Interpreting the natural history and pathogenesis of Nipah virus disease through clinical data, to inform clinical trial design: a systematic review

Nipah virus is a priority pathogen with high mortality and pandemic potential. Therapies for Nipah virus disease, such as monoclonal antibodies and antivirals, are under development and require clinical trials for evaluation. However, designing such trials is challenging due to the limited understanding of the clinical characteristics, pathogenesis, and current management of Nipah virus disease. In this Review, we gathered essential data from 59 studies reporting 717 Nipah virus disease cases, to inform trial design. Nearly all patients (618 [99%] of 624) had fever. Neurological symptoms included headache (419 [70%] of 601 patients), confusion (74 [65%] of 114), and altered consciousness (358 [62%] of 580); respiratory symptoms included cough (244 [45%] of 541) and difficulty in breathing (184 [58%] of 317). Imaging data revealed chest abnormalities (29 [80%] of 36) and brain involvement (40 [71%] of 56). Viral RNA was detectable early in illness across various sample types. The median case-fatality rate was 69% (IQR 31-88%), with 51 (26%) of 197 survivors presenting with persistent neurological deficits. Clinical management varied widely, with incomplete reporting limiting insights. Prospective observational studies are needed to generate actionable data on clinical case definitions, predictors of adverse outcomes, current standards of care, and standardised endpoints, to inform future trials.