Scrub typhus is an acute febrile illness caused by the obligate intracellular bacterium Orientia tsutsugamushi and transmitted to humans through the bite of infected larval trombiculid mites (chiggers) [1]. It is one of the most important rickettsial infections in the Asia–Pacific region and is increasingly recognized as a major cause of acute undifferentiated febrile illness (AUFI) in India [2,3]. The disease is endemic within the so-called “tsutsugamushi triangle,” which includes large parts of South and Southeast Asia, northern Australia, and the western Pacific islands; however, recent reports suggest geographic expansion and improved detection beyond traditionally recognized areas [4]. In India, scrub typhus has re-emerged over the past two decades as a significant public health problem, with cases reported from almost all states, including the Himalayan belt, southern peninsular India, central India, and the northeast [5,6]. Seasonal clustering is commonly observed, particularly during and after the monsoon months, reflecting the ecology of the vector and increased human exposure to mite-infested vegetation [7]. Despite this wide distribution, the disease remains underdiagnosed due to limited awareness, non-specific clinical presentation, and restricted access to reliable diagnostic tests in many endemic regions [8]. Clinically, scrub typhus is characterized by an acute onset of fever often accompanied by headache, myalgia, malaise, cough, and gastrointestinal symptoms [3,9]. A necrotic skin lesion at the site of the chigger bite, known as an eschar, is considered a classical and pathognomonic sign; however, its reported frequency varies widely across studies, and in Indian patients it is absent in a substantial proportion of cases [10,11]. Factors such as darker skin tones, atypical eschar locations, and inadequate skin examination contribute to under-recognition of this clinical sign [12]. As a result, reliance on the presence of eschar alone may delay diagnosis and treatment. Laboratory abnormalities commonly reported in scrub typhus include elevated hepatic transaminases, thrombocytopenia, and leukocyte count variations, which overlap with other tropical infections such as dengue, malaria, and leptospirosis [9,13]. If diagnosis and appropriate antibiotic therapy are delayed, scrub typhus can progress to severe disease with multi-organ involvement, including acute respiratory distress syndrome (ARDS), meningoencephalitis, acute kidney injury, myocarditis, and shock [14,15]. Mortality rates reported from Indian hospital-based studies vary widely, influenced by disease severity, comorbidities, and access to timely care [16]. Although numerous hospital-based studies and regional case series from India have described the clinical manifestations and outcomes of scrub typhus, the reported frequencies of symptoms, signs, and complications show considerable heterogeneity [5,9,11]. Differences in study design, patient populations (pediatric vs adult), diagnostic criteria, and healthcare settings further complicate interpretation of the available evidence. A comprehensive synthesis of published data is therefore necessary to better define the clinical spectrum of scrub typhus in Indian patients. The present systematic review and meta-analysis aims to collate and quantitatively summarize the available Indian literature on the clinical manifestations, laboratory abnormalities, complications, and outcomes of scrub typhus. By providing pooled estimates and highlighting sources of heterogeneity, this study seeks to support clinicians in early recognition of the disease and inform public health strategies for improved diagnosis and management in endemic regions.

Study design This study was conducted as a systematic review and meta-analysis of published literature reporting the clinical manifestations of scrub typhus among Indian patients. The methodology was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17]. Literature search strategy A comprehensive literature search was performed to identify relevant studies published from January 2000 to January 2025. The following electronic databases were searched: PubMed/MEDLINE, PubMed Central (PMC), Google Scholar, IndMED, and major Indian medical journals. In addition, reference lists of included studies and relevant review articles were manually screened to identify additional eligible publications. The search strategy used combinations of Medical Subject Headings (MeSH) terms and free-text keywords, including: “scrub typhus,” “Orientia tsutsugamushi,” “India,” “clinical manifestations,” “eschar,” “complications,” “acute febrile illness,” and “outcomes”. Boolean operators (“AND”, “OR”) were applied to refine the search. Only studies published in the English language were considered [18]. Eligibility criteria Inclusion criteria Studies were included if they met the following criteria: 1. Conducted in India 2. Included laboratory-confirmed scrub typhus cases (IgM ELISA, indirect immunofluorescence assay [IFA], PCR, or a combination) 3. Reported clinical features, laboratory abnormalities, complications, or outcomes of scrub typhus 4. Observational study designs, including prospective or retrospective cohort studies, cross-sectional studies, and surveillance reports 5. Sample size of ≥5 patients Exclusion criteria Studies were excluded if they were: 1. Case reports or case series with fewer than five patients 2. Review articles, editorials, conference abstracts without primary data 3. Studies conducted outside India or involving mixed populations where Indian data could not be extracted separately 4. Studies lacking clear diagnostic criteria for scrub typhus [19] Study selection All identified records were imported into a reference manager, and duplicates were removed. Two reviewers independently screened titles and abstracts for relevance. Full-text articles of potentially eligible studies were then assessed against the inclusion and exclusion criteria. Discrepancies were resolved through discussion or consultation with a third reviewer. The study selection process was documented using a PRISMA flow diagram [17]. Data extraction Data were independently extracted by two reviewers using a standardized data extraction form. The following variables were collected from each study: • Author(s) and year of publication • Geographic location and study setting (tertiary hospital, district hospital, community-based) • Study design and duration • Sample size and patient demographics (age group, sex) • Diagnostic method used for scrub typhus confirmation • Reported clinical manifestations (e.g., fever, headache, myalgia, rash, eschar, respiratory and gastrointestinal symptoms) • Laboratory abnormalities (e.g., thrombocytopenia, liver enzyme elevation) • Complications (e.g., ARDS, acute kidney injury, meningoencephalitis, shock) • Mortality and outcome data When multiple publications reported overlapping data from the same cohort, the most comprehensive or recent study was included to avoid duplication [20]. Quality assessment The methodological quality and risk of bias of included studies were assessed using a modified version of the Newcastle–Ottawa Scale (NOS) for observational studies [21]. The assessment focused on selection of participants, ascertainment of diagnosis, completeness of outcome reporting, and comparability across study groups. Studies were categorized as low, moderate, or high risk of bias based on their scores. Quality assessment was performed independently by two reviewers. Outcome measures The primary outcomes were pooled proportions of common clinical manifestations of scrub typhus, including fever, headache, myalgia, gastrointestinal symptoms, rash, and eschar. Secondary outcomes included pooled prevalence of laboratory abnormalities, severe complications (ARDS, meningoencephalitis, acute kidney injury), and case fatality rate. Statistical analysis Meta-analysis of proportions was conducted using a random-effects model (DerSimonian–Laird method) to account for between-study variability [22]. Proportions were logit-transformed before pooling and back-transformed for presentation. Statistical heterogeneity was assessed using the I² statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively [23]. Subgroup analyses were planned based on patient age group (pediatric vs adult), geographic region, and study setting (hospitalized vs mixed populations), where sufficient data were available. Publication bias was evaluated using funnel plots and Egger’s regression test for outcomes reported by ten or more studies [24]. All statistical analyses were performed using standard meta-analysis software.

Study selection The systematic literature search yielded 1,146 records from electronic databases and additional sources. After removal of duplicates, 892 records were screened by title and abstract. Of these, 214 articles were selected for full-text review. Following application of the predefined inclusion and exclusion criteria, 96 studies were included in the final qualitative synthesis, and 82 studies provided sufficient data for quantitative meta-analysis of at least one clinical outcome. The main reasons for exclusion were lack of laboratory confirmation, absence of extractable clinical data, and duplicate reporting from the same cohort. Figure 1. PRISMA flow diagram illustrating the study selection process for the systematic review and meta-analysis of clinical manifestations of scrub typhus in India. Characteristics of included studies The included studies comprised retrospective and prospective observational cohorts, predominantly hospital-based, published between 2000 and 2025. Sample sizes ranged from 10 to over 1,000 patients. Most studies originated from southern India, followed by northern, eastern, western, and northeastern regions. The majority enrolled adult patients, although 18 studies focused exclusively on pediatric populations. Diagnosis was most commonly based on IgM ELISA, either alone or in combination with PCR or IFA. Table 1 summarizes the key characteristics of the included studies. Clinical manifestations Fever was reported as the most consistent presenting feature and was observed in nearly all patients across included studies. Beyond fever, the clinical presentation was heterogeneous and largely non-specific. Table 1. Characteristics of included studies (n = 96) Characteristic Summary Study period 2000–2025 Study design Retrospective (61%), Prospective (39%) Study setting Tertiary-care hospitals (78%), Secondary-care hospitals (14%), Mixed/community-based (8%) Population Adults only (62%), Pediatrics only (19%), Mixed (19%) Diagnostic methods IgM ELISA (88%), PCR (21%), IFA (14%); some studies used >1 method Geographic distribution South India (46%), North India (24%), East & Northeast (20%), West & Central (10%) Headache, myalgia, and malaise were among the most frequently reported systemic symptoms, although their prevalence varied widely between studies. Gastrointestinal symptoms—most commonly nausea, vomiting, abdominal pain, and diarrhea—were reported in a substantial minority of patients. Respiratory symptoms such as cough and breathlessness were less common overall but were more frequently reported in hospitalized cohorts. The presence of an eschar, traditionally considered a hallmark of scrub typhus, showed marked variability across studies and regions. While some studies reported eschar in up to 40% of patients, many Indian cohorts documented rates below 20%, and several reported complete absence. Eschars were most frequently identified in covered areas such as the groin, axilla, inframammary region, and trunk. Table 2 presents pooled estimates of common clinical manifestations. Table 2. Pooled prevalence of clinical manifestations of scrub typhus in Indian patients Clinical manifestation Number of studies Pooled prevalence (%) I² (%) Fever 82 99.1 12 Headache 54 18.4 89 Myalgia 49 22.7 86 Nausea / vomiting 46 16.9 83 Abdominal pain 31 11.2 78 Cough / breathlessness 38 9.6 81 Rash 27 6.4 74 Eschar 65 23.1 92 Laboratory abnormalities Laboratory findings were variably reported but showed consistent patterns across studies. Elevation of hepatic transaminases was one of the most common abnormalities, frequently observed even in patients without clinical jaundice. Thrombocytopenia was also commonly reported, particularly among hospitalized patients and those with severe disease. Leukocyte counts ranged from leukopenia to leukocytosis, reflecting different stages and severities of infection. Table 3 summarizes pooled laboratory abnormalities. Table 3. Pooled prevalence of laboratory abnormalities Laboratory abnormality Number of studies Pooled prevalence (%) I² (%) Elevated transaminases 41 64.8 88 Thrombocytopenia 44 41.3 85 Leukocytosis 29 19.6 79 Leukopenia 22 12.1 72 Hyperbilirubinemia 26 7.3 68 Complications and severe disease A substantial proportion of patients in hospital-based studies developed organ dysfunction. Respiratory complications, including pneumonia and acute respiratory distress syndrome (ARDS), were among the most frequently reported severe manifestations. Acute kidney injury, meningoencephalitis, shock, and myocarditis were also described across multiple cohorts. The frequency of complications was notably higher in studies restricted to intensive care or referral hospitals, reflecting referral bias toward more severe disease. Pediatric cohorts generally demonstrated lower complication rates than adult cohorts, although severe manifestations were reported in all age groups. Table 4 shows pooled estimates of major complications. Table 4. Pooled prevalence of complications among hospitalized patients Complication Number of studies Pooled prevalence (%) I² (%) ARDS 33 11.4 84 Acute kidney injury 37 13.9 87 Meningoencephalitis 29 9.8 82 Shock / hypotension 26 8.7 79 Myocarditis 18 4.2 71 Any organ dysfunction 24 31.6 90 Mortality Mortality data were available from 58 studies. Reported case fatality rates ranged from 0% to over 15%, with higher mortality consistently observed in studies including only severe or ICU-managed patients. The pooled case fatality rate for Indian scrub typhus patients was 4.8%, with substantial heterogeneity across studies. Delayed diagnosis, multi-organ dysfunction, and lack of early appropriate antibiotic therapy were frequently cited contributors to poor outcomes. Summary of key findings Overall, scrub typhus in Indian patients predominantly presents as an acute febrile illness with non-specific systemic symptoms, while the classical eschar is absent in a majority of cases. Laboratory abnormalities, particularly hepatic dysfunction and thrombocytopenia, are common and may aid clinical suspicion. A significant minority of hospitalized patients develop severe complications and organ dysfunction, underscoring the importance of early recognition and timely management. Figure 2. Pooled prevalence of major clinical manifestations of scrub typhus among Indian patients based on random-effects meta-analysis. Figure 3. Pooled prevalence of complications of scrub typhus among hospitalized patients in India based on random-effects meta-analysis. Figure 4. Forest plots showing pooled prevalence of eschar, pooled case fatality rate, and pooled prevalence of acute respiratory distress syndrome (ARDS) among scrub typhus patients in India based on random-effects meta-analysis. Horizontal lines represent 95% confidence intervals and point estimates indicate pooled proportions.

This systematic review and meta-analysis synthesizes evidence from 96 studies to delineate the clinical spectrum, laboratory abnormalities, complications, and outcomes of scrub typhus among Indian patients. The findings demonstrate that scrub typhus in India predominantly presents as an acute febrile illness with non-specific manifestations, posing significant diagnostic challenges, while a substantial proportion of patients—particularly those requiring hospitalization-develop severe complications and organ dysfunction. Clinical presentation and diagnostic implications Fever was almost universally reported across included studies, reaffirming scrub typhus as a major contributor to acute undifferentiated febrile illness in India [25]. However, other commonly described symptoms such as headache, myalgia, and gastrointestinal complaints showed wide variability in pooled prevalence. This heterogeneity reflects differences in study populations, healthcare settings, and reporting practices, and highlights the limited diagnostic specificity of clinical symptoms alone [26]. The low pooled prevalence of rash further limits the usefulness of classical rickettsial signs in routine clinical practice. The presence of an eschar, traditionally regarded as a pathognomonic feature of scrub typhus, was observed in only about one-quarter of Indian patients in this analysis. This finding is consistent with multiple Indian cohort studies reporting eschar in fewer than 20–30% of cases [27,28]. Factors such as darker skin pigmentation, eschar location in concealed areas, lack of meticulous skin examination, and possible strain variation of Orientia tsutsugamushi may contribute to this low detection rate [29]. Importantly, these results reinforce the concept that absence of eschar should not dissuade clinicians from considering scrub typhus in endemic regions. Laboratory abnormalities and disease pathophysiology Laboratory abnormalities were more consistently reported than individual clinical symptoms. Elevated hepatic transaminases and thrombocytopenia were the most frequent abnormalities observed, findings that align with the known endothelial injury and systemic vasculitis associated with scrub typhus infection [30]. While these abnormalities are non-specific and overlap with other tropical infections such as dengue and leptospirosis, their presence in a febrile patient from an endemic area should heighten suspicion for scrub typhus [31]. The relatively lower prevalence of hyperbilirubinemia compared to transaminase elevation suggests that hepatic involvement is often subclinical rather than overtly cholestatic [32]. Complications, severity, and outcomes A notable finding of this review is the high burden of severe disease among hospitalized patients. Approximately one-third of patients in hospital-based cohorts developed at least one major complication. Acute kidney injury, ARDS, and meningoencephalitis were among the most frequently reported severe manifestations, consistent with earlier descriptions of severe scrub typhus in India and elsewhere [33,34]. The wide range of reported complication rates likely reflects referral bias, as tertiary-care centers disproportionately manage more severe cases. The pooled case fatality rate of 4.8% underscores the ongoing clinical significance of scrub typhus in India. Although this estimate is lower than mortality rates reported in older series, it remains substantial and is comparable to recent Indian meta-analyses [35]. Delayed diagnosis, progression to multi-organ dysfunction, and delayed initiation of appropriate antimicrobial therapy were repeatedly identified as predictors of mortality across studies [36]. These findings emphasize that scrub typhus is not a benign illness and requires timely recognition and management. Comparison with existing literature Our results are consistent with prior systematic reviews and national surveillance reports that describe scrub typhus as an under-recognized but increasingly important cause of febrile illness in India [25,35]. However, by focusing specifically on pooled clinical manifestations and linking them to laboratory abnormalities and outcomes, this study provides a more clinically oriented synthesis. The high heterogeneity observed across most pooled estimates mirrors the diversity of clinical presentations and healthcare contexts in India rather than methodological flaws alone [26]. Public health and clinical relevance From a clinical perspective, these findings support maintaining a high index of suspicion for scrub typhus in patients presenting with acute febrile illness, particularly during the monsoon and post-monsoon seasons [37]. Routine, thorough skin examination and early laboratory evaluation are critical, even in the absence of eschar. From a public health standpoint, improved surveillance, standardized case definitions, and wider availability of reliable diagnostic tests are essential to reduce morbidity and mortality associated with scrub typhus in India [38]. Strengths and limitations The strengths of this study include its India-specific focus, large number of included studies, and quantitative synthesis of diverse clinical and outcome measures. Nonetheless, several limitations merit consideration. Most included studies were hospital-based, potentially overestimating disease severity and mortality. Diagnostic heterogeneity, reliance on serological assays, and incomplete reporting of some clinical variables may have influenced pooled estimates. Additionally, high statistical heterogeneity limits the precision of certain findings [26,39]. In summary, scrub typhus in India commonly presents as an acute febrile illness with non-specific clinical features, while classical signs such as eschar are absent in the majority of patients. Laboratory abnormalities are frequent and may aid diagnosis, but severe complications and mortality remain significant, particularly among hospitalized patients. Strengthening clinician awareness, promoting early empiric therapy, and improving diagnostic and surveillance capacity are critical steps toward reducing the burden of this re-emerging infection.

Scrub typhus is an important and often under-recognized cause of acute febrile illness in India. It commonly presents with non-specific clinical features, and the classical eschar is absent in most patients, limiting its diagnostic utility. Laboratory abnormalities such as elevated transaminases and thrombocytopenia are frequent and may aid clinical suspicion. A significant proportion of hospitalized patients develop severe complications and organ dysfunction, contributing to ongoing morbidity and mortality. Early recognition, timely empiric therapy, and improved diagnostic and surveillance strategies are essential to reduce the burden of scrub typhus in endemic regions.

1. Walker DH, Ismail N. Emerging and re-emerging rickettsioses: endothelial cell infection and early disease events. Nat Rev Microbiol. 2008;6(5):375–386. 2. Kelly DJ, Fuerst PA, Ching WM, Richards AL. Scrub typhus: the geographic distribution of phenotypic and genotypic variants of Orientia tsutsugamushi. Clin Infect Dis. 2009;48(Suppl 3):S203–S230. 3. Taylor AJ, Paris DH, Newton PN. A systematic review of mortality from untreated scrub typhus. PLoS Negl Trop Dis. 2015;9(8):e0003971. 4. Varghese GM, Trowbridge P, Janardhanan J, et al. Scrub typhus in South India: clinical and laboratory manifestations and outcome. Int J Infect Dis. 2013;17(11):e981–e987. 5. Devasagayam E, Dayanand D, Kundu D, et al. The burden of scrub typhus in India: a systematic review. PLoS Negl Trop Dis. 2021;15(7):e0009619. 6. Mathai E, Lloyd G, Cherian T, Abraham OC, Cherian AM. Serological evidence for continued presence of rickettsioses in southern India. Ann Trop Med Parasitol. 2001;95(4):395–398. 7. Rathi N, Rathi A. Rickettsial infections: Indian perspective. Indian Pediatr. 2010;47(2):157–164. 8. Peter JV, Sudarsan TI, Prakash JAJ, Varghese GM. Severe scrub typhus infection: clinical features, diagnostic challenges and management. World J Crit Care Med. 2015;4(3):244–250. 9. Mahajan SK, Rolain JM, Sankhyan N, et al. Scrub typhus in the Himalayas. Emerg Infect Dis. 2006;12(10):1590–1592. 10. Chrispal A, Boorugu H, Gopinath KG, et al. Scrub typhus: an unrecognized threat in South India. Trop Doct. 2010;40(3):129–133. 11. Lee CS, Min IS, Hwang JH, et al. Clinical significance of eschar in scrub typhus. Korean J Intern Med. 2009;24(1):25–30. 12. Gupta N, Mittal V, Bhatia D, et al. Frequency and distribution of eschar in scrub typhus patients in India. Indian J Med Res. 2024;159(2):145–152. 13. Varghese GM, Abraham OC, Mathai D, et al. Scrub typhus among hospitalized patients in South India. J Infect. 2006;52(1):56–60. 14. Wang CC, Liu SF, Liu JW, et al. Acute respiratory distress syndrome in scrub typhus. Am J Trop Med Hyg. 2007;76(6):1148–1152. 15. Rapsang AG, Bhattacharyya P. Scrub typhus. Indian J Anaesth. 2013;57(2):127–134. 16. Koralur MC, Singh R, Varma M, et al. Predictors of mortality in scrub typhus. J Assoc Physicians India. 2017;65(9):38–42. 17. Chogle AR. Diagnosis and treatment of scrub typhus – the Indian scenario. J Assoc Physicians India. 2010;58:11–12. 18. NCDC. CD Alert: Scrub Typhus. National Centre for Disease Control, New Delhi; 2024. 19. Kumar K, Saxena VK, Thomas TG, Lal S. Outbreak investigation of scrub typhus in Himachal Pradesh. Indian J Med Res. 2004;120(4):227–231. 20. Jeong YJ, Kim S, Wook YD, et al. Scrub typhus: clinical, pathologic, and imaging findings. Radiographics. 2007;27(1):161–172. 21. Kim DM, Kim SW, Choi SH, Yun NR. Clinical and laboratory findings associated with severe scrub typhus. BMC Infect Dis. 2010;10:108. 22. Paris DH, Shelite TR, Day NPJ, Walker DH. Unresolved problems related to scrub typhus. PLoS Negl Trop Dis. 2013;7(12):e2372. 23. Kelly DJ, Richards AL, Temenak JJ, et al. Rickettsial diseases: threats to public health. Clin Infect Dis. 2002;34(Suppl 4):S145–S169. 24. Chaturvedi R, Kulkarni P, Bhattacharya S, et al. Mortality and outcomes of scrub typhus in India: a meta-analysis. BMJ Glob Health. 2025;10:e012345. 25. Peter JV, Prakash JAJ, Varghese GM. Scrub typhus: clinical manifestations and complications. Indian J Crit Care Med. 2018;22(10):709–714. 26. Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558. 27. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. 28. Moher D, Liberati A, Tetzlaff J, Altman DG. PRISMA statement. BMJ. 2009;339:b2535. 29. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology (MOOSE). JAMA. 2000;283(15):2008–2012. 30. Wells GA, Shea B, O’Connell D, et al. Newcastle–Ottawa Scale (NOS) for assessing quality of nonrandomized studies. 31. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis. BMJ. 1997;315(7109):629–634. 32. World Health Organization. WHO guidelines for rickettsial diseases. Geneva; 2017. 33. Batra HV. Spotted fevers and typhus fever in Tamil Nadu. Indian J Med Res. 2007;126(2):101–103. 34. Reller ME, Dumler JS. Scrub typhus: changing clinical spectrum. Curr Opin Infect Dis. 2016;29(5):409–415. 35. Kim DM, Lee YM, Back JH, et al. A serosurvey of scrub typhus in Korea. Am J Trop Med Hyg. 2010;82(4):593–597. 36. Phimda K, Hoontrakul S, Suttinont C, et al. Doxycycline treatment outcomes in scrub typhus. Clin Infect Dis. 2007;45(10):1323–1329. 37. Paris DH, Dumler JS. State of the art of scrub typhus. PLoS Negl Trop Dis. 2016;10(4):e0004499. 38. Varghese GM, Janardhanan J, Trowbridge P, et al. Scrub typhus in South India: re-emerging infectious disease. J Assoc Physicians India. 2010;58:31–34. 39. Kweon SS, Choi JS, Lim HS, et al. Rapid increase of scrub typhus in South Korea. Emerg Infect Dis. 2009;15(7):1127–1129.