ISSN: 0973-7510

E-ISSN: 2581-690X

Review Article | Open Access
Diptimayee Rout1, Ira Praharaj2, Siba Prasad Dalai3, Swati Mishra1 and Sarita Otta1
1Department of Microbiology, IMS and SUM Hospital, Kalinga Nagar, Bhubaneswar, Odisha, India.
2Regional Medical Research Centre (ICMR), Bhubaneswar, Odisha, India.
3Department of Medicine, IMS and SUM Hospital, Kalinga Nagar, Bhubaneswar, Odisha, India.
Article Number: 8638 | © The Author(s). 2023
J Pure Appl Microbiol. 2023;17(4):2060-2073.
Received: 20 April 2023 | Accepted: 21 October 2023 | Published online: 29 November 2023
Issue online: December 2023

Scrub typhus, an age old disease, is caused by the intracellular bacterium Orientia tsutsugamushi. It has reemerged in recent years due to factors like climatic changes and human encroachment because of rampant urbanization. The disease is endemic in the area known as the ‘tsutsugamushi triangle’ and has recently spread its fangs into various other continents like South America and Africa. Although the disease is endemic in India, there is a lack of appropriate sero-epidemiology in community settings. It is one of the essential causes of acute undifferentiated fever in tropical locations and, if untreated, can cause mortality ranging from 2-30% of cases. Early diagnosis is an important parameter in administering the non beta-lactam regimen to prevent complications and mortality. Yet, there is a lack of accurate and rapid methods for diagnosis in the early stage of the disease, more so in rural areas where the disease is supposed to be predominant. The gold standard diagnostic test has its problems. Recently, there have been reports of drug resistance to the standard scrub typhus regimen. There is a gap of a decade in the research into this entity. Thus, a new look into the disease, its epidemiology and the challenges in its diagnostic scenario is an apt topic for discussion.


Scrub Typhus, Orientia tsutsugamushi, IgM Capture ELISA, Indirect Immunofluorescence Assay


Scrub typhus was a disease of the pre-antibiotic era, especially during military operations, but even today causes one million cases annually worldwide.1 In the recent years it has reemerged as a significant public health issue due to multiple factors like climatic changes, human activities disturbing the ecological balance, beta-lactam antibiotics overuse and urbanization of rural areas.2 This disease is an underdiagnosed entity due to a lack of typical pathognomonic clinical features coupled with inadequate availability of appropriate laboratory methods. Thus there is limited epidemiological data regarding the disease globally.

Epidemiology of Scrub typhus
Scrub typhus is caused an intracellular Gram negative small pleomorphic coccobacilli named Orientia tsutsugamushi,3 which was previously under Rickettsia family. It is named as ‘tsutsugamushi’ (dangerous bug), after a jungle mite or chigger, which acts as a reservoir and transmits the disease to man by biting through pores or hair follicles on exposed skin. Human encroachment during deforestation, logging, road building, military operations, rice cultivation, etc., bring us close to infected chiggers, the parasitic stage in the vector Leptotrombidium mite. Climatic change due to global warming also has a role in the reemergence of this disease (Figure 1).4

Figure 1. The epidemiological triad of scrub typhus
The agent O. tsutsugamushi is maintained in its reservoir mites by transstadial and transovarian transmission and transmitted to man by bite of the larvae (chigger) in cases of human encroachment into mite habitat. Man to man transmission is not seen.

Tropical regions have appropriate temperatures and humidity for chigger activity and maintaining the pathogen in transovarian and transstadial transmission in the mites. Researchers have also noted horizontal transmission of Orientia among mites.5 Thus, the disease occurs around the year. However, in temperate zones like in the northern part of Japan, the mite activity is seasonal corresponding to the disease.6

Scrub typhus is endemic to a region denoted as the ‘‘tsutsugamushi triangle’’.South East Asian region is endemic for scrub typhus.7 But in recent times, the disease has surfaced in other non endemic areas like Europe, Chile, Peru, Middle East, African peninsula and sometimes with a different species of the bacteria, like O.chuto seen in the Middle East (Figure 2).8  In India, several states have varying ecological profile, like Haryana, Jammu, and Kashmir, Himachal Pradesh, Uttaranchal in north; Kerala, Tamil Nadu in South; Bihar, West Bengal, Assam in East; Maharashtra in West report this disease.9,10 Sero-prevalence of this infection in India is between 9.3% and 27.9%, and the mortality rate is around 30% among untreated individuals, as noted in passive national surveillance systems.7,11 Among acute onset febrile illness, scrub typhus constitutes about 25.3% of cases in India (Table 1).12

Figure 2. The Tsutsugamushi triangle and other area in the world where the disease has been reported.
Tsutugamushi triangle, an area approximating about 8 million km2 is endemic for scrub typhus. This extends in North from the Russian Far East, to Pakistan in the west, Australia in the south, and the Japan in the east. Seroprevalence of scrub typhus detected in recent studies,63 have been tabulated which ranges from mere 1.1% in Vietnam to 68.4 % in Japan. But apart from this, other area in globe like – Chile, United Arab Emirates, African countries ( Camroon, Kenya, congo, Tanjania) also have reported cases of scrub typhus.

Table (1):
Tabulation of recent studies in India on scrub typhus
Majority of the studies included acute undifferentiated fever cases in their inclusion criteria and were hospital based studies including adult patients

Author and year
Time period
Target population
No. of patients
No of cases detected
No. of deaths
Test used
Predominant month
Age & sex of patients
Subbalaxmi et al. [64]
Andhra Pradesh
August 2011 to December 2012
AUFI Cases >12 years
Weil felix test (>1:80) ICT
41 years; M>F
Sinha et al. [65]
Jaipur, Rajasthan
Oct-2012 to Dec-2012
 AUFI cases
Stephen et al. [66]
Puducherry Tamilnadu
Sep2012 to March 2013
AUFI cases
ICT test                                         IgM, IgG  ELISA (paired) Weil felix (Initial titre1:40 or OXK>320)
31 years; M=F
Krishna, Vasuki et al. [67]
Chennai        Tamilnadu
Sep 2010 to June 2011
Paediatric AUFI
Jakharia et al. [68]
Arunachal Pradesh
Seroprevalence study in community
>40 years; M=F
Rajendra prasad thakar [69]
July to October 2014
20 -50 year; F>M
H. Lalrinkima  [70]
October 2014 to December 2016
ICT test
November -February
21 – 30 year; M>F
Deepak jain [71]
July to Nov 2017
>14 yrs AUFI
39 year; F>M
Thakur et al. [72]
Various parts of India
2013- 2018
AUFI in hospitalized patients
IgM ELISA  andIFA ( Gilliam and Karp strains)
Laxmi R et al. [73]
July to October 2018
Suspected Scrub typhus
20 TO 50 year; F>M
Verma et al. [74]
Sep 2019 to Jan 2020
AUFI >18 yrs
20 TO 50 year; F>M

Orientia shows many genetic and antigenic variations resulting from variations in tsa gene, which codes for 56-kDa type specific antigen.1,13 There are around 30 serological types like kato, karp, kuroki, gilliam and kawasaki that as detected by immunoperoxidase reaction14 Litchfield strain is a novel strain detected in Australia.15 The correlation between this antigenic diversity and virulence is still unclear.

 Clinical presentation
Fever is the commonest presentation, seen in 95-100% of cases.16,17 Scrub typhus accounts for a significant chunk of “fever of unknown origin” in endemic regions. Even the term “typhus” is derived from Greek terminology ‘Typos’ meaning ‘fever with stupor’ The age group of 50-60 is commonly afflicted while, sex preponderance varies across different countries.3 A papular lesion is formed at the chigger bite site, which becomes larger with time, followed by necrosis and crusting in the centre and finally developing a black eschar, which is a pathognomonic feature of scrub typhus. The presence of eschar is specific (98.9%) for diagnosis of this disease but is limited by sensitivity, which varies between 7%-97%.7 Further, eschar is often absent in the South East Asian population and in endemic areas with less severe illness.18-20 Scrub typhus can present in varied forms ranging in severity from asymptomatic to multi organ failure.21 Common symptoms are myalgia, headache, nausea, vomiting, abdominal pain, cough, generalized lymphadenopathy and skin rash in varying combinations.3,22,23 Owing to its mimicking signs and symptoms, it took almost 30 years to prove the original finding of Coyttarus (1578) that typhoid and typhus were different diseases. Untreated cases may develop several complications generally occurring after the first week of illness. Various complications like acute renal failure, jaundice with rising liver enzymes, pneumonitis and acute respiratory distress syndrome, septic shock, myocarditis, meningoencephalitis and reversible deafness have been noted in prior studies.18,20 Renal involvement can be expected in about 9% of patients. Patients of meningoencephalitis often have CSF changes indistinguishable from viral or tuberculous meningitis. Unusual presentations include conjunctival hyperemia or erosion, gastrointestinal mucosal erosion without any predilecting site and acute abdomen.24,25 Septic shock ensues with further organ damage to liver, lungs, kidneys along with DIC.26,16,27,28 Elevated transaminases, thrombocytopenia and leukocytosis are the biochemical investigations pertinent to diagnosing the disease when used in combination (specificity and positive predictive value for diagnosis – 80%).29

Mortality from this disease varies from 7-30%,30 but much less in children.31 The possible patient factors associated with complicated cases are – age (≥60 years), patients without eschar, WBC counts >10000/mm and serum albumin level ≤3.0 g/dL.31,2 Being a great mimicker, diagnosis in the early stages is challenging yet important for successfully treating scrub typhus. The median case fatality rate is reduced to 1.4% in treated patients from 6% seen in late or untreated ones.11,29,32 Diagnosis is based on clinical suspicion with appropriate lab investigation.

Lab diagnosis of scrub typhus
Serological assays
Serological tests that detect antibodies to against scrub typhus, like Weil Felix test, ELISA, immunofluorescence and immunoperoxidase tests are the commonly performed tests for lab diagnosis. IgM is preferred over IgG detection as it can help diagnose recent infections. But, all there tests have many issues that needs addressing. A ≥ 4-fold increase in antibody titer between two consecutive samples is diagnostic,33 but often not practical. Secondly, a baseline titer (cut-off) is to be established in the geographical setting based on the endemicity of the disease for appropriate reporting, which is often lacking. There is wide variation across India in cut-off values of the various serological tests (Table 2).  Then again, most serological tests use an antigen cocktail of Karp, Kato, and Gilliam serotypes. But there are many other antigenic variations apart from these three, differing in different geographical regions of the world.1 For example, in mites collected from a single field in Malaysia, eight different serotypes were found.34 Boryong is the commonest serotype in South Korea in three-fourths of total isolates.35 Similarly, Kawasaki or Kuroki serotypes accounted for >90% of Kyushu island isolates of Japan.36 In India, data on serotype prevalence in different areas is still lacking. Thus, common serotypes must be explored and included as the antigen for serological testing purposes.

Table (2):
Cut off value calculated in different studies from various hospital based studies across India

Study Setting Cut off value Sensitivity Specificity
Manjunathachar et al. [87] Madhya Pradesh 0.73 (IgM) 95 100
Koraluru et al.  [79] Karnataka 1.0 (IgM) 85 95
Gupta et al. [88] New Delhi 0.87 (IgM) 100 94.12
Gupta A et a.l [89] Himachal Pradesh 0.46 (IgM) 91.7 99.5
Gautam et al. [81] Nepal 0.5 (IgM)
Karthikeyan et al. [85] Puducherry 0.4
Rawat et al.  [90] Uttarakhand 0.6 (IgM)
1.6 (IgG)
Verghese et al. [91] Vellore, South India 0.8 (IgM)
1.8 (IgG)

Immunofluorescence assay
Fomda et al. [82] Kashmir 1:128 (IgM)

1:256 (IgG)

Gupta et al. [88] New Delhi 1: 64 100 93.5
Gupta et al. [88] New Delhi 1:512 98
Gautam et al. [81] Nepal 1:128
Rawat et al. [90] Uttarakhand 1:512 (IgM)
1:2048 (IgG)
Verghese et al.  [91] Vellore, South India 0.251 (IgM)
0.205( IgG)

IFA, the gold standard test for detection suffers from many pitfalls. For example, in a Korean study, IFA had false negative results in six patients with a typical eschar which was positive for O. tsutsugamushi DNA.37 Further, it is labor intensive, needs resource settings and can have interoperator variations.7

Rapid test
The dot blot immunoassay dipstick is rapid, semi-quantitative, accurate and easy to use inexpensive point of care test that can also be used in rural settings.19,38 Rapid immunochromatographic test is another POC test with higher sensitivity and specificity of 96.8% and 93.3%, respectively when used for detection of IgM.39 Studies considering Bayesian class models show that ICT kits can even have higher specificity than IFA.40-42 ICT kits can be used with another method like LAMP/ PCR assays for improving accuracy (Table 3).

Table (3):
Various methods for laboratory diagnosis of scrub typhus
Indirect diagnostic methods comprise of method which detect antibodies developed against Orientia tsutsugamushi while direct methods detect the organism from the samples either by culture, animal inoculation or the DNA of the bacteria by amplification methods

Test Principle Advantages Issues
Weil Felix ≥ 4 times rise in titre to proteus OX-K and no reaction to proteus OX-2 or OX-19
Single titre ≥1:160 is also diagnostic (normal is ≤1:40[75]
Antibodies are detectable after 5 – 10 days following the onset of fever [9]
Easy to perform
Results are available overnight
Not a sensitive test
When positive, it is specific test.[76]
False negative – in UTI by Proteus, Leptospira infections etc.
KpKtGm-wc ELISA  or KpKtGm r56 ELISA
IgM capture ELISA
56-kDa protein (located on the outer membrane of O.tsutsugamushi highly reactive inducing antibodies[77]
Antigen used – whole cell antigen / r56 from the Karp, Kato, and Gilliam strains of O. tsutsugamushi [78]
Higher sensitivity and specificity than Weil felix
85% sensitive and specificity in comparison to IFA (InBios kit)
IgM capture ELISA can capture the acute infection
Specified Cut off is needed
Need paired sera
Many serotypes may need constant monitoring
Indirect immunofluorescence  antibody detection test (IFA) Uses fluorescein linked anti-human reporter antibody to detect the presence of scrub typhus-specifc antibodies (mostly against Karp, Kato, Gilliam) in the serum sample.[33]
An 20-fold rise in titre in paired (14 days) sampling is considered positive
Current Gold standard test for diagnosis Need Paired sera
Specified cutoffs needed
Specialized equipments required
Other methods offer fair sensitivity and specificity
Reexamination not possible
Indirect immunoperoxidase antibody detection test (IPA) Fluorescent antibody tagging is substituted by peroxidase tagging Preparations can be preserved for reexamination
All cells infected and uninfected can be visualised
Any serotype can be used as an antigen
Can measure either IgG or IgM
Sophisticated instruments are not necessary
Subjective readings
ICT Recombinant antigen mixture of 56-kDa outer-membrane proteins of Karp, Kato and, Gilliam strain is captured for detection of IgG and IgM antibodies to Orientia tsutsugamushi.
The serotypes can be changed as per endemicity in different geographical location
Fairly good sensitivity and specificity which is increased when used with other techniques like LAMP assays or IFA
Total antibody(IgG+IgM+ IgA) test has lesser specificity than IgM alone
IgM ICT kit is an important ruling in test
Sensitivity and specificity lesser than other serological techniques
All issues as in serological tests
PCR On blood sample targeting 56 kDa tsa, GroEL, 16s RNA and 47 kDa HtrA genes
Can be performed as conventional PCR, nested PCR, qualitative or quantitative real time PCR and LAMP assays
Diagnosis during first week of illness (Rickettsiamia)
No paired sera necessary
Eschar PCR has better sensitivity than blood/serum
Genetic diversity may cause false negativity.
False negative with previous treatment.
Extensive clinical evaluation is pending.
Targets the groEL gene, the 60 kDa heat shock protein of Orientia tsutsugamushi.[37]
The reaction can be quantitatively interpreted in real-time by measuring the turbidity or by fluorescence using intercalating dyes such as SYTO 9.
Thermo cyclers and other PCR set up for extraction and interpretation are not needed
Diagnostic accuracy more than other PCR methods
Advantage over serological testing in first week of illness
Further clinical evaluation needed
Cell culture Culture in cell lines like HeLa, BHK 21, Vero cells Improves sensitivity and specificity BSL-3 facility required
27 days for positivity.
Animal inoculation Detection of organism by Giemsa stain in tissues following intraperitoneal inoculation
Scrotal reaction following intra peritoneal injection of blood into male guinea pig
Sensitivity and specificity good BSL-3 facility
Time taking affair

Molecular assays
PCR, either conventional, nested or real-time PCR can be used for diagnosis of scrub typhus.43,44 Q-PCR is faster, has higher sensitivity and specificity and produces quantitative results than other methods.45 Q PCR has been already reported with targets like- 16S rRNA gene (using hydrolysis probes), 60-kDa heat shock GroEL gene and 47-kDa HtrA outer membrane protein gene. 46-48 Q PCR with 16S r RNA as the desired target has the highest sensitivity and accuracy compared to other targets and also when compared with immunofluorescence assay for diagnosis. Specimens from which PCR can be done are eschar, whole blood, clots or buffy coat. Immunohistochemical staining and PCR from eschar material are more sensitive and remains positive even after treatment.37,49 All the PCR assays remain positive only during the period of rickettsemia. Common genetic targets for OT detection are- tsa gene encoding the 56-kDa type-specific antigen; htrA gene coding for 47-kDa periplasmic serine protease48; groEL gene – Hsp60; 16S rRNA.50,51 Although the56-kDa antigen is highly specific,52,53 but variability in sequence can affect the annealing of the primer and reduce test sensitivity.44 Assay targeting the 16S rRNA gene showed a higher sensitivity than 56-kDa gene.51As O. tsutsugamushi genome has a high degree of genetic variations, improving specificity of the detection by using multiple genes approach either by conventional or real-time PCR is the need of the hour.

LAMP assay
LAMP assay with the groEL gene of Orientia tsutsugamushi has been tried.37 LAMP assay has many advantages such as not needing a thermal cycler and visual result reading. But, clinical use warrants further validation. A study has also shown that limit of detection with LAMP assay is 14 copies/μL compared with three copies/ μL for real-time PCR.50

STIC criteria for diagnosis of scrub typhus
Gold standard or reference test for scrub diagnosis includes IFA or IIP assays, which have many limitations for accurate diagnosis. Bayesian model showed that the IFA IgM assay has sensitivity and specificity of 70.0% and 83.8%, respectively.41 Keeping this in mind, STIC criteria (Figure 3) using a battery of tests with high specificity has been proposed as an alternative reference comparator for accurate diagnosis.54 Table 4 summarizes the commonly available serological and molecular tests for scrub typhus diagnosis.

Figure 3. STIC criteria for diagnosis of scrub typhus

Table (4):
The sensitivity, specificity, Positive predictive value and Negative predictive value of the common tests available for scrub typhus from various studies conducted from low and middle income country settings

Test for Scrub Typhus
Type of assay evaluated
Reference/Gold standard assay
Reported Sensitivity (95%CI) and specificity (95% CI)
Reported PPV (95%CI) and NPV (95% CI)
Study setting
Scrub Typhus Detect IgM ELISA kits
InBios International
IgM Microimmunofluorescence
85.3% (78.4–90.7)
95.5% (93.0–97.3)
94.8% (92.2–96.7)
Tertiary care hospital, Karnataka, India
Koraluru M, et al. [79]
Scrub Typhus Detect IgM ELISA kits
from InBios International
Conventional PCR positive for O.tsutsugamushi56kDa type specific antigen (TSA) or
47kDa htrA (high temperature requirement A) qPCR positive
92.41% (86.8–96)
93.67% (88.7–96.9)
93.59% (88.5–96.9)
92.50% (87.3–96.1)
Tertiary care hospital, Tamil Nadu India
Kannan K et al. [80]
Scrub Typhus Detect IgM ELISA kits
from InBios International
IgM Immunofluorescence test
84% (79.73–87.68)
94.82% (93.43-95.99)
95.44% ( 94.27–96.38)
Hospital setup, Central Nepal
Gautam R  et al. [81]
InBioS International, Inc. USA
86.67% (73.21–94.95)
97.86% (95.08–99.30)
88.64% (76.49–94.93)
97.45% (94.77–98.77)
Tertiary care hospital,  Kashmir
Fomda et al.  [82]
Conventional PCR
56 KDa gene
IgM Microimmunofluorescence
75.32% (67.8–81.8)
100% (95.4–100)
100% (96.5–100)
80.20% (73.9–85.5)
Tertiary care hospital, Tamil Nadu India
Kannan K et al. [80]
Real time PCR (47 KDa)
47 KDa gene
IgM Microimmunofluorescence
97.47% (93.8–99.3)
100% (96.5–100)
100% (96.5–100)

97.53% (93.6–99.3)

Tertiary care hospital, Tamil Nadu India
Kannan K et al. [80]
Real time PCR
Fourfold increases in IgM or IgG titer on IFA
91.9% (86.3- 95.7)

Tertiary care hospital , Korea
Yun et al.  [83]
Nested PCR
29.73% (15.87- 46.98)
99.58% (97.67- 99.99)
70.46% (9.37- 52.98)
0.71% (0.57 to 0.87)
Tertiary care hospital, Wardha, Maharastra
Roy S et al. [84]
47 kDa gene of O. tsutsugamushi
16.22% (6.19- 32.01)
99.16% (96.99–99.9)
0.84% (0.73 to 0.97)
Tertiary care hospital, Wardha, Maharastra
Roy S et al. [84]
groEl gene

Tertiary care hospital, Puducherry
Karthikeyan PA et al. [85]
Immune med ICT test kit
98.6% (96-100)
98.2% (96-99)
97.1% (94-99)
97.7 %(95-99)
99.1% (98-100)
96.4% (93-99)
98.2% (93-99)
Kim YJ et al. [86]
SD Bioline Tsutsugamushi  ICT kit
85.71% (67.32-95.88)
100% (80.33-100)
91.67% (72.96-98.73)
90.48% (69.58-98.55)
100% (65.62-100)
80.95% (58.08-94.44)
Tertiary care set up,  Tamil Nadu, India
Stephen S et al. [66]

Treatment of scrub typhus
The treatment options for scrub typhus are- doxycycline and tetracycline. Azithromycin, ciprofloxacin and rifampicin are effective alternatives where there is poor response to doxycycline. In pregnant women and children less than 8 years old, azithromycin is the preferred regimen. Severe disease needs to be treated with intravenous chloramphenicol with intravenous tetracycline. A recent multicentric study has concluded that combination therapy of intravenous doxycycline and azithromycin is a better treatment option for severe scrub typhus than any agent alone.55 There is no significant difference in outcome when azithromycin therapy is compared with other antibiotics singly or in combination in paediatric patients as noted in a recent meta-analysis.56 But recently, there have been reports of drug resistance, which needs further pondering.57-59

Prophylaxis of scrub typhus
Different localities have different antigenic variants of O. tsutsugamushi strains showing no to weak cross-protection. Thus, an effective vaccine for scrub typhus must account for multiple strains thriving in the population.60-62 WHO recommends single oral dose of tetracycline, doxycycline or chloramphenicol every 5 days for a total of 35 days for prophylaxis against Orientia infection63 as opposed to CDC which opines that such a prophylactic treatment may only delay the disease and also hinder diagnosis. Other safety measures include avoiding exposure to vegetation by using full-sleeved clothing, mats to sit on the grass, using shoes, cleaning the garments with insect repellant after a possible exposure to get rid of mites, and rodent control.63


Scrub typhus, a disease of wars, has raised its fangs with growing climate change and human activities encroaching on the habitat of the mite reservoir. Despite its long presence, there needs to be more data citing its actual prevalence, serotypes involved and determinants of clinical course, especially in India. One of the important reasons for this is the lack of a diagnostic test with desirable accuracy. Molecular methods are helpful early in the disease and are yet to be widely used for diagnosis. Adopting a rapid, accurate test protocol for clinical diagnosis of scrub typhus is necessary. Further clinical trials and research is needed for evaluating various regimens used for scrub typhus, keeping in mind the evolving drug resistance and its intracellular persistence causing relapses.


We sincerely acknowledge the support of S’O’A University, Kalinga Nagar, Bhubaneswar, Odisha, for their support in carrying out this review.

The authors declare that there is no conflict of interest.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.


All datasets generated or analyzed during this study are included in the manuscript.

Not applicable.

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