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.
Controlled human infection models (CHIMs) can accelerate vaccine development for infectious diseases. Mycobacterium tuberculosis is a human-adapted pathogen that is the leading infectious cause of death worldwide. M tuberculosis infection results in a spectrum of clinical outcomes that are incompletely modelled in animals. To date, the risks of infection, prolonged treatment, and sequelae related to CHIMs with M tuberculosis have been considered ethically unacceptable. However, recent advances in bacterial engineering have resulted in safe strains that could permit M tuberculosis CHIM studies with reduced risks. In this Personal View, we address the practical considerations for conducting a pulmonary M tuberculosis CHIM study. We summarise the ethical issues of M tuberculosis CHIM studies in tuberculosis-endemic and non-endemic settings; describe safety considerations, such as optimising the challenge dose and minimising risks to third parties; and outline and prioritise clinical, microbiological, immunological, and radiological endpoints that would render such a model useful for vaccine development.
Background: Trichophyton species cause the greatest burden of dermatophytosis worldwide, with the Trichophyton mentagrophytes species complex being particularly associated with the emergence of new aggressive infections. One emerging species, Trichophyton indotineae is notable for its clinical resistance to terbinafine antifungal treatment and rapid global spread. In this study we aim to characterise the epidemiology of this emerging pathogen using genomics.
Methods: In this retrospective genomic epidemiology study, to better understand the epidemiology of this disease, we sourced isolates collected from patients with severe cases of dermatophytosis (identified either by internal transcribed spacer sequencing or phenotypic characterisation) in the UK, Ireland, France, Canada, and India for the period 2014-23, including the T indotineae type strain from Japan. We used whole-genome sequencing to confirm 90 isolates were T indotineae, and antifungal susceptibility testing to assess susceptibility to terbinafine.
Findings: 103 cases of severe dermatophytosis caused by Trichophyton species collected between 2018 and 2023 in the UK, France, Canada, Ireland, and India were included in this study. Susceptibility testing indicated that 63 (70%) of 90 T indotineae isolates were resistant to terbinafine (minimum inhibitory concentration [MIC] ≥0·5 mg/L). Pairwise genetic distances showed very high identity with only 147 (range 1-414) single-nucleotide polymorphisms (SNPs) separating isolates that were nested within a monophyletic phylogeny, supporting a single evolutionary origin of T indotineae. Genome-wide analyses identified multiple non-synonymous SNPs in SQLE (ERG1), the squalene epoxidase target of terbinafine, that were associated with terbinafine in vitro resistance of 0·5 mg/L or higher. However, six isolates exhibited high MIC values without SQLE mutations, suggesting the presence of alternative resistance mechanisms.
Interpretation: That no clear geographical clustering of isolates was observed confirms the rapid transcontinental spread of T indotineae from its likely centre of diversity in Asia. Our findings highlight the importance of better genomic surveillance to understand and manage this severe and rapidly emerging terbinafine-resistant dermatophyte.
Funding: None.
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