A systematic review of the clinical profile of patients with bubonic plague and the outcome measures used in research settings

Abstract

AbstractBackgroundPlague is a zoonotic disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. Drugs that are currently recommended in treatment guidelines have been approved based on animal studies alone – no pivotal clinical trials in humans have yet been completed. As a result of the sparse clinical research attention received, there are a number of methodological challenges that need to be addressed in order to facilitate the collection of clinical trial data that can meaningfully inform clinicians and policy-makers. One such challenge is the identification of clinically-relevant endpoints, which are informed by understanding the clinical characterisation of the disease – how it presents and evolves over time, and important patient outcomes, and how these can be modified by treatment.Methodology/ Principal findingsThis systematic review aims to summarise the clinical profile of 1343 patients with bubonic plague described in 87 publications, identified by searching bibliographic databases for studies that meet pre-defined eligibility criteria. The majority of studies were individual case reports. A diverse group of signs and symptoms were reported at baseline and post-baseline timepoints – the most common of which was presence of a bubo, for which limited descriptive and longitudinal information was available. Death occurred in 15% of patients; although this varied from an average 10% in high-income countries to an average 17% in low- and middle-income countries. The median time to death was 1 day, ranging from 0 to 16 days.Conclusions/ SignificanceThis systematic review elucidates the restrictions that limited disease characterisation places on clinical trials for infectious diseases such as plague, which not only impacts the definition of trial endpoints but has the knock-on effect of challenging the interpretation of a trial’s results. For this reason and despite interventional trials for plague having taken place, questions around optimal treatment for plague persist.Author summaryPlague is an infectious disease that, despite affecting humans for more than 5000 years, has historically been the subject of limited drug development activity. In fact, the drugs currently used to treat plague have been approved based on experimental data alone – no major clinical trials have yet been completed that demonstrate the efficacy and safety of one treatment over another in humans. A major barrier to accomplishing this is that few research studies have taken place to date that can meaningfully inform the design of a clinical trial. We conducted this systematic review to gather and summarise all the existing information on the clinical profile of plague patients to understand whether sufficient information exists on which to design informative clinical trials that would provide clinicians and policy-makers with the information needed to make treatment decisions for patients.This study however found that, based on the existing literature, there is insufficient data that can be used to develop methodologies for future trials. Either time must be invested in to collecting robust clinical data or innovative trial designs need to be identified that can simultaneously collect much-needed observational data while also evaluating much-needed interventions.