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.

Background: Due to limited diagnostic capacity and availability of point-of-care tests, diagnosis of Clade I mpox in the geographical regions most affected is usually on clinical grounds. This may be complicated due to the similarity between mpox and varicella (chickenpox) lesions. Visual assessment of lesions is also used for determining clinical progress and to assess patient outcomes in clinical trials. However, there has been no investigation into whether clinicians can (i) identify Clade I mpox compared to other viral lesions (ii) differentiate between Clade I mpox lesion stages. Methodology/Principle findings: The objective of this study was to evaluate inter-rater reliability and agreement between clinicians assessing lesions in patients with Clade I mpox. We presented experienced clinicians with 17 images of Clade I mpox or varicella and asked them to independently indicate the most likely diagnosis–mpox or varicella–and to categorise the lesions according to their stage. When selecting the most likely diagnosis, accuracy varied across all images, the inter-rater reliability was poor (κ = 0.223; z = 10.1) and agreement was moderate (P_o = 68%). When categorising lesions according to their type, if a single lesion type was present in the image, inter-rater reliability was moderate (κ = 0.671, z = 40.6) and agreement was good (P_o = 78%), but when multiple lesion types were shown in an image, both inter-rater reliability (κ = 0.153, z = 10.5) and agreement (P_o = 29%) decreased substantially. Conclusions: This study demonstrates that there are presently limitations in using visual assessment to diagnose Clade I mpox and evaluate lesion stage and treatment outcomes, which have an impact on clinical practice, public health and clinical trials. More robust indicators and tools are required to inform clinical, public-health, and research priorities, but these must be implementable in countries affected by mpox.

We report on the protocolized use of tecovirimat (SIGA Technologies), an antiviral drug with activity against orthopoxviruses (including monkeypox and smallpox),¹ under an expanded access program for all patients with monkeypox virus (MPXV) disease in Mbaïki, Central African Republic, between December 2021 and February 2022.² Included in the study were 14 patients in whom MPXV infection had been diagnosed. All 14 patients tested positive for MPXV on at least one admission sample; of these patients, 12 had positive results on a real-time polymerase-chain-reaction (PCR) assay with a mean cycle threshold of 32 (range, 21 to 42); 12 were also positive on an MPXV CL3 assay that was specific for clade I (see the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org).

Background: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. Methods: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague ‘seasons’. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. Discussion: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. Trial registration: ClinicalTrials.gov NCT04110340. Registered on 1 October 2019

Background: The global mpox outbreak that started in May 2022 was caused by a novel clade IIb variant of the mpox virus (Orthopoxvirus monkeypox, MPXV). It differed from the traditional Western and Central Africa disease in transmission patterns and clinical presentation. Methods: To address the need for detailed clinical and virologic data, we conducted an observational cohort study (MOSAIC) during May 2022–July 2023 in individuals with confirmed MPXV infection enrolled in 6 European countries. Case management decisions were left to the attending physician. Participants were monitored for up to 6 months for clinical signs/symptoms and clinical and virologic outcomes through hospital visits, phone interviews, and self-administered questionnaires. Outcomes included time to lesion resolution, clinical status, and virus clearance. Results: The 518 participants not receiving any specific treatment (“untreated”) were diagnosed a median 5 days from symptom onset; 90% were managed as outpatients. Lesions were mostly cutaneous (88%) and perigenital (74%). By day 14 from the first polymerase chain reaction (PCR)–positive sample, 39% had resolved lesions. Time to 95% unculturable virus was longest in cutaneous lesions (52 days). A putative systemic antiviral was available for 57 participants, 44% as inpatients; 34% and 58% had resolved lesions by day 14 from the first PCR-positive sample and from treatment start, respectively. Time to 95% unculturable virus was 60 days in skin and oropharynx. No death or recrudescence occurred by day 180. Conclusions: MOSAIC provides comprehensive insights into the clinical and virologic characteristics of mpox caused by the clade IIb variant. The study forms the basis of clinical characterization for ongoing mpox outbreaks.

The ongoing global outbreak of mpox, caused by clade IIb mpox virus, poses significant challenges in accurately categorising and assessing the diversity of lesions. With lesion resolution being a key endpoint in clinical trials and observational studies, it is essential to evaluate the inter-rater reliability and agreement of clade IIb mpox lesion assessment among clinicians. Clinicians experienced in clade IIb mpox disease were surveyed online with 20 lesion images. They categorized lesions into active, crusted, resolved, or unclassifiable groups. Reliability was assessed with Fleiss' kappa and agreement with proportion of exact agreement. Fifty-three clinicians completed the survey, with a median self-reported confidence rating of 7 (on a scale of 1 to 10) in assessing mpox lesions. The inter-rater reliability was found to be moderate, with a Fleiss' kappa coefficient of 0.417 (p < 0.05, 95% CI: 0.409 - 0.425). The inter-rater agreement was 61%. This study demonstrates moderate inter-rater reliability and agreement in clade IIb mpox lesion assessment among clinicians. The findings emphasise the importance of standardising lesion classification systems to facilitate clinical care (e.g decision to start treatment) and public health (e.g. isolation) decisions and a need to explore alternative endpoints for clinical trials.