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.

Author summary

Clinical research in difficult-to-study infectious diseases such as Lassa fever is challenging. Only one controlled clinical trial has been conducted to assess the safety and efficacy of therapeutic interventions for Lassa fever (LF). Further research to test new and repurposed therapies is needed and should be supported by a methodological framework in which clinical trials can be consistently conducted for LF. To establish a basis for a standardised clinical trial methodology, we carried out 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. Our data corroborates the current characterisation of LF, and also highlights a broader range of other general symptoms that characterise the onset of LF, such as gastrointestinal illness and other nervous system and musculoskeletal disorders that are not commonly included as indicators of LF. These findings, however, should be tempered by the lack of systematic assessment and reporting of presenting signs and symptoms, their evolution following treatment, and outcomes at discharge in the historic literature. It is therefore evident that a standardised set of data variables and outcome measures should be developed and incorporated into future trials and reported to accelerate collective knowledge.