full-texts, by two independent reviewers at each stage. Data were extracted, verified, and summarised using descriptive statistics. Results 147 publications were included, primarily case reports (36%), case series (28%), and cohort studies (20%); only 2 quasi-randomised studies (1%) were found. Data are mostly from Nigeria (52% of individuals, 41% of publications) and Sierra Leone (42% of individuals, 31% of publications). The results corroborate the World Health Organisation characterisation of LF presentation. However, a broader spectrum of presenting symptoms is evident, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. The overall case fatality ratio was 30% in laboratory-confirmed cases (1896/6373 reported in 109 publications). Conclusion Systematic review is an important tool in the clinical characterisation of diseases with limited publications. The results herein provide a more complete understanding of the spectrum of disease which is relevant to clinical trial design. This review demonstrates the need for coordination across the LF research community to generate harmonised research methods that can contribute to building a strong evidence base for new treatments and foster confidence in their integration into clinical care.

Exotic viral hepatitis: A review on epidemiology, pathogenesis, and treatment

“…Up to 80% of patients infected with the Lassa virus will develop subclinical or mild disease, especially in endemic areas. After an incubation period of 1-3 weeks, characteristic pharyngitis, headache, vomiting and abdominal pain are observed as the main symptoms according to a recent systematic review (62). When progressing to the next stage (after 7 days), clinical hallmarks typically include facial oedema, neurological disorders, such as convulsions, encephalopathy, and bleeding.…”

A standardised Phase III clinical trial framework to assess therapeutic interventions for Lassa fever

“…The earlier systematic review indicated that a low proportion of patients presented with these symptoms (except fever) on admission: sore throat– 44%; hearing loss– 4%; bleeding– 18%. [ 5 ] Due to potential low inclusions based on these criteria, the analysis team decided to raise this issue with the stakeholders at the next meeting.…”

“…[2] Symptoms are often non-specific and most commonly include fever alongside headache, vomiting and abdominal pain, with a small proportion of patients presenting with clinically severe, life-threatening symptoms, such as seizure, breathing difficulty and shock. [4,5] In hospitalised cases, the case fatality rate (CFR) is reported to be 24-27% [6,7] overall and 34% for pregnant women [8]-however in a recent cohort study taking place in a research setting, the CFR for hospitalised cases was 13% for adults and 6% for children. [9] Despite a weak evidence base, the primary treatment for LF is ribavirin in conjunction with supportive care.…”

“…First, a systematic review was carried out to describe the clinical characteristics and outcomes of LF and to guide the consultation process–the results of which have been reported separately. [ 5 ] These results generated an initial list of potential inclusion and exclusion criteria, case definitions, patient outcomes and data variables that were included in the first round of the consultation survey. Second, a stakeholder consultation was established to consider the key elements of a clinical trial framework for LF.…”

Statistical Distribution of Lassa Fever in Edo State, Nigeria

“…Merson, Bourner, Jalloh, Erber, Sallam, Flahault & Olliaro [6] extracted, verified, and summarized some primary clinical investigations and reports of patients with Lassa fever, both suspected and confirmed in some selected published works using descriptive statistics. Most of the data were from Nigeria and their findings showed that the main symptoms of Lassa fever include: gastrointestinal sickness, as well as other neural system and musculoskeletal issues that aren't usually considered Lassa Fever symptoms.…”