Systematic review of the scrub typhus treatment landscape: Assessing the feasibility of an individual participant-level data (IPD) platform
Authors: Saraswati Kartika , Maguire Brittany J , McLean Alistair RD , Singh-Phulgenda Sauman , Ngu Roland C , Newton Paul N , Day Nicholas PJ , Guérin Philippe J 
Published: April 2021

AbstractBackgroundScrub typhus is an acute febrile illness caused by intracellular bacteria from the genus Orientia. It is estimated that one billion people are at risk, with one million cases annually mainly affecting rural areas in Asia-Oceania. Relative to its burden, scrub typhus is understudied, and treatment recommendations vary with poor evidence base. These knowledge gaps could be addressed by establishing an individual participant-level data (IPD) platform, which would enable pooled, more detailed and statistically powered analyses to be conducted. This study aims to assess the characteristics of scrub typhus treatment studies and explore the feasibility and potential value of developing a scrub typhus IPD platform to address unanswered research questions.Methodology/Principal FindingsWe conducted a systematic literature review looking for prospective scrub typhus clinical treatment studies published from 1998 to 2020. Six electronic databases (Ovid Embase, Ovid Medline, Ovid Global Health, Cochrane Library, Scopus, Global Index Medicus), ClinicalTrials.gov, and WHO ICTRP were searched. We extracted data on study design, treatment tested, patient characteristics, diagnostic methods, geographical location, outcome measures, and statistical methodology.Among 3,100 articles screened, 127 were included in the analysis. 12,079 participants from 12 countries were enrolled in the identified studies. ELISA, PCR, and eschar presence were the most commonly used diagnostic methods. Doxycycline, azithromycin, and chloramphenicol were the most commonly administered antibiotics. Mortality, complications, adverse events, and clinical response were assessed in most studies. There was substantial heterogeneity in the diagnostic methods used, treatment administered (including dosing and duration), and outcome assessed across studies. There were few interventional studies and limited data collected on specific groups such as children and pregnant women.Conclusions/SignificanceThere were a limited number of interventional trials, highlighting that scrub typhus remains a neglected disease. The heterogeneous nature of the available data reflects the absence of consensus in treatment and research methodologies and poses a significant barrier to aggregating information across available published data without access to the underlying IPD. There is likely to be a substantial amount of data available to address knowledge gaps. Therefore, there is value for an IPD platform that will facilitate pooling and harmonisation of currently scattered data and enable in-depth investigation of priority research questions that can, ultimately, inform clinical practice and improve health outcomes for scrub typhus patients.Author summaryScrub typhus is a febrile illness most commonly found in rural tropical areas. It is caused by a Gram-\negative bacteria belonging to the family Rickettsiaceae and transmitted by mites when they feed on vertebrates. There is an estimate of one million cases annually, with an estimated one billion people at risk, mostly in Asia-Oceania. But relative to the scale of the problem, scrub typhus is largely understudied. Evidence-based treatment recommendations by policymakers vary or are non-existent. We searched databases and registries for prospective scrub typhus clinical treatment studies published from 1998 to 2020 and reviewed them. Data from clinical trials and particularly for specific groups, such as pregnant women and children, were minimal. The methods used to measure treatment efficacy were heterogeneous, making it difficult to directly compare or conduct a meta-analysis based on aggregated data. One way to improve the current level of evidence would be by pooling and analysing individual participant-level data (IPD), i.e. the raw data from individual participants in completed studies. This review demonstrated that there is scope for developing a database for individual participant data to enable more detailed analyses. IPD meta-analyses could be a way to address knowledge gaps such as optimum dosing for children.