Neglected rickettsial diseases in Southeast Asia: Twenty-five years of progress in surveillance, diagnostics, and clinical research

BACKGROUND: Rickettsial diseases, including scrub typhus and murine typhus, are major yet persistently under-recognised causes of acute febrile illness in Southeast Asia. Limited diagnostic capacity, ecological complexity, and non-specific clinical presentation have historically contributed to the underestimation of their burden. METHODS: We synthesised 25 years (2001-2025) of integrated epidemiological, clinical, diagnostic, molecular, ecological, and treatment research conducted across Southeast Asia. Evidence from prospective surveillance, hospital-based cohorts, seroepidemiology, molecular characterisation, in vitro isolation, genomic analyses, and randomised clinical trials was reviewed to identify convergent findings and policy-relevant lessons. FINDINGS: Rickettsial infections account for 10%-25% of hospitalised acute febrile illness cases in many endemic settings and are important causes of central nervous system infection, severe disease, and adverse pregnancy outcomes. Diagnostic advances include calibrating IFA and ELISA cut-offs, evaluating rapid diagnostic tests and LAMP assays, developing highly sensitive real-time PCR platforms, and genomic analyses revealing extensive strain diversity. Whole-genome sequencing and multilocus typing demonstrate high recombination and weak geographic structuring of the core genome despite antigenic heterogeneity. Randomised trials confirm doxycycline as first-line therapy for scrub typhus, while azithromycin shows inferior efficacy for murine typhus. Integrated One Health investigations have clarified ecological drivers and vector-host dynamics, and community engagement initiatives have improved awareness in high-risk populations. INTERPRETATION: Sustained regional investment has transformed rickettsial research from fragmented studies into an integrated surveillance, diagnostic, and translational research framework. This experience provides a transferable model for addressing neglected vector-borne diseases and strengthening febrile illness management in endemic settings. Continued support for laboratory capacity, genomic surveillance, and clinical research is essential to maintain progress and improve regional health system resilience.