Systematic review of the scrub typhus treatment landscape: Assessing the feasibility of an individual participant-level data (IPD) platform

Abstract

Background Scrub 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 findings We 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/significance There 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.

An Overview of the Clinical Profile and Risk Factors Associated with Severe Scrub Typhus Infection: A Hospital Based Study in Coimbatore

“…So far, research on ST vaccine development has been unsuccessful owing to the wide genetic variation of the organism and the organism's weakness and short lifespan. Active infection is managed using antibiotics such as doxycycline, tetracycline, azithromycin, or rifampicin as first-line drugs or a combination of chloramphenicol and tetracycline in case of resistance to firstline drugs [31] . Limitations: A few limitations that could be listed include the sample size of 47 participants, which may be considered small for a study aiming to assess risk factors associated with severe ST infection.…”

Doxycycline vs azithromycin in patients with scrub typhus: a systematic review of literature and meta-analysis

“…However, recent cases have also been reported in Peru and Kenya [ 3 ]. Despite the high burden, scrub typhus is neglected, with limited high-quality studies available to inform treatment decisions [ 4 ]. In a systematic review from India, scrub typhus was the aetiology in a quarter of hospitalised patients with AUFI [ 5 ].…”

“…The median mortality of scrub typhus is 6% in untreated patients, but it falls to 1.4% in adequately treated patients [ 2 ]. In a systematic review of the treatment landscape, doxycycline and azithromycin were the most common antibiotics used for management [ 4 ]. Indian Guidelines recommend either drug to treat scrub typhus without any clear preference [ 6 ].…”