https://orcid.org/0000-0001-6576-726X
Figures
Abstract
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.
Author summary
Rickettsial diseases, such as scrub typhus and murine typhus, are common yet frequently overlooked causes of fever in Southeast Asia. Because symptoms resemble those of many other infections, these diseases are often misdiagnosed or treated late, leading to preventable complications. Over the past 25 years, collaborative research across Thailand, Laos, Vietnam, and neighbouring countries has improved understanding of how these infections spread, how they can be diagnosed more accurately, and how best to treat them. Studies have shown that rickettsial infections account for a substantial proportion of hospitalised fever cases and can cause severe disease, especially in children and pregnant women. Diagnostic improvements, including calibrated serological tests and molecular assays, have enhanced detection and surveillance. Genomic studies have revealed high genetic diversity, which may explain why single-antigen tests perform inconsistently. Clinical trials have strengthened treatment recommendations, confirming doxycycline as an effective therapy for scrub typhus. This review summarises the lessons learned from a quarter-century of research and highlights how sustained regional investment can build durable health system capacity to manage neglected infectious diseases.
Citation: Blacksell SD, Robinson MT, Saraswati K, Perrone C, Batty EM, Wongsantichon J, et al. (2026) Neglected rickettsial diseases in Southeast Asia: Twenty-five years of progress in surveillance, diagnostics, and clinical research. PLoS Negl Trop Dis 20(5): e0014318. https://doi.org/10.1371/journal.pntd.0014318
Editor: Bin Gong, University of Texas Medical Branch, UNITED STATES OF AMERICA
Published: May 26, 2026
Copyright: © 2026 Blacksell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: o This research was funded in whole or in part by the Wellcome Trust [grant number 315982/Z/24/Z] (SDB, MTR, EMB, NPJD). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal’s policy, and the authors of this manuscript have the following competing interests: SDB is a section editor at PLoS Neglected Tropical Diseases.
1. Introduction
Rickettsial diseases are caused by vector-borne, Gram-negative, intracellular bacteria belonging to the order Rickettsiales [1]. The primary antigenic groups of human interest are the Scrub Typhus Group (STG), mainly caused by Orientia tsutsugamushi; the Spotted Fever Group (SFG), which includes over 20 Rickettsia species; and the Typhus Group (TG), which includes murine typhus (Rickettsia typhi) and epidemic typhus (Rickettsia prowazekii) [2,3]. These groups are distinguished based on their vectors, antigenic properties, and clinical manifestations [4]. Despite their high incidence across Asia and emerging presence in other regions, these zoonotic infections are frequently misdiagnosed or overlooked due to their nonspecific clinical presentation and diagnostic limitations [4]. Neglect persists despite scrub typhus causing especially substantial morbidity and mortality across diverse populations, including children, pregnant women, and rural communities.
Rickettsial diseases have been recognised in Asia for more than a century, with early descriptions of scrub typhus in Japan in the late nineteenth century and subsequent identification across Southeast Asia. During the Second World War, scrub typhus caused substantial morbidity among Allied forces, prompting intensive investigations by military research groups in the Maldives, India, and Myanmar that helped clarify the transmission, clinical features, and vector ecology of scrub typhus and other typhus group infections [5–7]. Post-war research units, including those in Kuala Lumpur, further advanced diagnostic approaches and therapeutic evaluation, contributing to the adoption of chloramphenicol as an effective treatment before the tetracycline era [6,8]. Despite these advances, civilian research activity remained limited for decades. Until approximately 25 years ago, rickettsioses in much of Southeast Asia were under-recognised outside military or outbreak settings, with diagnostic capacity largely confined to specialised centres, far from patients.
This review synthesises epidemiological, clinical, diagnostic, and ecological evidence on rickettsial diseases generated over the past two decades across Southeast Asia. Evidence is drawn from a combination of long-running research collaborations, national hospital-based studies, community serosurveys, pregnancy and paediatric cohorts, and One Health investigations conducted by multiple academic, governmental, and non-governmental groups across the region. While several insights derive from established research programmes with sustained capacity for surveillance and diagnostics, findings are interpreted alongside independent studies from diverse geographic and health-system contexts to identify convergent regional patterns and inform generalisable policy and practice recommendations.
2. Methods
This article presents a narrative synthesis of rickettsial disease research conducted in Southeast Asia, including Thailand, Lao PDR (Laos), Cambodia, Myanmar, Malaysia, Indonesia, and Vietnam, between 2001 and 2025. The review integrates published literature with findings from long-term surveillance programmes conducted by the authors and collaborating institutions in Southeast Asia. Relevant studies were identified through targeted searches of PubMed, Web of Science, and institutional project outputs, combined with expert knowledge of long-running surveillance programmes in the region. This review was conducted as a narrative synthesis and does not follow formal systematic or scoping review methodology. Study selection was guided by targeted literature searches and the authors’ knowledge of long-standing research programmes in the region.
3. Rickettsial disease burden and epidemiology in Southeast Asia
3.1 Overview: Burden, heterogeneity, and under-recognition
The epidemiology of rickettsial diseases in Southeast Asia is highly heterogeneous, reflecting variation in ecological conditions, land use, vector distributions, and patterns of human behaviour. Rural and peri-urban areas characterised by agriculture, forest fringes, and seasonal labour are consistently associated with a higher risk for scrub typhus. Across Thailand [9–18], Laos [19–25], Cambodia [26–28], Myanmar [29–31], Malaysia [32–34], Indonesia [35–38], Vietnam [39–47] (Table 1), reported scrub typhus seroprevalence varies widely depending on study design, the population sampled, and the diagnostic methods used; from less than 1% to approximately 15% in Malaysia, Indonesia, and some urban or low-risk Thai settings to 30–60% in rural Thailand, Myanmar and Vietnam. Urban transmission of murine typhus remains an important but often overlooked contributor to the burden of febrile illness [19,22]. This heterogeneity underscores that rickettsial disease burden cannot be inferred from single-site studies or narrow ecological assumptions and highlights the limitations of surveillance systems that rely on pathogen-specific testing or passive reporting.
3.2 Magnitude of burden: Incidence, seroprevalence, and hidden transmission
Taken together, studies demonstrate that rickettsial infections are among the most common yet persistently neglected causes of febrile illness across Southeast Asia. Clinical studies identify rickettsioses as leading causes of fever [19,22,48], while serological and ecological investigations reveal far greater population exposure than recognised by routine passive surveillance [49–53]. This evidence provides a strong foundation for integrating rickettsial diagnostics into febrile illness algorithms and prioritising rickettsioses within regional public health policy.
Across Southeast Asia, rickettsial infections have consistently emerged as major causes of acute febrile illness in both hospitalised and community populations. In Thailand, early prospective studies from the Thai-Myanmar border demonstrated that arthropod-borne infections, particularly scrub typhus and murine typhus, were the leading causes of fever in pregnancy, accounting for a substantial proportion of non-malarial febrile episodes and contributing to adverse maternal and neonatal outcomes [9]. Subsequent studies in northern Thailand confirmed that rickettsial diseases were among the most common aetiologies of acute undifferentiated fever in both adults and children, frequently rivalling or exceeding dengue in incidence [10–12]. Paediatric cohorts hospitalised with scrub typhus showed significant morbidity, including organ dysfunction, and mortality, underscoring that these infections are not benign and that delayed recognition translates directly into avoidable harm [11].
Across Thailand, clinical, laboratory, and radiological studies have established scrub typhus as a frequent and often severe cause of hospitalised febrile illness. Among 130 Thai patients, pulmonary involvement was common, with interstitial infiltrates and consolidation frequently observed, demonstrating that scrub typhus is a systemic infection with substantial respiratory morbidity [54]. Another study described the development of a simple risk-scoring system to predict scrub typhus severity using seven years of retrospective data from two university-affiliated hospitals in northern Thailand. The score incorporates readily available clinical and laboratory parameters to stratify patients into non-severe, severe, and fatal risk categories with good predictive accuracy, although external validation is required before routine clinical use [55]. Subsequent studies in northeastern Thailand identified specific clinical features, including the presence of eschar, electrocardiographic abnormalities, and markers of organ dysfunction, as strong predictors of fatal outcome, underscoring the importance of early recognition and treatment in endemic settings [56]. Despite consistent and mounting evidence of the importance of rickettsial diseases, even in endemic settings, specific treatment is seldom included in empiric regimens [57].
In Thailand, seroprevalence in rural communities, hill-tribe populations, and along landscape gradients frequently exceeds 20%–30% in adults, with strong associations with agricultural activity, proximity to forests, and occupational risk [15,16]. A nationwide seroepidemiological study assessed the IgG seroprevalence of STG, TG, and SFG rickettsiae among Royal Thai Army recruits using archived sera from 2007 to 2008 and 2012 [58]. The findings demonstrate widespread rickettsial exposure in Thailand, with STG showing the highest and significantly increasing seroprevalence over time, particularly in southern regions, highlighting the endemic nature of rickettsioses and underscoring the need for improved awareness, surveillance, and prevention efforts [58,59].
In Myanmar, hospital- and community-based studies quantified both seroprevalence and incidence, confirming rickettsial infections as common causes of fever and indicating far broader exposure than is captured by routine case detection [29–31,58].
In Laos, prospective studies have shown that O. tsutsugamushi, spotted fever group Rickettsia, and R. typhi together account for a substantial fraction of hospitalised febrile and central nervous system (CNS) infections [19–22,60], and are among the leading causes of acute undifferentiated fever [19,22]. Strikingly, doxycycline-responsive infections such as scrub typhus, murine typhus, and leptospirosis were more common causes of CNS infections than ‘conventional’ bacterial pathogens, suggesting that doxycycline should be added to third-generation cephalosporins in the empirical treatment of CNS infections.
Longitudinal analyses link incidence to land-use change, seasonality, and climate variability [24]; however, even within countries, seasonality and the relative importance of climatic drivers (e.g., temperature and relative humidity) can vary [61]. Across multiple countries, transmission is consistently associated with agricultural intensification and environmental disruption [24,35,36,38,61,62].
Studies from Vietnam show that scrub typhus and murine typhus are major causes of undifferentiated febrile illness, together accounting for 10%–40% of adult and paediatric cases in hospital-based studies, and are also important contributors to central nervous system infections [41,44,45]. Serological surveys across multiple regions demonstrate high population exposure, with seroprevalence varying widely by geography and reflecting heterogeneous ecological risk [39,42,43]. Historical and contemporary evidence indicate sustained endemic transmission over several decades, highlighting persistent diagnostic gaps and suggesting that the actual burden of rickettsial disease in Vietnam remains substantially underestimated [46].
Compared with scrub typhus and murine typhus, relatively little research has been performed on SFG rickettsioses in Asia. A regional synthesis [62] demonstrated that SFG Rickettsia spp. are widely distributed across diverse ecological settings in Asia, with transmission strongly associated with tick vectors, land-use patterns, wildlife hosts, and climatic drivers, yet human disease remains under-recognised and under-diagnosed due to limited molecular confirmation and surveillance capacity. Importantly, the review found no robust evidence for the presence of epidemic typhus (R. prowazekii) or rickettsialpox (R. akari) in Southeast Asia, although few investigations have specifically targeted these pathogens. The apparent absence of reported cases, therefore, likely reflects limited focussed surveillance rather than confirmed absence, highlighting the need for expanded molecular diagnostics, vector studies, and ecological investigations to better define the burden and distribution of SFG rickettsioses in the region.
3.3 Urban and peri-urban rickettsial transmission
Importantly, rickettsial transmission is not confined to rural or forest-fringe settings. Urban and peri-urban investigations in Bangkok, Yangon, Vientiane, Peninsular Malaysia, and Indonesia identify murine typhus and spotted fever group rickettsioses as frequent but under-recognised causes of febrile illness, often misdiagnosed as dengue or leptospirosis [16,24,29–34,63]. Molecular detection of O. tsutsugamushi and significant prevalence of anti-O. tsutsugamushi IgG in Vientiane may reflect urban transmission in parks and farmland within the city, or movement of people between the city and surrounding rural areas [64]. Detection of rickettsial pathogens in domestic animals, small mammals, and ectoparasites within urban environments further supports sustained urban transmission cycles [13,14]. Complementing human data, One Health investigations document the widespread circulation of rickettsiae in animal reservoirs and vectors across the region, including in urban and peri-urban environments [13,14,23,25]. Comparable patterns are reported across Malaysia and Indonesia [32–36,62].
Outbreak investigations in northern and central Thailand documented spatially clustered scrub typhus transmission linked to local ecological conditions, including peri-urban and industrial landscapes, demonstrating that disease risk extends beyond traditional endemic zones [65,66]. Urban and peri-urban transmission further challenges the assumption that rickettsioses, except murine typhus, are confined to rural areas, as molecular detection of R. felis and R. felis-like DNA in human and dog blood samples in Bangkok confirms their circulation in metropolitan environments [67].
Synthesising these findings, rickettsioses are increasingly recognised as major yet under-appreciated causes of febrile illness in both endemic populations and travellers, with frequent misdiagnosis and delayed therapy persisting, particularly during periods of health-system strain [68].
3.4 Populations at highest risk
Rickettsial diseases in Southeast Asia disproportionately affect populations already vulnerable to health inequities. In endemic settings, scrub typhus and other rickettsial infections are most common among agricultural workers and rural communities, where occupational and environmental exposure to vector-infested habitats increases infection risk and limited access to diagnostics and care delays appropriate treatment. Studies in rural Thailand demonstrate that socio-demographic factors, such as occupation and local ecological conditions, significantly influence human exposure to O. tsutsugamushi, highlighting that livelihoods tied to agriculture and domestic animal ownership are associated with a greater risk of exposure [15].
Pregnant women, older adults, and children represent particularly high-risk groups for severe outcomes [69]. Although data on typhus in pregnancy remains limited [70,71], cohort and case-series analyses from Asia show that scrub typhus and murine typhus during pregnancy are associated with substantial rates of adverse maternal and foetal outcomes, including miscarriage, stillbirth, preterm delivery, and growth restriction, particularly when diagnosis and treatment are delayed [72]. Paediatric infections likewise frequently present with severe clinical manifestations when diagnosis is delayed, and rickettsial diseases are increasingly recognised as under-appreciated contributors to acute febrile illness across local communities in the region [34]. These patterns reinforce the need for febrile illness strategies that explicitly consider vulnerable populations, incorporating targeted risk assessment and accessible diagnostics rather than relying solely on broad syndromic approaches that may miss or delay identification of rickettsial infections, especially in high-risk groups.
Older adults represent an additional under-characterised high-risk group. Although data remain limited in Southeast Asia, increasing age is associated with a greater risk of severe disease, organ dysfunction, and mortality in scrub typhus, likely reflecting comorbidities and delayed healthcare access. Improved age-stratified surveillance and clinical studies are needed to better define disease burden and optimise management in ageing populations.
In children, multiple cohort studies from Southeast Asia demonstrate that scrub typhus is a significant cause of hospitalised febrile illness, with potential for severe complications including organ dysfunction and death when diagnosis is delayed. These findings highlight the need for paediatric-specific diagnostic algorithms and earlier empiric treatment strategies in endemic settings.
3.5 Implications for health systems and surveillance
Taken together, these epidemiological patterns highlight a persistent mismatch between the actual burden of rickettsial diseases and their recognition within health systems in Southeast Asia (Panel 1). Although scrub typhus, murine typhus, and related infections are major causes of undifferentiated febrile illness, their incidence is consistently underestimated due to under-recognition, limited diagnostic capacity, and frequent misclassification in routine clinical care [2,68]. Most patients present to district-level facilities where laboratory confirmation is rarely available, contributing to delayed or incorrect diagnoses. Marked regional heterogeneity in seroprevalence and case detection further indicates that passive reporting fails to capture key transmission dynamics [68]. Thailand is the only Southeast Asian country where scrub typhus is notifiable through a national disease surveillance system. The heterogeneous distribution of cases reported, with the highest numbers in the north, northeast, and south, is described in other countries with surveillance systems (China, Taiwan, South Korea, and Japan). Even at the scale of a single Thai province, Chiang Rai, case distribution shows marked heterogeneity, apparently influenced by elevation, population size, habitat complexity, and landcover diversity [61,73]. In this context, sentinel surveillance approaches, including hospital-based fever studies and complementary serological, animal, or environmental monitoring, provide a feasible and cost-effective means of identifying under-recognised transmission and informing public health priorities [74,75].
4. Diagnosis and pathogen characterisation
Diagnostic uncertainty has long hindered recognition, treatment, and surveillance of rickettsial infections in Southeast Asia. Through influential studies (Table 2) and collaborations, diagnostics are gradually moving from fragmented, ad hoc systems to a more standardised, evidence-based system. The mainstay of laboratory diagnosis remains serology, which ideally requires paired acute and convalescent samples to assess antibody titre rises. This limits the utility of serological diagnosis in the acute setting. For Southeast Asian health systems, these findings show that relying solely on a rapid diagnostic test based on serology is inadequate for managing febrile illness; calibrated (and ideally combined) serological and molecular diagnostics are crucial for surveillance, outbreak detection, and policy [2]. These advances shape national guidelines, surveillance, and case management protocols.
4.1 Standardisation and development of serological methods
The lack of standardised locally appropriate indirect immunofluorescence assay (IFA) cut-offs and the intrinsic limitations of antibody-based detection for scrub typhus, and probably other rickettsioses, lead to inconsistencies in case definitions [52,53], resulting in misclassification, false positives, and overdiagnosis of co-infections [76]. These issues hinder cross-study comparisons and accurate burden estimates across regions. Geographically appropriate serological cut-offs are vital for reliable disease estimates, reporting, and inclusion in fever algorithms. Field evaluations demonstrated that finger-prick blood spots can reliably replace venous blood for IFA testing, making it feasible in low-resource settings [77]. Variability in IFA slide interpretation highlighted the need for standardised training and quality control [78]. Precise serological calibration proved clinically crucial in paediatric cases [79]. Collaborations in Thailand led to the incorporation of recombinant antigens for the 56-kDa scrub typhus protein into ELISA protocols, thereby improving accuracy and standardisation [80]. These efforts advance a more consistent, accessible, and clinically relevant diagnostic framework for rickettsial diseases.
Early diagnostic approaches for scrub typhus were constrained by reliance on single-strain antigens, limiting sensitivity in settings characterised by high strain diversity. Building on accumulating evidence of genetic and antigenic heterogeneity, Chao et al. demonstrated that ELISA platforms incorporating recombinant proteins from multiple O. tsutsugamushi strains substantially improved diagnostic accuracy in endemic populations [81]. This work provided practical confirmation that multivalent antigen design could overcome regional strain variability and anticipated later genomic and antigenic geographic variation findings. It marked a shift away from narrowly targeted assays toward regionally robust serological tools suitable for both surveillance and clinical use.
4.2 Evaluation of commercial and in-house rapid diagnostic tests
Coordinated efforts in Thailand and Laos translated diagnostic principles into rapid, field-deployable formats. Broadly reactive lateral flow assays detecting IgM and IgG against O. tsutsugamushi demonstrated improved sensitivity across diverse clinical presentations, but field evaluations revealed substantial variability in performance, underscoring the need for local validation of point-of-care tests; similarly, in endemic settings, about 30% of RDT-confirmed cases were found to be false positives [82–84]. Multiple evaluations of IgM-based rapid diagnostic tests (RDTs) for scrub typhus and murine typhus showed wide variability in sensitivity (24%–96%) and specificity (73%–100%), limiting their reliability for early clinical decision-making [85,86]. However, combining antibody-based RDTs with molecular tools such as loop-mediated isothermal amplification (LAMP) improved detection during the acute phase of infection [87].
A systematic review and meta-analysis confirmed the inconsistent performance of commercially available scrub typhus RDTs and reinforced the need for validated point-of-care diagnostics tailored to local strain diversity and setting [84]. Alternative formats such as dot-ELISA using recombinant 56-kDa antigens achieved high diagnostic accuracy while remaining technically simple, demonstrating that performance gains depend on antigen selection rather than assay complexity [88]. Collectively, experience across Southeast Asia shows that no single rapid test is sufficient, that antibody-based assays have limited utility early in infection, and that local validation is essential, highlighting the need for integrated diagnostic strategies for both clinical care and surveillance.
4.3 Evaluation of commercial and in-house ELISAs
Studies validated site-specific ELISA cut-offs, enabling more accurate diagnosis in Thailand, Laos, and Bangladesh using the commercial InBios ELISA [89–91]. Building on this work, optimal cut-off values were identified for the de facto in-house scrub typhus IgM and IgG ELISA developed by the US Navy’s Naval Medical Research Center (Silver Spring, Maryland, USA) [92–94], thereby reducing diagnostic misclassification and improving the accuracy of surveillance and case management. Subsequent systematic review synthesised evidence from more than 20 regional studies, guiding the use of scrub typhus ELISA thresholds and supporting harmonised recommendations across laboratories [95].
4.4 Redefining diagnostic thresholds
Improving diagnostic cut-offs for rickettsial and other neglected infections addresses the persistent challenge posed by the absence of a reliable gold standard. Bayesian latent class modelling was employed to assess diagnostic accuracy in the absence of a reference standard, enabling the derivation of thresholds applicable to Chiang Rai, northern Thailand [93,96,97]. This work was extended through investigations of humoral immunity in murine typhus, resulting in more accurate, location-specific IFA cut-offs across different disease phases [98]. In addition, the first systematic review of murine typhus IFA thresholds was conducted, providing an evidence base to support diagnostic standardisation [99]. Collectively, these efforts contributed to a shift toward harmonised, evidence-based diagnostic approaches adopted by regional laboratories, helping address long-standing challenges such as assay variability and operator dependence characteristic of many neglected tropical diseases.
4.5 Molecular diagnostics and other innovations
Molecular assays rapidly became central to rickettsial diagnostics in Southeast Asia. Early work in rural Thailand demonstrated that PCR for O. tsutsugamushi could be implemented in low-resource laboratories, thereby improving early diagnosis and clinical management [100]. Subsequent optimisation of highly sensitive quantitative PCR assays targeting the groEL and 47-kDa genes improved diagnostic performance for local strains [101], and the development of multiplex PCR platforms enabled simultaneous detection and differentiation of Orientia and Rickettsia species while maintaining high analytical sensitivity [102]. These approaches supported syndromic diagnosis in settings where multiple rickettsial pathogens co-circulate, and serology is often uninformative.
Further refinement introduced multiplex real-time PCR assays incorporating internal host-response controls, thereby improving reliability during the acute, pre-seroconversion phase of illness [103]. Today, the 47-kDa real-time PCR assay developed by the US Navy remains the most widely used molecular test for the diagnosis of scrub typhus [104]. PCR assays targeting the 16S rRNA gene have also demonstrated high sensitivity and specificity with the additional benefit of detecting a broader range of strains [105]. Eschar swab PCR, performed only for patients with eschars, has become an excellent diagnostic tool for scrub typhus, offering high sensitivity and specificity while being minimally invasive in clinical and field settings compared to traditional blood-based methods [106,107]. In parallel, LAMP-based assays provided rapid, affordable diagnostic options suitable for district hospitals, with prospective studies confirming their clinical utility [87,108–110]. Together, these advances established a layered diagnostic framework that integrates molecular assays, rapid tests, and serology, which is now embedded in febrile illness guidelines across Southeast Asia [74]. Some authors have also targeted repeated regions of the O. tsutsugamushi genome (the traD gene), substantially increasing PCR sensitivity compared to a single-gene target [111,112]. More recently, recombinase-assisted amplification and CRISPR/Cas assays have been developed and tested, with promising results [113–115]. These technologies could simplify the use of molecular methods in peripheral or field settings.
These advances collectively reframed rickettsial diagnostics in Southeast Asia as a layered system rather than a single test solution. Serology, rapid tests, and molecular assays each serve distinct roles across the clinical and surveillance continuum. Experience demonstrates that effective rickettsial diagnosis depends not on the wholesale adoption of any one platform, but on calibrated integration of tools matched to epidemiology, clinical need, and laboratory capacity. This systems-based approach has direct implications for national febrile illness algorithms, laboratory referral pathways, and regional preparedness for both endemic and emerging vector-borne infections.
5. In vitro isolation of Orientia and Rickettsia spp.
Effective diagnostics, molecular characterisation, and vaccine development for rickettsial diseases depend on the in vitro isolation of viable pathogens. As obligate intracellular bacteria, O. tsutsugamushi and Rickettsia spp. require specialised culture techniques, biosafety facilities, and expert handling. At a time when regional capacity for rickettsial culture was limited, a reference platform for in vitro isolation was established to support diagnostics, genomics, and pathogenesis studies.
5.1 Building in vitro culture capacity
The first O. tsutsugamushi isolates obtained in Thailand in the 2000s were recovered from fever patients in collaboration with Udon Thani Hospital, northeastern Thailand [116] and the Shoklo Medical Research Unit (SMRU) on the Thai-Myanmar border [12,117,118] between 2004 and 2006 at the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Bangkok. In vitro isolation was attempted in Vero cells, and O. tsutsugamushi was isolated from 12 samples (sensitivity 46.7%), with a time to isolation of 16–37 days (median 27 days) [117]. In vitro cultures continue to be obtained from clinical samples of patients with fever in Chiang Rai and Mae Sot (i.e., SMRU), Thailand, to the present day.
From 2008 to 2014, the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU) and MORU-Bangkok expanded in vitro isolation efforts in Thailand and Laos, processing over 3,200 patient blood samples and establishing one of the largest regional collections of O. tsutsugamushi and R. typhi isolates in Southeast Asia [119]. This bank of in vitro isolates has supported the validation of serological assays, molecular and antigenic characterisation, and preclinical vaccine development, while also generating detailed data on determinants of culture success. At Mahosot Hospital in Vientiane, overall isolation success was 7.9%, rising to 17.3% among patients with positive rapid diagnostic tests, serology, or PCR results. Isolation success was strongly seasonal, peaking at 28.3% in November, and was associated with longer illness duration, positive quantitative PCR, the absence of prolonged antibiotic use, buffy coat inoculation, and shorter delays between sample collection and culture.
5.2 Optimising culture and storage methods
Subsequent studies optimised protocols for yield, purification, and cryopreservation [120]. Building on these, further optimisation informed best practices for handling and storing rickettsial isolates. These improvements maintained long-term viability and preserved antigenic and genomic integrity, while passaging protocols minimised genetic drift. These improvements help strains retain their diagnostic accuracy and viability for applications such as ELISA and genome sequencing. The isolate bank underpins ongoing research in diagnostics and genomics, supporting standardisation, surveillance, and vaccine development.
5.3 Extending culture capacity into one health investigations
While early in vitro isolation focussed on human clinical specimens, subsequent work showed that culture platforms could be extended to outbreak and ecological investigations. Following a scrub typhus outbreak at a military training base in central Thailand, O. tsutsugamushi was successfully isolated from rodents captured in the affected area, directly linking human cases to local animal reservoirs [121]. This demonstrated that viable O. tsutsugamushi could be recovered from field-collected wildlife under operational conditions, thereby enabling the integration of clinical surveillance, field ecology, and laboratory science. Importantly, animal-derived isolates were incorporated into the same culture and banking pipelines as human strains, enabling comparative genomic, antigenic, and diagnostic studies. Together, this work established in vitro isolation as a core enabling technology for One Health rickettsiology, underpinning outbreak investigation, ecological inference, and translational research in endemic settings.
6. Genetic and antigenic characterisation
Understanding the genetic and antigenic diversity of O. tsutsugamushi has been vital to addressing persistent challenges in diagnosis, surveillance, and vaccine development. These studies have highlighted the heterogeneity of O. tsutsugamushi and its implications for diagnostics and control strategies.
6.1 Single-gene diversity studies
Initial molecular characterisation of O. tsutsugamushi focussed on the 56-kDa type-specific antigen (TSA) gene, the principal target of most diagnostic and serological assays. Sequencing of clinical isolates from Thailand and Laos demonstrated extensive genetic heterogeneity within and between sites, challenging the assumption that a single antigenic target could adequately represent regional diversity [122,123] (Table 3). Among 23 isolates obtained from patients in north-eastern (Udon Thani) and western Thailand between 2003 and 2005, multiple genotypes were identified, including Karp-, Gilliam-, TA716-, and TA763-like strains, with considerable sequence diversity comparable to global strain variation [122]. More recent molecular surveillance in Chiang Rai and Mae Sot in northern Thailand confirmed continued circulation of diverse strains, including Karp-, Gilliam-, Taiwan-, P23-, and CM606-like genotypes, with eschar-derived PCR demonstrating the highest diagnostic sensitivity [107]. Similarly, a genotyping study in northern Vietnam identified substantial diversity among PCR-confirmed cases, with Karp predominating (55%) alongside TA763, Gilliam (Japan variant), and Kato strains [124]. Parallel analysis of the 47-kDa htrA gene in human isolates further demonstrated marked sequence variability, indicating that antigenic heterogeneity extends beyond the TSA locus [125]. At the ecological level, rodent surveillance by Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand, yielded multiple novel isolates, some unique to specific local transmission foci [121], reinforcing evidence of ongoing diversification in enzootic reservoirs. Investigation of O. tsutsugamushi-positive larval trombiculid mites collected from small mammals across Thailand revealed marked heterogeneity in genotypes, as determined by sequencing of the 56kDa gene [126]. The presence of multiple O. tsutsugamushi genotypes within individual mites raises the possibility that co-feeding transmission may contribute to pathogen diversification, consistent with evidence of extensive recombination in O. tsutsugamushi populations [126,127]. A nationwide human study in Thailand further demonstrated pronounced spatial structuring of genotypes, with distinct strain clusters dominating different ecological zones and substantial heterogeneity even within provinces [128].
Collectively, these findings demonstrate a highly heterogeneous pathogen population across Southeast Asia and provide a mechanistic explanation for the inconsistent performance of single-antigen diagnostic assays, supporting the need for multivalent diagnostic platforms and vaccine strategies that account for substantial geographic turnover and local strain diversity [129–131].
6.2 Whole-genome sequencing and structural genomics
To explore the genomic diversity of O. tsutsugamushi beyond single-gene analysis, studies employed multilocus sequence typing (MLST) and long-read whole-genome sequencing of locally cultivated isolates. These methods provided a high-resolution view of genetic variation, recombination, and genome structure. These efforts uncovered exceptionally high rates of homologous recombination, resulting in extensive intra-species genetic variability [127]. MLST analyses of isolates from Cambodia, Vietnam and Thailand further demonstrated that, despite strong geographic clustering observed in the highly variable 56-kDa antigen gene, the core genome exhibits weak geographic structuring and forms a single regional metapopulation, with ancestral haplotypes maintained through ongoing recombination in mite vectors [132]. MLST studies of 74 clinical O. tsutsugamushi isolates from three Lao locations, compared with isolates from Udon Thani, northeast Thailand, demonstrated high diversity and recombination in the population, with ~8% mixed infection [133]. In the same study, there was low population differentiation between Vientiane and Udon Thani, on opposite sides of the Mekong River, but a distinct population in Salavan, southern Laos [133].
Whole-genome sequencing of Thai O. tsutsugamushi isolates yielded six complete genomes, providing the first detailed insights into the structure of Southeast Asian strains. Further analysis revealed a small core genome (~657 genes), embedded within highly repetitive, fragmented regions, complicating assembly and comparative genomics [134]. The discovery of the organism’s genomic plasticity was striking, with abundant mobile genetic elements, gene duplications, and pseudogenes contributing to low synteny across strains, even within similar areas [134]. The study also found important discrepancies between 56kDa and whole-genome genotyping, highlighting the need for a better understanding of relatedness among strains. Target enrichment approaches have shown promise, enabling the generation of partial O. tsutsugamushi sequences from mites and rats to investigate phylogeographic clustering across host species [124] and to facilitate sequencing of clinical isolates of O. tsutsugamushi and R. prowazekii [135]. Nanopore sequencing of an R. typhi isolate in Lao PDR demonstrated that MinION data can generate complete genomes in resource-limited settings and was followed by a larger study comparing recent isolates from Laos with a historical collection [136]. These data represent the first complete genome sequences of R. typhi isolates collected over the last 50 years and demonstrate extremely low genetic diversity across the species over a 90-year timespan, a stark contrast to the complex genetics of O. tsutsugamushi [137].
6.3 Antigenic cartography
Antigenic cartography, adapted from influenza research, was used to visualise cross-reactive relationships among scrub typhus strains based on IFA data from Thai isolates [138]. It showed extensive cross-reactivity, with antigenic distances often not correlating with genetic ones, highlighting limitations of sequence data alone. The approach emphasises the need for multivalent or geographic-specific antigen panels to enhance serology-based diagnostics.
7. Redefining the pathogenesis of rickettsial infections
Historically, the pathogenesis of scrub typhus and murine typhus was poorly understood, with limited data on cellular targets, immune responses, or pathogen-specific mechanisms of rickettsial pathogenesis. Key findings link clinical phenotypes to immune pathways, overturn assumptions about cellular targets, and support vaccine development through novel animal models. These advances were supported by long-standing regional partnerships, including AFRIMS in Bangkok, which has played a central role in animal models, vector biology, and translational immunology for rickettsial diseases in Southeast Asia.
7.1 Comparative human immunopathology and experimental models
Comparative clinical studies in Laos and Thailand first demonstrated that scrub typhus and murine typhus elicit distinct immune response profiles in endemic populations. Biomarker analyses showed stronger endothelial activation in murine typhus, whereas scrub typhus was characterised by heightened monocyte and leukocyte activation, with divergent coagulation and inflammatory pathways closely linked to disease severity [139,140]. These differences align with clinical patterns: murine typhus usually presents as a milder, viral-like illness (although CNS manifestations, such as reduced consciousness, can occur), while scrub typhus is more likely to cause intense inflammation and multi-organ involvement. The isolation of local O. tsutsugamushi strains enabled the development of more physiologically relevant infection models. Intradermal infection of Swiss CD-1 mice demonstrated that virulent strains disseminate more rapidly than less pathogenic isolates, establishing a mechanistic link between strain variation and clinical severity [141]. This approach captured early host–pathogen interactions at the dermal entry site, advancing pathogenesis research beyond artificial intravenous models.
Building on this work, non-human primate models using rhesus and cynomolgus macaques reproduced human-like disease, systemic dissemination, and robust cellular immune responses, providing platforms for immunopathogenesis and vaccine evaluation [142–144]. Comparative macaque studies further demonstrated strain-specific differences in clinical progression and immune responses, informing antigen selection for vaccine development [145]. Histopathological studies of human eschars suggest that early infection is characterised by predominant infection of dendritic cells and monocytes, rather than endothelial cells, challenging the traditional view of primary endothelial tropism [146].
7.2 Vector ecology
Vector ecology has been central to understanding scrub typhus transmission in Southeast Asia. The disease is maintained in enzootic cycles involving trombiculid mite larvae (chiggers), small mammals, and ecological niches, especially but not exclusively secondary vegetation, forest fringes, and agricultural land. Experimental work, including the establishment and maintenance of a laboratory chigger colony at the Armed Forces Research Institute of Medical Sciences (AFRIMS) in Thailand, has been critical for elucidating vector competence, transovarial transmission, and strain diversity of O. tsutsugamushi, providing foundational insights into transmission dynamics [5,147]. Advances in mite taxonomic identification using autofluorescence microscopy and mitochondrial coi gene sequencing have been critical in advancing this neglected and challenging area of vector ecology for scrub typhus [148].
In Northern Thailand, field studies have identified habitat complexity and ecotones as important determinants of scrub typhus [149–151]. High rodent density in fragmented habitats likely supports the maintenance of vector species of chigger; the factors that influence risk of scrub typhus infection at different scales remain poorly understood [150]. Human behaviour substantially modifies exposure risk. In Northern Thailand, studies have shown that agricultural practices, forest-related activities, and ground-level occupational exposure increase the likelihood of contact with infected chigger habitats. At the same time, limited awareness and delayed healthcare-seeking contribute to underdiagnosis [49,150]. Together, these findings emphasise that rickettsial transmission in Southeast Asia is shaped by the interaction between vector ecology and socio-behavioural factors, reinforcing the need for integrated ecological surveillance and community-level prevention strategies.
8. Treatment and intervention studies
Collaborative studies strengthen impact by linking laboratory research with clinical practice. Integration of improved diagnostics with prospective clinical studies has enabled randomised controlled trials defining optimal antimicrobial treatment for rickettsial infections. These findings have directly informed regional treatment protocols and international guidelines for the management of febrile illness.
8.1 Randomised controlled trials (RCTs)
Randomised controlled trials have provided stronger evidence for the treatment of rickettsial diseases, increasing confidence in clinical management across endemic settings. In Thailand, a randomised trial comparing a 7-day course of doxycycline with a 3-day course of azithromycin demonstrated that azithromycin was non-inferior for the treatment of scrub typhus and leptospirosis, with similar fever clearance times and fewer adverse events. However, doxycycline remained the more affordable option [152]. In Laos, a randomised trial at Mahosot Hospital showed that, in contrast, for uncomplicated murine typhus, although 3 days and 7 days of oral doxycycline were safe and efficacious, 3 days of azithromycin were inferior in terms of fever clearance time [153]. The reason why azithromycin has inferior efficacy to doxycycline in murine typhus but not in scrub typhus remains to be determined. Also, the optimal duration of doxycycline treatment in uncomplicated scrub typhus remains to be determined. For severe scrub typhus, a multicentre trial conducted by the Christian Medical College, Vellore, across multiple sites in India demonstrated that while intravenous doxycycline or azithromycin monotherapy was effective and well tolerated, combination therapy was a superior therapeutic option [154]. Together, these trials directly informed treatment guidelines for severe scrub typhus across Asia and improved clinical care pathways for rickettsial infections in endemic and resource-limited settings.
8.2 Antimicrobial resistance
Reports of reduced clinical responsiveness to doxycycline in scrub typhus were first described in northern Thailand in the 1990s, with documented delayed fever clearance times suggesting possible antimicrobial resistance in O. tsutsugamushi isolates from Chiang Rai Province [155,156]. These observations prompted concern regarding emerging doxycycline resistance in Southeast Asia. Subsequent laboratory investigations, including cell culture–based susceptibility testing of Thai and Lao isolates, did not demonstrate high-level resistance but did reveal variability in in vitro susceptibility profiles [157]. More recent re-examination of clinical and microbiological evidence from Thailand & Lao concluded that convincing evidence of stable doxycycline resistance is lacking, with delayed clinical responses more likely attributable to host and pathogen strain diversity, or pharmacokinetic factors, rather than to true antimicrobial resistance [158]. However, based on the genomes of reference and Lao strains, it was determined that O. tsutsugamushi would be intrinsically resistant to fluoroquinolones in vivo [116]. This class of antibiotics, as well as cotrimoxazole, should not be used for the treatment of scrub typhus. Collectively, current evidence supports the continued use of doxycycline as the first-line therapy for scrub typhus in Southeast Asia, while highlighting the importance of ongoing clinical and molecular surveillance.
8.3 Rickettsial infections in pregnancy
Studies along the Thai–Myanmar border, led by the SMRU, identified scrub typhus and murine typhus as major, under-recognised threats to maternal and neonatal health, and found that they were often misdiagnosed or untreated due to limited diagnostic capacity. Foetal outcomes were also adversely affected, with increased rates of miscarriage and stillbirth observed among infected women, particularly when maternal diagnosis was delayed or missed [72]. This study was among the first prospective investigations worldwide to quantify the maternal and perinatal burden of rickettsial diseases. Scrub typhus in pregnancy presents a major diagnostic and therapeutic dilemma in resource-limited endemic settings. Case reports and cohort data from Southeast Asia demonstrate high rates of adverse maternal and foetal outcomes, including miscarriage, stillbirth, preterm birth, and low birth weight, with poor neonatal outcomes reported in up to 36%–42% of cases [72]. In a case report from the Thai–Myanmar border, chloramphenicol treatment was associated with maternal survival but not foetal survival, highlighting the difficult risk–benefit decisions required when managing severe disease [159]. Evidence supporting azithromycin, the most commonly used alternative in pregnancy, remains limited, and azithromycin is likely to have limited efficacy in murine typhus. Fever clearance time appears associated with pregnancy outcome, underscoring the urgent need for prospective trials and context-appropriate treatment guidelines in endemic areas. The evidence regarding the safety of doxycycline use during pregnancy for treating rickettsial infections has also been reviewed [160]. Given the adverse outcomes associated with scrub typhus in pregnancy, and the increasing evidence of its safety in pregnancy, doxycycline is the drug of choice.
8.4 Community engagement
Despite increased recognition of rickettsial diseases as a major infectious cause of fever in the region, they remain largely ignored by the public and, often, by healthcare workers. Recently, in northern Thailand, a community engagement project promoted disease prevention and successfully increased knowledge and awareness of scrub typhus among at-risk populations [161].
9. Summary of impacts and future directions
Over two decades of integrated rickettsial research across Southeast Asia, our understanding of these infections has been fundamentally reshaping how they are diagnosed and managed. Through global and regional collaborations (see Table 4), this body of work has reframed scrub typhus, murine typhus, and related rickettsioses from obscure academic entities into core components of febrile illness policy, surveillance, and clinical care across multiple health systems (see Panel 1 and Table 5 for summary).
Between 2001 and 2025, 318 publications on scrub typhus and 97 on murine typhus were identified from Southeast Asian institutions (Fig 1). Scrub typhus output increased markedly after 2012, peaking at 27 publications in 2025, whereas murine typhus publications remained comparatively lower, with a maximum annual output of 10 in 2019. The sustained increase in publications on scrub typhus from Southeast Asian institutions, with more than half (55.0%) involving affiliations with MORU and LOMWRU, reflects not only the regional disease burden but also institutional leadership and funding. The MORU network units in Thailand and Laos have been identified as the most productive global institution in scrub typhus research [162], and diagnostic-focussed bibliometric analyses further confirm their central role in advancing laboratory methodologies for rickettsial diseases [163].
The impact of these studies goes beyond publications. Epidemiological platforms have shown that rickettsial infections account for 10%–25% of acute febrile admissions, challenging the idea that malaria and viral infections are the primary drivers of fever. Diagnostic research built the first regional architecture for rickettsial serology and testing in Asia, fixing decades of inconsistent case definitions and enabling reliable burden estimates. Culture and isolate banking developed regional capacity for pathogen analysis, assay validation, and translational research, skills once limited to a few high-income laboratories. Genomic studies explained why many diagnostics fail in endemic areas, guiding the design of better, multivalent assays. All these efforts created a translational pipeline from ecology to treatment, policy, and preparedness. This integrated system sets the programme apart from traditional research, showing how sustained investment can turn fragmented studies into lasting public health infrastructure.
Several lessons emerge. First, pathogen-agnostic febrile illness surveillance is vital for detecting under-recognised causes of severe disease in settings with limited diagnostics. Second, diagnostic strategies must be tailored to local epidemiology and distinguish between tools for patient management and those for surveillance and policy. Third, empirical treatment, like early doxycycline in suitable cases, remains a practical, evidence-based approach to prevent morbidity and mortality as diagnostics improve. Fourth, local collaborative research agenda decision-making allows responsiveness to key but neglected local research questions. Lastly, these gains require sustained lab platforms, harmonised methods, and a trained regional workforce, not short-term projects.
The identification and validation of prognostic biomarkers represent an important future direction for improving clinical management of rickettsial diseases. Studies from Southeast Asia have demonstrated associations between host immune responses, endothelial activation, and disease severity, suggesting that biomarker-based risk stratification may be feasible. Integration of such biomarkers into clinical algorithms could enable early identification of patients at risk of severe disease, guide triage decisions, and optimise resource allocation. However, further validation across diverse populations and translation into affordable, point-of-care formats will be essential before routine implementation.
This evidence base has limitations. Much of the data comes from sentinel sites with better diagnostic capabilities, so they are not nationally representative. Diagnostic thresholds, assays, and case definitions vary, complicating comparisons. Many Southeast Asian countries are underrepresented in surveillance, with only Thailand having a mandatory national surveillance system. Still, consistent findings across diverse methods and populations support the conclusion that rickettsial diseases are common, often under-recognised, clinically significant, and respond well to low-cost interventions when health systems are well coordinated.
Looking ahead, Southeast Asia faces rising risks from vector-borne and zoonotic infections due to climate change, land use change, urbanisation, and population mobility [24]. The strategies here, integrated fever surveillance, calibrated diagnostics, regional labs, and clinical trials, provide a transferable preparedness framework for endemic and emerging pathogens. However, these capabilities are fragile. Sentinel platforms decline without funding; calibration standards drift; in vitro isolate collections and molecular capacity weaken or disappear; and health systems revert to reactive fever management. Recent research on anti-rickettsial vaccines in Southeast Asia is extremely limited, but renewed efforts, especially for scrub typhus, could improve prevention [130,131].
Emerging technologies, including artificial intelligence (AI)-supported diagnostics and digital surveillance systems, offer important opportunities to strengthen rickettsial disease detection and reporting in Southeast Asia. AI-based approaches could support the integration of clinical, laboratory, and epidemiological data to improve diagnostic accuracy in settings where confirmatory testing is limited. In parallel, expansion of national surveillance systems, building on existing sentinel platforms, is feasible and would substantially improve burden estimation, outbreak detection, and public health response. However, implementation will depend on sustained investment in digital infrastructure, data standardisation, and integration with existing health systems. Experience from Thailand, where scrub typhus is notifiable, demonstrates that scalable surveillance is achievable, although broader regional adoption remains limited.
Collectively, this synthesis provides new perspectives by linking long-term epidemiological trends, diagnostic advances, and clinical trial evidence into a coherent regional framework. This integrated view highlights how sustained investment in collaborative research platforms can directly translate into improved patient management and more effective public health strategies for neglected febrile illnesses.
The past 25 years have taught a key lesson: progress against neglected infectious diseases depends on long-term investment in health systems, not just on studies with dedicated funding. Maintaining regional frameworks enables early detection of ecological shifts, quick validation of diagnostics, and real-time data integration. The recent development of the Asia-Pacific Rickettsial Conferences has facilitated liaison and a more coordinated approach. Southeast Asia’s rickettsial research infrastructure offers a foundation for broader epidemic preparedness. Despite high disease burdens, especially for scrub typhus, funding remains limited to address these neglected issues and shape policy. This review shows that with sustained support, endemic regions can produce world-class science, inform policy, and build resilient health systems. The future focus should be on preserving, strengthening, and scaling these platforms.
Panel 1. Implications for febrile illness policy in Southeast Asia. These points synthesise key insights derived from 25 years of integrated epidemiological, clinical, diagnostic, and translational research across Southeast Asia, highlighting how sustained regional collaboration has transformed rickettsial diseases from under-recognised causes of fever into actionable priorities for clinical management and public health policy.
- Rickettsial diseases should be explicitly incorporated into national undifferentiated febrile illness (UFI) guidelines, particularly in rural and peri-urban settings where access to diagnostic services is limited.
- Empiric doxycycline therapy should be considered early for patients with compatible clinical syndromes, especially CNS infections, given its low cost, safety profile, and proven mortality benefit.
- Reliance on rapid serology-based diagnostic tests alone is insufficient; calibrated serological and molecular diagnostics, ideally combined at the point of care, remain essential for surveillance and outbreak detection.
- Sentinel surveillance platforms, including hospital-based systems, provide cost-effective approaches to monitoring rickettsial transmission in endemic regions. Ensure that scrub typhus is a nationally reportable infection.
- Regional laboratory harmonisation and training networks are feasible and critical for ensuring diagnostic comparability, outbreak preparedness, rapid pathogen identification, and locally appropriate diagnostic cut-offs.
- Integrated One Health approaches linking human, animal, and environmental surveillance will strengthen preparedness for emerging and re-emerging vector-borne diseases.
Key learning points, key papers, and advances in rickettsial diagnostics in Southeast Asia
Learning points
- Rickettsial infections are major but persistently under-recognised causes of acute febrile illness in Southeast Asia, frequently accounting for 10%–25% of hospitalised cases.
- Diagnostic limitations, particularly reliance on poorly standardised serology, have historically led to underestimation of disease burden and misclassification of cases.
- Locally validated serological cut-offs and integration of molecular diagnostics have substantially improved detection, surveillance, and clinical management.
- Early empiric treatment with doxycycline remains highly effective and is critical for reducing morbidity and mortality in endemic settings.
- Long-term regional investment in laboratory platforms, surveillance systems, and collaborative research networks can transform neglected diseases into integrated public health priorities.
Key papers in the field
- Mayxay M, Castonguay-Vanier J, Chansamouth V, Dubot-Peres A, Paris DH, Phetsouvanh R, et al. Causes of non-malarial fever in Laos: a prospective study. Lancet Glob Health. 2013;1(1):e46-54. https://doi.org/10.1016/S2214-109X(13)70008-1. PubMed PMID: 24748368; PubMed Central PMCID: PMCPMC3986032.Dittrich S et al. CNS infections in Laos. Lancet Glob Health. 2015.
- Phongmany S, Rolain JM, Phetsouvanh R, Blacksell SD, Soukkhaseum V, Rasachack B, et al. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis. 2006;12(2):256–62. https://doi.org/10.3201/eid1202.050900. PubMed PMID: 16494751; PubMed Central PMCID: PMCPMC3373100.
- Varghese GM, Dayanand D, Gunasekaran K, Kundu D, Wyawahare M, Sharma N, et al. Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus. N Engl J Med. 2023;388(9):792–803. https://doi.org/10.1056/NEJMoa2208449. PubMed PMID: 36856615; PubMed Central PMCID: PMCPMC7614458.
- Blacksell SD, Bryant NJ, Paris DH, Doust JA, Sakoda Y, Day NP. Scrub typhus serologic testing with the indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to a lot of confusion. Clin Infect Dis. 2007;44(3):391–401. Epub 20070103. https://doi.org/10.1086/510585. PubMed PMID: 17205447.
- Batty EM, Chaemchuen S, Blacksell S, Richards AL, Paris D, Bowden R, et al. Long-read whole genome sequencing and comparative analysis of six strains of the human pathogen Orientia tsutsugamushi. PLoS Negl Trop Dis. 2018;12(6):e0006566. Epub 20180606. https://doi.org/10.1371/journal.pntd.0006566. PubMed PMID: 29874223; PubMed Central PMCID: PMCPMC6005640.
Advantages of emerging diagnostic technologies
- Molecular assays (PCR, LAMP) enable early detection during the acute phase when serology is often negative.
- Multiplex and quantitative PCR platforms allow simultaneous detection and differentiation of co-circulating rickettsial pathogens.
- Integration of molecular, serological, and rapid tests provides a layered diagnostic framework adaptable to different clinical and surveillance settings.
Disadvantages of emerging diagnostic technologies
- Diagnostic performance is highly dependent on local validation, including strain diversity and appropriate serological cut-offs.
- Molecular diagnostics require infrastructure, training, and quality assurance systems that remain limited in many endemic settings.
- Rapid diagnostic tests show variable sensitivity and specificity, limiting their reliability for standalone clinical decision-making.
Acknowledgments
We would like to acknowledge the enduring influence of the late Professor Sir Nicholas White and Dr Rattanaphone Phetsouvanh, whose contributions to tropical medicine in Southeast Asia were profound. Their work, mentorship, and commitment to advancing research in the region have shaped both the field and the many researchers and clinicians who continue this work today. They are deeply missed. The authors acknowledge the use of ChatGPT 5.4 for coding support for Fig 1.
References
- 1. Xu J, Gu XL, Jiang ZZ, Cao XQ, Wang R, Peng QM. Pathogenic Rickettsia, Anaplasma, and Ehrlichia in Rhipicephalus microplus ticks collected from cattle and laboratory hatched tick larvae. PLOS Negl Trop Dis. 2023;17(8):e0011546.
- 2. Aung AK, Spelman DW, Murray RJ, Graves S. Rickettsial infections in Southeast Asia: implications for local populace and febrile returned travelers. Am J Trop Med Hyg. 2014;91(3):451–60. pmid:24957537
- 3. Low VL, Tan TK, Khoo JJ, Lim FS, AbuBakar S. An overview of rickettsiae in Southeast Asia: vector-animal-human interface. Acta Trop. 2020;202:105282. pmid:31778642
- 4. Tshokey T, Ko AI, Currie BJ, Munoz-Zanzi C, Goarant C, Paris DH, et al. Leptospirosis, melioidosis, and rickettsioses in the vicious circle of neglect. PLoS Negl Trop Dis. 2025;19(1):e0012796. pmid:39847571
- 5. Kelly DJ, Fuerst PA, Ching W-M, Richards AL. Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. Clin Infect Dis. 2009;48 Suppl 3:S203-30. pmid:19220144
- 6. Philip CB. Tsutsugamushi disease in World War II. J Parasitol. 1948;34(3):169–91. pmid:18867393
- 7. Sayen JJ, Pond HS, et al. Scrub typhus in Assam and Burma; a clinical study of 616 cases. Medicine (Baltimore). 1946;25:155–214. pmid:20986167
- 8. Smadel JE, Woodward TE, Ley HL, Lewthwaite R. Chloramphenicol (Chloromycetin) in the treatment of tsutsugamushi disease (Scrub typhus). J Clin Invest. 1949;28(5 Pt 2):1196–215. pmid:16695792
- 9. McGready R, Ashley EA, Wuthiekanun V, Tan SO, Pimanpanarak M, Viladpai-Nguen SJ, et al. Arthropod borne disease: the leading cause of fever in pregnancy on the Thai-Burmese border. PLoS Negl Trop Dis. 2010;4(11):e888. pmid:21103369
- 10. Wangrangsimakul T, Althaus T, Mukaka M, Kantipong P, Wuthiekanun V, Chierakul W, et al. Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand. PLoS Negl Trop Dis. 2018;12(5):e0006477. pmid:29852003
- 11. Wangrangsimakul T, Greer RC, Chanta C, Nedsuwan S, Blacksell SD, Day NPJ, et al. Clinical characteristics and outcome of children hospitalized with scrub typhus in an area of endemicity. J Pediatric Infect Dis Soc. 2020;9(2):202–9. pmid:30864670
- 12. McGready R, Blacksell SD, Luksameetanasan R, Wuthiekanun V, Jedsadapanpong W, Day NPJ, et al. First report of an Orientia tsutsugamushi type TA716-related scrub typhus infection in Thailand. Vector Borne Zoonotic Dis. 2010;10(2):191–3. pmid:19492945
- 13. Fa-Ngoen C, Kaewmongkol G, Inthong N, Tanganuchitcharnchai A, Abdad MY, Siengsanan-Lamont J, et al. Serological detection of Rickettsia spp. and evaluation of blood parameters in pet dogs and cats from Bangkok and neighboring provinces. PLoS One. 2024;19(3):e0297373. pmid:38452006
- 14. Rungrojn A, Chaisiri K, Paladsing Y, Morand S, Junjhon J, Blacksell SD. Prevalence and molecular characterization of Rickettsia spp. from wild small mammals in public parks and urban areas of Bangkok Metropolitan, Thailand. Trop Med Infect Dis. 2021;6(4). pmid:34842856
- 15. Chaisiri K, Tanganuchitcharnchai A, Kritiyakan A, Thinphovong C, Tanita M, Morand S, et al. Risk factors analysis for neglected human rickettsioses in rural communities in Nan province, Thailand: a community-based observational study along a landscape gradient. PLoS Negl Trop Dis. 2022;16(3):e0010256. pmid:35320277
- 16. Tasak N, Apidechkul T, Law ACK, Abdad MY, Srichan P, Perrone C, et al. Prevalence of and factors associated with scrub typhus exposure among the hill tribe population living in high incidence areas in Thailand: a cross-sectional study. BMC Public Health. 2023;23(1):2394. pmid:38041104
- 17. Rattanakomol P, Khongwichit S, Poovorawan Y. Flea-borne rickettsioses and scrub typhus in patients with suspected arbovirus infection in Bangkok, Thailand. Vector Borne Zoonotic Dis. 2024;24(10):649–55. pmid:38946645
- 18. Manosroi J, Chutipongvivate S, Auwanit W, Manosroi A. Determination and geographic distribution of Orientia tsutsugamushi serotypes in Thailand by nested polymerase chain reaction. Diagn Microbiol Infect Dis. 2006;55(3):185–90. pmid:16626907
- 19. Phongmany S, Rolain JM, Phetsouvanh R, Blacksell SD, Soukkhaseum V, Rasachack B. Rickettsial infections and fever, Vientiane, Laos. Emerg Infect Dis. 2006;12(2):256–62. pmid:16494751
- 20. Dubot-Peres A, Mayxay M, Phetsouvanh R, Lee SJ, Rattanavong S, Vongsouvath M. Management of central nervous system infections, Vientiane, Laos, 2003-2011. Emerg Infect Dis. 2019;25(5):898–910. pmid:31002063
- 21. Dittrich S, Rattanavong S, Lee SJ, Panyanivong P, Craig SB, Tulsiani SM, et al. Orientia, rickettsia, and leptospira pathogens as causes of CNS infections in Laos: a prospective study. Lancet Glob Health. 2015;3(2):e104-12. pmid:25617190
- 22. Mayxay M, Castonguay-Vanier J, Chansamouth V, Dubot-Pérès A, Paris DH, Phetsouvanh R, et al. Causes of non-malarial fever in Laos: a prospective study. Lancet Glob Health. 2013;1(1):e46-54. pmid:24748368
- 23. Nguyen HM, Theppannga W, Vongphayloth K, Douangngeun B, Blacksell SD, Robinson MT. Screening of ectoparasites from domesticated dogs for bacterial pathogens in Vientiane, Lao PDR. Zoonoses Public Health. 2020;67(8):862–8. pmid:32649049
- 24. Roberts T, Parker DM, Bulterys PL, Rattanavong S, Elliott I, Phommasone K, et al. A spatio-temporal analysis of scrub typhus and murine typhus in Laos; implications from changing landscapes and climate. PLoS Negl Trop Dis. 2021;15(8):e0009685. pmid:34432800
- 25. Elliott I, Kumlert R, Thangnimitchok N, Blacksell SD, Tanganuchitcharnchai A, Paris DH, et al. Orientia tsutsugamushi in chiggers and small mammals in Laos. Vector Borne Zoonotic Dis. 2022;22(10):505–11. pmid:36255415
- 26. Chheng K, Carter MJ, Emary K, Chanpheaktra N, Moore CE, Stoesser N, et al. A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia. PLoS One. 2013;8(4):e60634. pmid:23593267
- 27. Kelly GC, Rachmat A, Tran LK, Supaprom C, Phireak H, Prom S, et al. Clinical manifestations, risk factors, and disease burden of rickettsiosis, Cambodia, 2007-2020. Emerg Infect Dis. 2025;31(6):1069–80. pmid:40439354
- 28. Mueller TC, Siv S, Khim N, Kim S, Fleischmann E, Ariey F, et al. Acute undifferentiated febrile illness in rural Cambodia: a 3-year prospective observational study. PLoS One. 2014;9(4):e95868. pmid:24755844
- 29. Bowhay TR, Myat TO, Oo WT, Mone HK, Sharples KJ, Robinson MT, et al. Prevalence and risk factors for murine typhus, scrub typhus and spotted fever group rickettsioses among adolescent and adult patients presenting to Yangon General Hospital, Yangon, Myanmar. Trop Med Int Health. 2025;30(9):966–77. pmid:40671672
- 30. Oo WT, Bowhay TR, Myat TO, Htike WW, Lwin KT, Blacksell SD, et al. Estimating scrub typhus and murine typhus incidence among adolescents and adults in Yangon, Myanmar. Trop Med Int Health. 2025;30(9):978–86. pmid:40693720
- 31. Elders PND, Swe MMM, Phyo AP, McLean ARD, Lin HN, Soe K, et al. Serological evidence indicates widespread distribution of rickettsioses in Myanmar. Int J Infect Dis. 2021;103:494–501. pmid:33310022
- 32. Salgado Lynn M, William T, Tanganuchitcharnchai A, Jintaworn S, Thaipadungpanit J, Lee MH, et al. Spotted fever rickettsiosis in a wildlife researcher in Sabah, Malaysia: a case study. Trop Med Infect Dis. 2018;3(1):29. pmid:30274426
- 33. Yuhana Y, Tanganuchitcharnchai A, Sujariyakul P, Sonthayanon P, Chotivanich K, Paris DH, et al. Diagnosis of murine typhus by serology in peninsular Malaysia: a case report where rickettsial illnesses, leptospirosis and dengue co-circulate. Trop Med Infect Dis. 2019;4(1). pmid:30708964
- 34. Yuhana MY, Hanboonkunupakarn B, Tanganuchitcharnchai A, Sujariyakul P, Sonthayanon P, Chotivanich K, et al. Rickettsial infections are neglected causes of acute febrile illness in Teluk Intan, Peninsular Malaysia. Trop Med Infect Dis. 2022;7(5):77. pmid:35622704
- 35. Saraswati K, Elliott I, Day NPJ, Baird JK, Blacksell SD, Ristiyanto, et al. Geographical distribution of scrub typhus and risk of Orientia tsutsugamushi infection in Indonesia: evidence mapping. PLoS Negl Trop Dis. 2023;17(9):e0011412. pmid:37747922
- 36. Saraswati K, Baird JK, Blacksell SD, Grijsen ML, Day NPJ. History of scrub typhus in Indonesia. Trans R Soc Trop Med Hyg. 2025;119(4):338–45. pmid:40036232
- 37. Aiemjoy K, Katuwal N, Vaidya K, Shrestha S, Thapa M, Teunis P, et al. Estimating the seroincidence of scrub typhus using antibody dynamics after infection. Am J Trop Med Hyg. 2024;111(2):267–76. pmid:38861980
- 38. Saraswati K, Tanganuchitcharnchai A, Ongchaikupt S, Mukaka M, Day NPJ, Baird JK, et al. Scrub typhus in Indonesia: a cross-sectional analysis of archived fever studies samples. Trans R Soc Trop Med Hyg. 2024;118(5):321–7. pmid:38205975
- 39. Trung NV, Hoi LT, Hoa TM, Huong DT, Huyen MT, Tien VQ, et al. Systematic surveillance of rickettsial diseases in 27 hospitals from 26 provinces throughout Vietnam. Trop Med Infect Dis. 2022;7(6). pmid:35736967
- 40. Pryor WH Jr, Irving GS, Kundin WD, Taylor GD, Ziegler RF, Dixon DF Jr, et al. A serologic survey of military personnel and dogs in Thailand and South Vietnam for antibodies to Arboviruses, Rickettsia tsutsugamushi, and Pseudomonas pseudomallei. Am J Vet Res. 1972;33(10):2091–5. pmid:4627553
- 41. Tran HTD, Hattendorf J, Do HM, Hoang TT, Hoang HTH, Lam HN, et al. Ecological and behavioural risk factors of scrub typhus in central Vietnam: a case-control study. Infect Dis Poverty. 2021;10(1):110. pmid:34412700
- 42. Trung NV, Hoi LT, Dien VM, Huong DT, Hoa TM, Lien VN, et al. Clinical manifestations and molecular diagnosis of scrub typhus and murine typhus, Vietnam, 2015-2017. Emerg Infect Dis. 2019;25(4):633–41. pmid:30882318
- 43. Trung NV, Hoi LT, Thuong NTH, Toan TK, Huong TTK, Hoa TM, et al. Seroprevalence of scrub typhus, typhus, and spotted fever among rural and urban populations of northern Vietnam. Am J Trop Med Hyg. 2017;96(5):1084–7. pmid:28500808
- 44. Hamaguchi S, Cuong NC, Tra DT, Doan YH, Shimizu K, Tuan NQ, et al. Clinical and epidemiological characteristics of scrub typhus and murine typhus among hospitalized patients with acute undifferentiated fever in northern Vietnam. Am J Trop Med Hyg. 2015;92(5):972–8. pmid:25778504
- 45. Nadjm B, Thuy PT, Trang VD, Ha LD, Kinh NV, Wertheim HF. Scrub typhus in the northern provinces of Vietnam: an observational study of admissions to a national referral hospital. Trans R Soc Trop Med Hyg. 2014;108(11):739–40. pmid:25253616
- 46. Azuma M, Nishioka Y, Ogawa M, Takasaki T, Sone S, Uchiyama T. Murine typhus from Vietnam, imported into Japan. Emerg Infect Dis. 2006;12(9):1466–8. pmid:17073110
- 47. Le-Viet N, Le V-N, Chung H, Phan D-T, Phan Q-D, Cao T-V, et al. Prospective case-control analysis of the aetiologies of acute undifferentiated fever in Vietnam. Emerg Microbes Infect. 2019;8(1):339–52. pmid:30866787
- 48. Acestor N, Cooksey R, Newton PN, Ménard D, Guerin PJ, Nakagawa J, et al. Mapping the aetiology of non-malarial febrile illness in Southeast Asia through a systematic review--terra incognita impairing treatment policies. PLoS One. 2012;7(9):e44269. pmid:22970193
- 49. Elliott I, Pearson I, Dahal P, Thomas NV, Roberts T, Newton PN. Scrub typhus ecology: a systematic review of Orientia in vectors and hosts. Parasit Vectors. 2019;12(1):513. pmid:31685019
- 50. Tay ST, Ho TM, Rohani MY, Devi S. Antibodies to Orientia tsutsugamushi, Rickettsia typhi and spotted fever group rickettsiae among febrile patients in rural areas of Malaysia. Trans R Soc Trop Med Hyg. 2000;94(3):280–4. pmid:10974999
- 51. Tay ST, Mohamed Zan HA, Lim YAL, Ngui R. Antibody prevalence and factors associated with exposure to Orientia tsutsugamushi in different aboriginal subgroups in West Malaysia. PLoS Negl Trop Dis. 2013;7(8):e2341. pmid:23936576
- 52. Blacksell SD, Bryant NJ, Paris DH, Doust JA, Sakoda Y, Day NPJ. Scrub typhus serologic testing with the indirect immunofluorescence method as a diagnostic gold standard: a lack of consensus leads to a lot of confusion. Clin Infect Dis. 2007;44(3):391–401. pmid:17205447
- 53. Le KK, Saraswati K, Wongsantichon J, Day NPJ, Blacksell SD. Diagnostic heterogeneity in scrub typhus serology: a scoping review of IFA thresholds and regional standardisation needs (2005-2024). PLoS Negl Trop Dis. 2025;19(10):e0013540. pmid:41124227
- 54. Charoensak A, Chawalparit O, Suttinont C, Niwattayakul K, Losuwanaluk K, Silpasakorn S, et al. Scrub typhus: chest radiographic and clinical findings in 130 Thai patients. J Med Assoc Thai. 2006;89(5):600–7. pmid:16756043
- 55. Sriwongpan P, Krittigamas P, Tantipong H, Patumanond J, Tawichasri C, Namwongprom S. Clinical risk-scoring algorithm to forecast scrub typhus severity. Risk Manag Healthc Policy. 2013;7:11–7. pmid:24379733
- 56. Thipmontree W, Tantibhedhyangkul W, Silpasakorn S, Wongsawat E, Waywa D, Suputtamongkol Y. Scrub typhus in northeastern Thailand: eschar distribution, abnormal electrocardiographic findings, and predictors of fatal outcome. Am J Trop Med Hyg. 2016;95(4):769–73. pmid:27573633
- 57. Greer RC, Intralawan D, Mukaka M, Wannapinij P, Day NPJ, Nedsuwan S, et al. Retrospective review of the management of acute infections and the indications for antibiotic prescription in primary care in northern Thailand. BMJ Open. 2018;8(7):e022250. pmid:30061442
- 58. Gonwong S, Mason CJ, Chuenchitra T, Khanijou P, Islam D, Ruamsap N, et al. Nationwide seroprevalence of scrub typhus, typhus, and spotted fever in young Thai men. Am J Trop Med Hyg. 2022;106(5):1363–9. pmid:35378507
- 59. Linsuwanon P, Krairojananan P, Rodkvamtook W, Leepitakrat S, Davidson S, Wanja E. Surveillance for scrub typhus, rickettsial diseases, and leptospirosis in us and multinational military training exercise cobra gold sites in Thailand. US Army Med Dep J. 2018;(1–18):29–39. pmid:30165719
- 60. Olsen SJ, Campbell AP, Supawat K, Liamsuwan S, Chotpitayasunondh T, Laptikulthum S, et al. Infectious causes of encephalitis and meningoencephalitis in Thailand, 2003-2005. Emerg Infect Dis. 2015;21(2):280–9. pmid:25627940
- 61. Wangrangsimakul T, Elliott I, Nedsuwan S, Kumlert R, Hinjoy S, Chaisiri K, et al. The estimated burden of scrub typhus in Thailand from national surveillance data (2003-2018). PLoS Negl Trop Dis. 2020;14(4):e0008233. pmid:32287307
- 62. Satjanadumrong J, Robinson MT, Hughes T, Blacksell SD. Distribution and ecological drivers of spotted fever group rickettsia in Asia. Ecohealth. 2019;16(4):611–26. pmid:30993545
- 63. Lokida D, Hadi U, Lau C-Y, Kosasih H, Liang CJ, Rusli M, et al. Underdiagnoses of Rickettsia in patients hospitalized with acute fever in Indonesia: observational study results. BMC Infect Dis. 2020;20(1):364. pmid:32448167
- 64. Vallée J, Thaojaikong T, Moore CE, Phetsouvanh R, Richards AL, Souris M, et al. Contrasting spatial distribution and risk factors for past infection with scrub typhus and murine typhus in Vientiane City, Lao PDR. PLoS Negl Trop Dis. 2010;4(12):e909. pmid:21151880
- 65. Rodkvamtook W, Gaywee J, Kanjanavanit S, Ruangareerate T, Richards AL, Sangjun N. Scrub typhus outbreak, northern Thailand, 2006-2007. Emerg Infect Dis. 2013;19(5):774–7. pmid:23647883
- 66. Rodkvamtook W, Kuttasingkee N, Linsuwanon P, Sudsawat Y, Richards AL, Somsri M, et al. Scrub typhus outbreak in Chonburi Province, Central Thailand, 2013. Emerg Infect Dis. 2018;24(2):361–5. pmid:29350148
- 67. Mongkol N, Suputtamongkol Y, Taweethavonsawat P, Foongladda S. Molecular evidence of rickettsia in human and dog blood in Bangkok. Vector Borne Zoonotic Dis. 2018;18(6):297–302. pmid:29683400
- 68. Ngamprasertchai T, Hanboonkunupakarn B, Piyaphanee W. Rickettsiosis in southeast Asia: summary for international travellers during the COVID-19 pandemic. Trop Med Infect Dis. 2022;7(2):18. pmid:35202213
- 69. Sriwongpan P, Krittigamas P, Kantipong P, Kunyanone N, Patumanond J, Namwongprom S. Clinical indicators for severe prognosis of scrub typhus. Risk Manag Healthc Policy. 2013;6:43–9. pmid:24235852
- 70. Alam M, Deb AS, Afrin A, Rahman A, Islam KM, Jahan MI. Orientia tsutsugamushi a likely contributor to stillbirths and neonatal deaths in Bangladesh, 2017-2024. Am J Trop Med Hyg. 2026. pmid:41701983
- 71. Zhao P, Dong T, Lu H, Zhu R, Zhao S, Tao W, et al. Scrub typhus in pregnancy: a 10-year multicenter study in resource-limited settings in China. PLoS Negl Trop Dis. 2025;19(1):e0012829. pmid:39836661
- 72. McGready R, Prakash JAJ, Benjamin SJ, Watthanaworawit W, Anantatat T, Tanganuchitcharnchai A, et al. Pregnancy outcome in relation to treatment of murine typhus and scrub typhus infection: a fever cohort and a case series analysis. PLoS Negl Trop Dis. 2014;8(11):e3327. pmid:25412503
- 73. Blache N, Chalvet-Monfray K, Kumlert R, Hinjoy S, Morand S. Scrub typhus in Nan province (Thailand): seventeen years of data to understand the impact of land cover change. PLoS Negl Trop Dis. 2025;19(9):e0013552. pmid:40966247
- 74. Robinson MT, Satjanadumrong J, Hughes T, Stenos J, Blacksell SD. Diagnosis of spotted fever group Rickettsia infections: the Asian perspective. Epidemiol Infect. 2019;147:e286. pmid:31587667
- 75. Ahantarig A, Malaisri P, Hirunkanokpun S, Sumrandee C, Trinachartvanit W, Baimai V. Detection of Rickettsia and a novel Haemaphysalis shimoga symbiont bacterium in ticks in Thailand. Curr Microbiol. 2011;62(5):1496–502. pmid:21318277
- 76. Phommasone K, Paris DH, Anantatat T, Castonguay-Vanier J, Keomany S, Souvannasing P, et al. Concurrent infection with murine typhus and scrub typhus in southern Laos--the mixed and the unmixed. PLoS Negl Trop Dis. 2013;7(8):e2163. pmid:24009783
- 77. Phetsouvanh R, Blacksell SD, Jenjaroen K, Day NPJ, Newton PN. Comparison of indirect immunofluorescence assays for diagnosis of scrub typhus and murine typhus using venous blood and finger prick filter paper blood spots. Am J Trop Med Hyg. 2009;80(5):837–40. pmid:19407134
- 78. Phetsouvanh R, Thojaikong T, Phoumin P, Sibounheuang B, Phommasone K, Chansamouth V, et al. Inter- and intra-operator variability in the reading of indirect immunofluorescence assays for the serological diagnosis of scrub typhus and murine typhus. Am J Trop Med Hyg. 2013;88(5):932–6. pmid:23478577
- 79. Looareesuwan P, Aiemjoy K, Charoensakulchai S, Thaipadungpanit J, Wongsantichon J, Tanganuchitcharnchai A, et al. Diagnostic challenges and antibody kinetics in a paediatric traveller with scrub typhus. J Travel Med. 2023;30(8):taad143. pmid:37952213
- 80. Chankate P, Kalambaheti T, Kosoltanapiwat N, Tanganuchitcharnchai A, Blacksell SD, Chantratita N, et al. A use of 56-kDa recombinant protein of Orientia tsutsugamushi karp serotype in serodiagnosis of scrub typhus by enzyme-linked immunosorbent assay in Thais. Trop Med Infect Dis. 2022;8(1):10. pmid:36668917
- 81. Chao C-C, Zhang Z, Belinskaya T, Thipmontree W, Tantibhedyangkul W, Silpasakorn S, et al. An ELISA assay using a combination of recombinant proteins from multiple strains of Orientia tsutsugamushi offers an accurate diagnosis for scrub typhus. BMC Infect Dis. 2017;17(1):413. pmid:28601091
- 82. Silpasakorn S, Waywa D, Hoontrakul S, Suttinont C, Losuwanaluk K, Suputtamongkol Y. Performance of SD Bioline Tsutsugamushi assays for the diagnosis of scrub typhus in Thailand. J Med Assoc Thai. 2012;95 Suppl 2:S18-22. pmid:22574525
- 83. Silpasakorn S, Srisamut N, Ekpo P, Zhang Z, Chao C-C, Ching W-M, et al. Development of new, broadly reactive, rapid IgG and IgM lateral flow assays for diagnosis of scrub typhus. Am J Trop Med Hyg. 2012;87(1):148–52. pmid:22764306
- 84. Saraswati K, Day NPJ, Mukaka M, Blacksell SD. Scrub typhus point-of-care testing: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2018;12(3):e0006330. pmid:29579046
- 85. Blacksell SD, Jenjaroen K, Phetsouvanh R, Tanganuchitcharnchai A, Phouminh P, Phongmany S, et al. Accuracy of rapid IgM-based immunochromatographic and immunoblot assays for diagnosis of acute scrub typhus and murine typhus infections in Laos. Am J Trop Med Hyg. 2010;83(2):365–9. pmid:20682883
- 86. Blacksell SD, Jenjaroen K, Phetsouvanh R, Wuthiekanun V, Day NPJ, Newton PN, et al. Accuracy of AccessBio immunoglobulin M and total antibody rapid immunochromatographic assays for the diagnosis of acute scrub typhus infection. Clin Vaccine Immunol. 2010;17(2):263–6. pmid:20016046
- 87. Blacksell SD, Paris DH, Chierakul W, Wuthiekanun V, Teeratakul A, Kantipong P, et al. Prospective evaluation of commercial antibody-based rapid tests in combination with a loop-mediated isothermal amplification PCR assay for detection of Orientia tsutsugamushi during the acute phase of scrub typhus infection. Clin Vaccine Immunol. 2012;19(3):391–5. pmid:22219313
- 88. Rodkvamtook W, Zhang Z, Chao C-C, Huber E, Bodhidatta D, Gaywee J, et al. Dot-ELISA rapid test using recombinant 56-kDa protein antigens for serodiagnosis of scrub typhus. Am J Trop Med Hyg. 2015;92(5):967–71. pmid:25802430
- 89. Kingston HWF, Blacksell SD, Tanganuchitcharnchai A, Laongnualpanich A, Basnyat B, Day NPJ, et al. Comparative accuracy of the InBios scrub typhus detect IgM rapid test for the detection of IgM antibodies by using conventional serology. Clin Vaccine Immunol. 2015;22(10):1130–2. pmid:26291089
- 90. Blacksell SD, Tanganuchitcharnchai A, Nawtaisong P, Kantipong P, Laongnualpanich A, Day NPJ, et al. Diagnostic accuracy of the InBios scrub typhus detect enzyme-linked immunoassay for the detection of IgM antibodies in Northern Thailand. Clin Vaccine Immunol. 2015;23(2):148–54. pmid:26656118
- 91. Blacksell SD, Kingston HWF, Tanganuchitcharnchai A, Phanichkrivalkosil M, Hossain M, Hossain A, et al. Diagnostic accuracy of the InBios scrub typhus Detect™ ELISA for the detection of IgM antibodies in Chittagong, Bangladesh. Trop Med Infect Dis. 2018;3(3):95. pmid:30274491
- 92. Elders PND, Dhawan S, Tanganuchitcharnchai A, Phommasone K, Chansamouth V, Day NPJ, et al. Diagnostic accuracy of an in-house Scrub Typhus enzyme linked immunoassay for the detection of IgM and IgG antibodies in Laos. PLoS Negl Trop Dis. 2020;14(12):e0008858. pmid:33284807
- 93. Blacksell SD, Lim C, Tanganuchitcharnchai A, Jintaworn S, Kantipong P, Richards AL, et al. Optimal cutoff and accuracy of an IgM enzyme-linked immunosorbent assay for diagnosis of acute scrub typhus in Northern Thailand: an alternative reference method to the IgM immunofluorescence assay. J Clin Microbiol. 2016;54(6):1472–8. pmid:27008880
- 94. Phanichkrivalkosil M, Tanganuchitcharnchai A, Jintaworn S, Kantipong P, Laongnualpanich A, Chierakul W, et al. Determination of optimal diagnostic cut-offs for the naval medical research center scrub typhus IgM ELISA in Chiang Rai, Thailand. Am J Trop Med Hyg. 2019;100(5):1134–40. pmid:30860022
- 95. Saraswati K, Phanichkrivalkosil M, Day NPJ, Blacksell SD. The validity of diagnostic cut-offs for commercial and in-house scrub typhus IgM and IgG ELISAs: a review of the evidence. PLoS Negl Trop Dis. 2019;13(2):e0007158. pmid:30716070
- 96. Lim C, Blacksell SD, Laongnualpanich A, Kantipong P, Day NPJ, Paris DH, et al. Optimal Cutoff Titers for Indirect Immunofluorescence Assay for Diagnosis of Scrub Typhus. J Clin Microbiol. 2015;53(11):3663–6. pmid:26354819
- 97. Lim C, Paris DH, Blacksell SD, Laongnualpanich A, Kantipong P, Chierakul W, et al. How to determine the accuracy of an alternative diagnostic test when it is actually better than the reference tests: a re-evaluation of diagnostic tests for scrub typhus using bayesian LCMs. PLoS One. 2015;10(5):e0114930. pmid:26024375
- 98. Phakhounthong K, Mukaka M, Dittrich S, Tanganuchitcharnchai A, Day NPJ, White LJ, et al. The temporal dynamics of humoral immunity to Rickettsia typhi infection in murine typhus patients. Clin Microbiol Infect. 2020;26(6):781.e9-781.e16. pmid:31678231
- 99. Dhawan S, Robinson MT, Stenos J, Graves SR, Wangrangsimakul T, Newton PN, et al. Selection of diagnostic cutoffs for murine typhus IgM and IgG immunofluorescence assay: a systematic review. Am J Trop Med Hyg. 2020;103(1):55–63. pmid:32274984
- 100. Sonthayanon P, Chierakul W, Wuthiekanun V, Blacksell SD, Pimda K, Suputtamongkol Y, et al. Rapid diagnosis of scrub typhus in rural Thailand using polymerase chain reaction. Am J Trop Med Hyg. 2006;75(6):1099–102. pmid:17172374
- 101. Paris DH, Aukkanit N, Jenjaroen K, Blacksell SD, Day NPJ. A highly sensitive quantitative real-time PCR assay based on the groEL gene of contemporary Thai strains of Orientia tsutsugamushi. Clin Microbiol Infect. 2009;15(5):488–95. pmid:19416296
- 102. Paris DH, Blacksell SD, Stenos J, Graves SR, Unsworth NB, Phetsouvanh R, et al. Real-time multiplex PCR assay for detection and differentiation of rickettsiae and orientiae. Trans R Soc Trop Med Hyg. 2008;102(2):186–93. pmid:18093627
- 103. Tantibhedhyangkul W, Wongsawat E, Silpasakorn S, Waywa D, Saenyasiri N, Suesuay J, et al. Use of multiplex real-time PCR to diagnose scrub typhus. J Clin Microbiol. 2017;55(5):1377–87. pmid:28202789
- 104. Jiang J, Chan T-C, Temenak JJ, Dasch GA, Ching W-M, Richards AL. Development of a quantitative real-time polymerase chain reaction assay specific for Orientia tsutsugamushi. Am J Trop Med Hyg. 2004;70(4):351–6. pmid:15100446
- 105. Yun NR, Kim C-M, Kim DY, Seo J-W, Kim D-M. Clinical usefulness of 16S ribosomal RNA real-time PCR for the diagnosis of scrub typhus. Sci Rep. 2021;11(1):14299. pmid:34253778
- 106. Kim D-M, Kim HL, Park CY, Yang TY, Lee JH, Yang JT, et al. Clinical usefulness of eschar polymerase chain reaction for the diagnosis of scrub typhus: a prospective study. Clin Infect Dis. 2006;43(10):1296–300. pmid:17051495
- 107. Rungrojn A, Batty EM, Perrone C, Abdad MY, Wangrangsimakul T, Brummaier T, et al. Molecular diagnosis and genotyping of Orientia tsutsugamushi in Maesot and Chiangrai, Thailand. Front Trop Dis. 2023;4:fitd.2023.1146138. pmid:39376595
- 108. Paris DH, Blacksell SD, Nawtaisong P, Jenjaroen K, Teeraratkul A, Chierakul W, et al. Diagnostic accuracy of a loop-mediated isothermal PCR assay for detection of Orientia tsutsugamushi during acute Scrub Typhus infection. PLoS Negl Trop Dis. 2011;5(9):e1307. pmid:21931873
- 109. Watthanaworawit W, Turner P, Turner C, Tanganuchitcharnchai A, Richards AL, Bourzac KM, et al. A prospective evaluation of real-time PCR assays for the detection of Orientia tsutsugamushi and Rickettsia spp. for early diagnosis of rickettsial infections during the acute phase of undifferentiated febrile illness. Am J Trop Med Hyg. 2013;89(2):308–10. pmid:23732256
- 110. Sonthayanon P, Chierakul W, Wuthiekanun V, Thaipadungpanit J, Kalambaheti T, Boonsilp S, et al. Accuracy of loop-mediated isothermal amplification for diagnosis of human leptospirosis in Thailand. Am J Trop Med Hyg. 2011;84(4):614–20. pmid:21460019
- 111. Keller CA, Hauptmann M, Kolbaum J, Gharaibeh M, Neumann M, Glatzel M, et al. Dissemination of Orientia tsutsugamushi and inflammatory responses in a murine model of scrub typhus. PLoS Negl Trop Dis. 2014;8(8):e3064. pmid:25122501
- 112. Chao C-C, Belinskaya T, Zhang Z, Jiang L, Ching W-M. Assessment of a sensitive qPCR assay targeting a multiple-copy gene to detect Orientia tsutsugamushi DNA. Trop Med Infect Dis. 2019;4(3):113. pmid:31370347
- 113. Park BJ, Heo ST, Kim M, Yoo JR, Bae EJ, Kang SY, et al. A CRISPR-Cas12a-based universal rapid scrub typhus diagnostic method targeting 16S rRNA of Orientia tsutsugamushi. PLoS Negl Trop Dis. 2025;19(1):e0012826. pmid:39841710
- 114. Chao C-C, Belinskaya T, Zhang Z, Ching W-M. Development of recombinase polymerase amplification assays for detection of Orientia tsutsugamushi or Rickettsia typhi. PLoS Negl Trop Dis. 2015;9(7):e0003884. pmid:26161793
- 115. Bhardwaj P, Nanaware NS, Behera SP, Kulkarni S, Deval H, Kumar R, et al. CRISPR/Cas12a-based detection platform for early and rapid diagnosis of scrub typhus. Biosensors (Basel). 2023;13(12):1021. pmid:38131781
- 116. Tantibhedhyangkul W, Angelakis E, Tongyoo N, Newton PN, Moore CE, Phetsouvanh R, et al. Intrinsic fluoroquinolone resistance in Orientia tsutsugamushi. Int J Antimicrob Agents. 2010;35(4):338–41. pmid:20138477
- 117. Luksameetanasan R, Blacksell SD, Kalambaheti T, Wuthiekanun V, Chierakul W, Chueasuwanchai S, et al. Patient and sample-related factors that effect the success of in vitro isolation of Orientia tsutsugamushi. Southeast Asian J Trop Med Public Health. 2007;38(1):91–6. pmid:17539252
- 118. McGready R, Wuthiekanun V, Ashley EA, Tan SO, Pimanpanarak M, Viladpai-Nguen SJ, et al. Diagnostic and treatment difficulties of pyelonephritis in pregnancy in resource-limited settings. Am J Trop Med Hyg. 2010;83(6):1322–9. pmid:21118943
- 119. Ming DK, Phommadeechack V, Panyanivong P, Sengdatka D, Phuklia W, Chansamouth V, et al. The isolation of Orientia tsutsugamushi and Rickettsia typhi from human blood through mammalian cell culture: a descriptive series of 3,227 samples and outcomes in the Lao People’s Democratic Republic. J Clin Microbiol. 2020;58(12):e01553-20. pmid:32999008
- 120. Giengkam S, Blakes A, Utsahajit P, Chaemchuen S, Atwal S, Blacksell SD, et al. Improved quantification, propagation, purification and storage of the obligate intracellular human pathogen Orientia tsutsugamushi. PLoS Negl Trop Dis. 2015;9(8):e0004009. pmid:26317517
- 121. Rodkvamtook W, Ruang-Areerate T, Gaywee J, Richards AL, Jeamwattanalert P, Bodhidatta D, et al. Isolation and characterization of Orientia tsutsugamushi from rodents captured following a scrub typhus outbreak at a military training base, Bothong district, Chonburi province, central Thailand. Am J Trop Med Hyg. 2011;84(4):599–607. pmid:21460017
- 122. Blacksell SD, Luksameetanasan R, Kalambaheti T, Aukkanit N, Paris DH, McGready R, et al. Genetic typing of the 56-kDa type-specific antigen gene of contemporary Orientia tsutsugamushi isolates causing human scrub typhus at two sites in north-eastern and western Thailand. FEMS Immunol Med Microbiol. 2008;52(3):335–42. pmid:18312580
- 123. Parola P, Blacksell SD, Phetsouvanh R, Phongmany S, Rolain J-M, Day NPJ, et al. Genotyping of Orientia tsutsugamushi from humans with scrub typhus, Laos. Emerg Infect Dis. 2008;14(9):1483–5. pmid:18760027
- 124. Nguyen HLK, Pham HTT, Nguyen TV, Hoang PV, Le MTQ, Takemura T, et al. The genotypes of Orientia tsutsugamushi, identified in scrub typhus patients in northern Vietnam. Trans R Soc Trop Med Hyg. 2017;111(3):137–9. pmid:28531311
- 125. Jiang J, Paris DH, Blacksell SD, Aukkanit N, Newton PN, Phetsouvanh R, et al. Diversity of the 47-kD HtrA nucleic acid and translated amino acid sequences from 17 recent human isolates of Orientia. Vector Borne Zoonotic Dis. 2013;13(6):367–75. pmid:23590326
- 126. Takhampunya R, Korkusol A, Promsathaporn S, Tippayachai B, Leepitakrat S, Richards AL, et al. Heterogeneity of Orientia tsutsugamushi genotypes in field-collected trombiculid mites from wild-caught small mammals in Thailand. PLoS Negl Trop Dis. 2018;12(7):e0006632. pmid:30011267
- 127. Sonthayanon P, Peacock SJ, Chierakul W, Wuthiekanun V, Blacksell SD, Holden MTG, et al. High rates of homologous recombination in the mite endosymbiont and opportunistic human pathogen Orientia tsutsugamushi. PLoS Negl Trop Dis. 2010;4(7):e752. pmid:20651929
- 128. Ruang-Areerate T, Jeamwattanalert P, Rodkvamtook W, Richards AL, Sunyakumthorn P, Gaywee J. Genotype diversity and distribution of Orientia tsutsugamushi causing scrub typhus in Thailand. J Clin Microbiol. 2011;49(7):2584–9. pmid:21593255
- 129. Mendell NL, Xu G, Shelite TR, Bouyer DH, Walker DH. A murine model of waning scrub typhus cross-protection between heterologous strains of Orientia tsutsugamushi. Pathogens. 2022;11(5):512. pmid:35631033
- 130. Walker DH. Scrub typhus – scientific neglect, ever-widening impact. N Engl J Med. 2016;375(10):913–5. pmid:27602663
- 131. Walker DH, Mendell NL. A scrub typhus vaccine presents a challenging unmet need. NPJ Vaccines. 2023;8(1):11. pmid:36759505
- 132. Wongprompitak P, Duong V, Anukool W, Sreyrath L, Mai TTX, Gavotte L, et al. Orientia tsutsugamushi, agent of scrub typhus, displays a single metapopulation with maintenance of ancestral haplotypes throughout continental South East Asia. Infect Genet Evol. 2015;31:1–8. pmid:25577986
- 133. Phetsouvanh R, Sonthayanon P, Pukrittayakamee S, Paris DH, Newton PN, Feil EJ, et al. The diversity and geographical structure of orientia tsutsugamushi strains from scrub typhus patients in Laos. PLoS Negl Trop Dis. 2015;9(8):e0004024. pmid:26317624
- 134. Batty EM, Chaemchuen S, Blacksell S, Richards AL, Paris D, Bowden R, et al. Long-read whole genome sequencing and comparative analysis of six strains of the human pathogen Orientia tsutsugamushi. PLoS Negl Trop Dis. 2018;12(6):e0006566. pmid:29874223
- 135. Paskey AC, Schully KL, Voegtly LJ, Arnold CE, Cer RZ, Frey KG, et al. A proof of concept for a targeted enrichment approach to the simultaneous detection and characterization of rickettsial pathogens from clinical specimens. Front Microbiol. 2024;15:1387208. pmid:38659991
- 136. Keeratipusana C, Phuklia W, Phommadeechack V, Thaipadungpanit J, Chansamouth V, Phommasone K, et al. Complete genomes of Rickettsia typhi reveal a clonal population. PLoS Negl Trop Dis. 2025;19(12):e0013828. pmid:41460881
- 137. Elliott I, Batty EM, Ming D, Robinson MT, Nawtaisong P, de Cesare M, et al. Oxford nanopore MinION sequencing enables rapid whole genome assembly of Rickettsia typhi in a resource-limited setting. Am J Trop Med Hyg. 2020;102(2):408–14. pmid:31820709
- 138. James SL, Blacksell SD, Nawtaisong P, Tanganuchitcharnchai A, Smith DJ, Day NPJ, et al. Antigenic relationships among human pathogenic Orientia tsutsugamushi isolates from Thailand. PLoS Negl Trop Dis. 2016;10(6):e0004723. pmid:27248711
- 139. Paris DH, Jenjaroen K, Blacksell SD, Phetsouvanh R, Wuthiekanun V, Newton PN, et al. Differential patterns of endothelial and leucocyte activation in “typhus-like” illnesses in Laos and Thailand. Clin Exp Immunol. 2008;153(1):63–7. pmid:18505434
- 140. Paris DH, Chansamouth V, Nawtaisong P, Löwenberg EC, Phetsouvanh R, Blacksell SD, et al. Coagulation and inflammation in scrub typhus and murine typhus--a prospective comparative study from Laos. Clin Microbiol Infect. 2012;18(12):1221–8. pmid:22192733
- 141. Sunyakumthorn P, Paris DH, Chan T-C, Jones M, Luce-Fedrow A, Chattopadhyay S, et al. An intradermal inoculation model of scrub typhus in Swiss CD-1 mice demonstrates more rapid dissemination of virulent strains of Orientia tsutsugamushi. PLoS One. 2013;8(1):e54570. pmid:23342173
- 142. Sumonwiriya M, Paris DH, Sunyakumthorn P, Anantatat T, Jenjaroen K, Chumseng S, et al. Strong interferon-gamma mediated cellular immunity to scrub typhus demonstrated using a novel whole cell antigen ELISpot assay in rhesus macaques and humans. PLoS Negl Trop Dis. 2017;11(9):e0005846. pmid:28892515
- 143. Sunyakumthorn P, Somponpun SJ, Im-Erbsin R, Anantatat T, Jenjaroen K, Dunachie SJ, et al. Characterization of the rhesus macaque (Macaca mulatta) scrub typhus model: susceptibility to intradermal challenge with the human pathogen Orientia tsutsugamushi Karp. PLoS Negl Trop Dis. 2018;12(3):e0006305. pmid:29522521
- 144. Paris DH, Chattopadhyay S, Jiang J, Nawtaisong P, Lee JS, Tan E, et al. A nonhuman primate scrub typhus model: protective immune responses induced by pKarp47 DNA vaccination in cynomolgus macaques. J Immunol. 2015;194(4):1702–16. pmid:25601925
- 145. Inthawong M, Sunyakumthorn P, Wongwairot S, Anantatat T, Dunachie SJ, Im-Erbsin R, et al. A time-course comparative clinical and immune response evaluation study between the human pathogenic Orientia tsutsugamushi strains: Karp and Gilliam in a rhesus macaque (Macaca mulatta) model. PLoS Negl Trop Dis. 2022;16(8):e0010611. pmid:35925895
- 146. Paris DH, Phetsouvanh R, Tanganuchitcharnchai A, Jones M, Jenjaroen K, Vongsouvath M, et al. Orientia tsutsugamushi in human scrub typhus eschars shows tropism for dendritic cells and monocytes rather than endothelium. PLoS Negl Trop Dis. 2012;6(1):e1466. pmid:22253938
- 147. Frances SP, Watcharapichat P, Phulsuksombati D, Tanskul P. Transmission of Orientia tsutsugamushi, the aetiological agent for scrub typhus, to co-feeding mites. Parasitology. 2000;120(Pt 6):601–7. pmid:10874723
- 148. Kumlert R, Chaisiri K, Anantatat T, Stekolnikov AA, Morand S, Prasartvit A, et al. Autofluorescence microscopy for paired-matched morphological and molecular identification of individual chigger mites (Acari: Trombiculidae), the vectors of scrub typhus. PLoS One. 2018;13(3):e0193163. pmid:29494599
- 149. Chaisiri K, Cosson J-F, Morand S. Infection of rodents by Orientia tsutsugamushi, the agent of scrub typhus in relation to land use in Thailand. Trop Med Infect Dis. 2017;2(4):53. pmid:30270910
- 150. Elliott I, Thangnimitchok N, Chaisiri K, Wangrangsimakul T, Jaiboon P, Day NPJ, et al. Orientia tsutsugamushi dynamics in vectors and hosts: ecology and risk factors for foci of scrub typhus transmission in northern Thailand. Parasit Vectors. 2021;14(1):540. pmid:34663445
- 151. Linsuwanon P, Auysawasdi N, Wongwairot S, Leepitakrat S, Rodkhamtook W, Wanja E, et al. Assessing scrub typhus and rickettsioses transmission risks in the Chiang Rai province of northern Thailand. Travel Med Infect Dis. 2021;42:102086. pmid:34044127
- 152. Phimda K, Hoontrakul S, Suttinont C, Chareonwat S, Losuwanaluk K, Chueasuwanchai S, et al. Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus. Antimicrob Agents Chemother. 2007;51(9):3259–63. pmid:17638700
- 153. Newton PN, Keolouangkhot V, Lee SJ, Choumlivong K, Sisouphone S, Choumlivong K, et al. A prospective, open-label, randomized trial of doxycycline versus azithromycin for the treatment of uncomplicated murine typhus. Clin Infect Dis. 2019;68(5):738–47. pmid:30020447
- 154. Varghese GM, Dayanand D, Gunasekaran K, Kundu D, Wyawahare M, Sharma N, et al. Intravenous doxycycline, azithromycin, or both for severe scrub typhus. N Engl J Med. 2023;388(9):792–803. pmid:36856615
- 155. Watt G, Chouriyagune C, Ruangweerayud R, Watcharapichat P, Phulsuksombati D, Jongsakul K, et al. Scrub typhus infections poorly responsive to antibiotics in northern Thailand. Lancet. 1996;348(9020):86–9. pmid:8676722
- 156. Watt G, Kantipong P, Jongsakul K, Watcharapichat P, Phulsuksombati D, Strickman D. Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. Lancet. 2000;356(9235):1057–61. pmid:11009140
- 157. Phuklia W, Panyanivong P, Sengdetka D, Sonthayanon P, Newton PN, Paris DH, et al. Novel high-throughput screening method using quantitative PCR to determine the antimicrobial susceptibility of Orientia tsutsugamushi clinical isolates. J Antimicrob Chemother. 2019;74(1):74–81. pmid:30295746
- 158. Wangrangsimakul T, Phuklia W, Newton PN, Richards AL, Day NPJ. Scrub typhus and the misconception of doxycycline resistance. Clin Infect Dis. 2020;70(11):2444–9. pmid:31570937
- 159. Watthanaworawit W, Kolakowska E, Hanboonkunupakarn B, Ling C, McGready R. Scrub typhus infection in pregnancy: the dilemma of diagnosis and treatment in a resource-limited setting. Clin Case Rep. 2016;4(6):584–8. pmid:27398202
- 160. Cross R, Ling C, Day NPJ, McGready R, Paris DH. Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation?. Expert Opin Drug Saf. 2016;15(3):367–82. pmid:26680308
- 161. Perrone C, Kanthawang N, Cheah PY, Intralawan D, Lee SJ, Nedsuwan S, et al. Community engagement around scrub typhus in northern Thailand: a pilot project. Trans R Soc Trop Med Hyg. 2024;118(10):666–73. pmid:38708716
- 162. Musa TH, Ahmad T, Li W, Kawuki J, Wana MN, Musa HH. A bibliometric analysis of global scientific research on scrub typhus. Biomed Res Int. 2020;2020:5737893. pmid:33123578
- 163. Dixit R, Manikandan S, Gopalan N, Mohanty BS, Behera SK. Temporal trends in diagnostic evolutions for rickettsial diseases including scrub typhus: a bibliometric study. Pathog Glob Health. 2025;119(3–4):75–86. pmid:40089993
- 164. Herwanto V, Widiastuti SU, Gunawan, Lie KC. Beyond the fever: a serial report on moderate to severe murine typhus cases and diagnostic hurdles in Indonesia. Trop Med Infect Dis. 2025;10(8):204. pmid:40864107
- 165. Riswari SF, Prodjosoewojo S, Mony SR, Megantara I, Iskandar S, Mayasari W, et al. Murine typhus is a common cause of acute febrile illness in Bandung, Indonesia. PLoS One. 2023;18(7):e0283135. pmid:37418452
- 166. Paris DH, Blacksell SD, Newton PN, Day NPJ. Simple, rapid and sensitive detection of Orientia tsutsugamushi by loop-isothermal DNA amplification. Trans R Soc Trop Med Hyg. 2008;102(12):1239–46. pmid:18565558