Scrub typhus, a neglected infectious disease caused by obligate intracellular bacteria Orientia tsutsugamushi, is a major cause of acute non-malarial fever in the tropics. Difficulties surrounding diagnosis have hampered our understanding of disease burden, which in turn negatively impacts awareness. Using national surveillance data, I highlighted the high burden of scrub typhus in Thailand with a substantial rise in cases over time. Spatially, disease burden was greatest in the northern region and geographical and meteorological factors may contribute to disease prevalence. Scrub typhus contributes significantly to the febrile disease burden in Chiangrai, northern Thailand, with 22.5% of adults admitted to hospital with acute undifferentiated fever diagnosed with the disease. I described the disease in adults and found presence of eschar and elevated liver enzymes to be predictive of scrub typhus. Scrub typhus in children remains understudied and in this thesis, I characterised paediatric scrub typhus in Chiangrai, showing that the disease was frequently severe and potentially fatal with complication and treatment failure rates of 40% and 23%, respectively. Severe hepatitis was found to be predictive of treatment failure in this cohort.
In the 1990s, reports of putative drug resistant scrub typhus emerged from northern Thailand. This proved controversial at the time as doxycycline resistant Orientia tsutsugamushi had not been described. Studies on treatment outcome and its determinants were not pursued, leading to uncertainty regarding optimal scrub typhus treatment. I reviewed the evidence on drug resistant scrub typhus extensively and concluded that doxycycline resistance may have been misconceived. Finally, I described my ongoing role as principal investigator for the Scrub Typhus Antibiotic Resistance Trial, a randomised controlled trial comparing the efficacy of 7 days of doxycycline versus 3 days of doxycycline versus 3 days of azithromycin in northern Thailand. Detailed immunological, microbiological and pharmacological analyses are embedded, which should provide clarity on the determinants of treatment outcome and whether drug resistance is illusory.</p
