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Fulltext Development and preliminary evaluation of an IgM dot-immunobinding assay (IgM-DIA) for rapid serodiagnosis of scrub typhus infection

Koay AS, Tay ST, Cheong YM, Yasin RM

Southeast Asian J. Trop. Med. Public Health, 1995 Jun;26(2):350-3.
PMID: 8629074

An IgM dot-immunobinding assay (IgM-DIA) was developed for the diagnosis of scrub typhus infection. The whole cell antigens of Karp, Kato and Gilliam strains of Rickettsia tsutsugamushi were immobilized onto nitrocellulose paper and reacted with patients sera. The presence of IgM R. tsutsugamushi specific antibody in the patient sera could be detected by the observation of a visible brown dot on the nitrocellulose paper. The IgM-DIA has a sensitivity of 90.4% and specificity of 81.4% as compared to the indirect immunoperoxidase test. The IgM-DIA is rapid, simple, cost-effective, does not require microscope or incubator. It is recommended as a rapid screening test for the diagnosis of scrub typhus infection in the field or rural area within the hyperendemic region.

Matched MeSH terms: Scrub Typhus/diagnosis*
Scrub typhus antibody in mammals in three habitats in Sabah

Muul I, Lim BL, Gan E

Southeast Asian J. Trop. Med. Public Health, 1974 Mar;5(1):80-4.
PMID: 4209140
Matched MeSH terms: Scrub Typhus/immunology*
Distribution of Leptotrombidium (Leptotrombidium) arenicola (Acarina: Trombiculidae) on the ground in West Malaysia

Upham RW, Hubert AA, Phang OW, Mat YB, Rapmund G

J Med Entomol, 1971 Oct 30;8(4):401-6.
PMID: 5159254
Matched MeSH terms: Scrub Typhus/etiology
Serological evidence for a high incidence of transmission of Rickettsia tsutsugamushi in two Orang Asli settlements in Peninsular Malaysia

Brown GW, Robinson DM, Huxsoll DL

Am J Trop Med Hyg, 1978 Jan;27(1 Pt 1):121-3.
PMID: 415625

Two communities of Orang Asli (aborigines) in Peninsular Malaysia were observed for evidence of Rickettsia tsutsugamushi infection over periods of 1-8 mo. Sequential sera were examined for antibody by the indirect immunofluorescence test. The incidence of infection in the two self-selected populations in the two communities was calculated to be 3.9% per month and 3.2% per month.

Matched MeSH terms: Scrub Typhus/epidemiology*
Fulltext A Rejang river rash

Lim JL

Malays Fam Physician, 2014;9(1):33-34.
PMID: 25606297 MyJurnal

A 30-year-old Iban woman presented to a rural primary healthcare clinic located along the Batang Rejang in Sarawak. She had a 2-day history of rash, which started over her trunk and later spread to her face and limbs. What started out as individual erythematous maculopapular spots later coalesced to form larger raised blotches. The rash was extremely pruritic and affected her sleep, and hence her visit. The rash was preceded by high grade, persistent fever that was temporarily relieved by paracetamol. She also complained of malaise, arthralgia and myalgia. Her appetite had been poor since the onset of the fever. She lived in a long house at the edge of the jungle. Although she did not have a history of going into the jungle to forage, she went regularly to the river to wash clothes. Clinically, she appeared lethargic and had bilateral conjunctival injection. Her left anterior cervical lymph nodes were palpable. There were erythematous macules measuring 5 to 15 mm distributed over her whole body but predominantly over the chest and abdominal region (Figure 1). An unusual skin lesion was discovered at the right hypochondriac region. This lesion resembled a cigarette burn with a necrotic centre (Figure 2). There was no evidence of hepato-splenomegaly. Examination of the other systems was unremarkable. On further questioning, the patient admitted being bitten by a ‘kutu babi’ or mite 3 days before the onset of her fever.

Matched MeSH terms: Scrub Typhus*
Comparative evaluation of the indirect immunoperoxidase test for the serodiagnosis of rickettsial disease

Kelly DJ, Wong PW, Gan E, Lewis GE

Am J Trop Med Hyg, 1988 Mar;38(2):400-6.
PMID: 3128129 DOI: 10.4269/ajtmh.1988.38.400

An indirect immunoperoxidase test was compared with an indirect fluorescent antibody test and the Weil-Felix OXK test for serodiagnosis of scrub typhus by measuring the rickettsial antigen specific activity of IgG, IgM, and whole globulin. Acute and convalescent sera from 50 Rickettsia tsutsugamushi isolate-positive scrub typhus patients and from 45 febrile patients diagnosed as having diseases other than scrub typhus were tested. The receiver operating characteristic for each test showed that the indirect immunoperoxidase and indirect fluorescent antibody tests were more sensitive and specific than the Weil-Felix test using convalescent and acute as well as paired sera. The indirect immunoperoxidase test showed no cross-reactivity when R. tsutsugamushi antigen was tested against sera collected from patients living outside the scrub typhus-endemic area with diseases other than scrub typhus. The indirect immunoperoxidase and indirect fluorescent antibody tests were comparable in measured response to R. tsutsugamushi, R. typhi, and TT-118 (spotted fever group) antigen. Thus the indirect immunoperoxidase test represents a sensitive, specific, reproducible, and practical semiquantitative test for rickettsial disease diagnosis.

Matched MeSH terms: Scrub Typhus/diagnosis*
Expression of recombinant proteins of Orientia tsutsugamushi and their applications in the serodiagnosis of scrub typhus

Tay ST, Rohani MY, Ho TM, Devi S

Diagn Microbiol Infect Dis, 2002 Oct;44(2):137-42.
PMID: 12458119

In this study, recombinant proteins that encompassed the AD I-AD III regions of 56 kDa immunodominant gene of 2 Orientia tsutsugamushi (OT) serotypes; Gilliam and TA763 were expressed in Escherichia coli. Both recombinant proteins exhibited serologic cross-reactivity with the rabbit antisera against various OT serotypes, as evaluated by enzyme-linked immunosorbent assay (ELISA), but not against other rickettsial species, including Rickettsia typhi, R. prowazekii and TT118 SFG rickettsiae. The feasibility of using the recombinant proteins as a diagnostic reagent was further evaluated by ELISA using sera from blood donors and scrub typhus patients. The results suggested a higher affinity of the antihuman IgM than IgG with both recombinant proteins. The IgM ELISA findings were agreeable with the results of indirect immunoperoxidase (IIP) assay especially with sera of high antibody (1:1600). However, more than one antigen are probably needed for development of an effective assay for serodiagnosis of scrub typhus in endemic areas.

Matched MeSH terms: Scrub Typhus/diagnosis*; Scrub Typhus/immunology
Seroepidemiologic survey of Orientia tsutsugamushi, Rickettsia typhi, and TT118 spotted fever group rickettsiae in rubber estate workers in Malaysia

Tee TS, Kamalanathan M, Suan KA, Chun SS, Ming HT, Yasin RM, et al.

Am J Trop Med Hyg, 1999 Jul;61(1):73-7.
PMID: 10432060

The seroprevalence of Orientia tsutsugamushi, Rickettsia typhi, and TT118 spotted fever group (SFG) rickettsiae in 300 rubber estate workers in Slim River, Malaysia was determined in December 1996 and March 1997. In December, which was the wet season, 23.3%, 3.0%, and 57.3% of the population had antibodies detected against the three rickettsiae, respectively. The highest seropositive rate of 40% was detected for single infection with SFG rickettsiae, followed by a rate of 15.3% for both O. tsutsugamushi and SFG rickettsiae among the rubber estate workers. Subjects less than 21 years old had a lower seroprevalence of SFG rickettsiae compared with the other age groups. Indians had a higher seroprevalence of O. tsutsugamushi compared with other ethnic groups. Rubber tappers had a higher seroprevalence of SFG rickettsiae compared with other occupational groups. During the dry season in March 1997, there was a significant increase in the seroprevalence of R. typhi. The seroconversion rates for IgM against O. tsutsugamushi, R. typhi, and SFG rickettsiae were 5.7%, 12.3%, and 15.1%, respectively, during the four-month period. Significant variations of antibody titers towards the three rickettsiae was noted among subjects who were bled twice. This suggests a significant and continual exposure of rubber estate workers to the three rickettsiae.

Matched MeSH terms: Scrub Typhus/immunology; Scrub Typhus/epidemiology*
A serological survey of scrub, tick, and endemic typhus in Sabah, East Malaysia

Taylor AC, Hii J, Kelly DJ, Davis DR, Lewis GE

Southeast Asian J. Trop. Med. Public Health, 1986 Dec;17(4):613-9.
PMID: 3107139

A seroepidemiological survey of 837 people and 383 febrile patients was performed in rural areas of Sabah. We determined that the rickettsial diseases scrub typhus and endemic typhus were uncommon causes of febrile illness, as was tick typhus, except in forest dwelling peoples. The rate of occurrence of SFGR specific antibody was 16.5% among 412 forest dwellers, indicating that tick typhus may be a frequent cause of illness in this population.

Matched MeSH terms: Scrub Typhus/diagnosis; Scrub Typhus/epidemiology*
Fulltext Antibody prevalence and factors associated with exposure to Orientia tsutsugamushi in different aboriginal subgroups in West Malaysia

Tay ST, Mohamed Zan HA, Lim YA, Ngui R

PLoS Negl Trop Dis, 2013;7(8):e2341.
PMID: 23936576 DOI: 10.1371/journal.pntd.0002341

Limited data is available on the current status of scrub typhus infection in the aboriginal population in Malaysia. This study was aimed to provide recent data on the degree of exposure of 280 individuals from seven aboriginal subgroups to Orientia tsutsugamushi (causative agent of scrub typhus) in West Malaysia. The environment, socioeconomic and behavioural risk factors associated with the disease were also investigated.

Matched MeSH terms: Scrub Typhus/epidemiology*
Fulltext Febrile illness in Malaysia--an analysis of 1,629 hospitalized patients

Brown GW, Shirai A, Jegathesan M, Burke DS, Twartz JC, Saunders JP, et al.

Am J Trop Med Hyg, 1984 Mar;33(2):311-5.
PMID: 6324601

We studied 1,629 febrile patients from a rural area of Malaysia, and made a laboratory diagnosis in 1,025 (62.9%) cases. Scrub typhus was the most frequent diagnosis (19.3% of all illnesses) followed by typhoid and paratyphoid (7.4%); flavivirus infection (7.0%); leptospirosis (6.8%); and malaria (6.2%). The hospital mortality was very low (0.5% of all febrile patients). The high prevalence of scrub typhus in oil palm laborers (46.8% of all febrile illnesses in that group) was confirmed. In rural Malaysia, therapy with chloramphenicol or a tetracycline would be appropriate for undiagnosed patients in whom malaria has been excluded. Failure to respond to tetracycline within 48 hours would usually suggest a diagnosis of typhoid, and indicate the need for a change in therapy.

Matched MeSH terms: Scrub Typhus/diagnosis
Multi-laboratory evaluation of a scrub typhus diagnostic kit

Kelly DJ, Wong PW, Gan E, Chye CT, Cowan D, Lewis GE

Am J Trop Med Hyg, 1990 Sep;43(3):301-7.
PMID: 2121057

Scrub typhus is a major cause of febrile illness throughout the Asia-Pacific region. It is commonly undiagnosed, partly because of the lack of a simple, reliable diagnostic test which can be used in clinical laboratories. The indirect immunoperoxidase technique, configured into a test kit, was provided to technicians who were trained in its use. They used the kit during a 2 year field trial in their respective clinical hospital laboratories throughout Malaysia. In an evaluation using 1,722 consecutive sera tested in those laboratories, the kit was found to have a median sensitivity for IgG detection of 0.85 (range 0.33-0.95), a median specificity of 0.94 (range 0.88-1.00), reproducibility of 0.86, and efficiency of 0.92 when compared to the reference laboratory. In a proficiency survey in which 10 laboratories received 3 coded test samples, all but 2 laboratories had results within 1 dilution of the reference laboratory in quantitating specific IgG, whereas 7 laboratories were within 1 dilution in quantitating IgM. The shelf life of the kit was at least 1 year at 4 degrees C.

Matched MeSH terms: Scrub Typhus/diagnosis*
Rickettsia tsutsugamushi antibody in mother/cord pairs of sera

Shirai A, Brown GW, Gan E, Huxsoll DL, Groves MG

Jpn. J. Med. Sci. Biol., 1981 Feb;34(1):37-9.
PMID: 6790744
Matched MeSH terms: Scrub Typhus/epidemiology
Epitope mapping of the Sta58 major outer membrane protein of Rickettsia tsutsugamushi

Lachumanan R, Devi S, Cheong YM, Rodda SJ, Pang T

Infect Immun, 1993 Oct;61(10):4527-31.
PMID: 7691753

Binding studies of 160 overlapping, synthetic octapeptides from the hydrophilic regions of the Sta58 major outer membrane protein of Rickettsia tsutsugamushi with sera from patients with scrub typhus revealed 15 immunodominant peptides which are recognized by all the sera tested. Further analysis of the specificity of peptide binding with five of these peptides indicated that the peptides showed significantly stronger binding to scrub typhus patients' sera than they did to sera from patients with other febrile illnesses common in the region, i.e., malaria, dengue fever, typhoid fever, and leptospirosis. The main antibody class binding to these peptides appears to be immunoglobulin M, and there appears to be little correlation between reactivity with peptides and antibody titers measured by the indirect immunoperoxidase test.

Matched MeSH terms: Scrub Typhus/immunology*
Fulltext Antibiotics for treating scrub typhus

El Sayed I, Liu Q, Wee I, Hine P

Cochrane Database Syst Rev, 2018 09 24;9:CD002150.
PMID: 30246875 DOI: 10.1002/14651858.CD002150.pub2

BACKGROUND: Scrub typhus, an important cause of acute fever in Asia, is caused by Orientia tsutsugamushi, an obligate intracellular bacterium. Antibiotics currently used to treat scrub typhus include tetracyclines, chloramphenicol, macrolides, and rifampicin.
OBJECTIVES: To assess and compare the effects of different antibiotic regimens for treatment of scrub typhus.
SEARCH METHODS: We searched the following databases up to 8 January 2018: the Cochrane Infectious Diseases Group specialized trials register; CENTRAL, in the Cochrane Library (2018, Issue 1); MEDLINE; Embase; LILACS; and the metaRegister of Controlled Trials (mRCT). We checked references and contacted study authors for additional data. We applied no language or date restrictions.
SELECTION CRITERIA: Randomized controlled trials (RCTs) or quasi-RCTs comparing antibiotic regimens in people with the diagnosis of scrub typhus based on clinical symptoms and compatible laboratory tests (excluding the Weil-Felix test).
DATA COLLECTION AND ANALYSIS: For this update, two review authors re-extracted all data and assessed the certainty of evidence. We meta-analysed data to calculate risk ratios (RRs) for dichotomous outcomes when appropriate, and elsewhere tabulated data to facilitate narrative analysis.
MAIN RESULTS: We included six RCTs and one quasi-RCT with 548 participants; they took place in the Asia-Pacific region: Korea (three trials), Malaysia (one trial), and Thailand (three trials). Only one trial included children younger than 15 years (N = 57). We judged five trials to be at high risk of performance and detection bias owing to inadequate blinding. Trials were heterogenous in terms of dosing of interventions and outcome measures. Across trials, treatment failure rates were low.Two trials compared doxycycline to tetracycline. For treatment failure, the difference between doxycycline and tetracycline is uncertain (very low-certainty evidence). Doxycycline compared to tetracycline may make little or no difference in resolution of fever within 48 hours (risk ratio (RR) 1.14, 95% confidence interval (CI) 0.90 to 1.44, 55 participants; one trial; low-certainty evidence) and in time to defervescence (116 participants; one trial; low-certainty evidence). We were unable to extract data for other outcomes.Three trials compared doxycycline versus macrolides. For most outcomes, including treatment failure, resolution of fever within 48 hours, time to defervescence, and serious adverse events, we are uncertain whether study results show a difference between doxycycline and macrolides (very low-certainty evidence). Macrolides compared to doxycycline may make little or no difference in the proportion of patients with resolution of fever within five days (RR 1.05, 95% CI 0.99 to 1.10; 185 participants; two trials; low-certainty evidence). Another trial compared azithromycin versus doxycycline or chloramphenicol in children, but we were not able to disaggregate date for the doxycycline/chloramphenicol group.One trial compared doxycycline versus rifampicin. For all outcomes, we are uncertain whether study results show a difference between doxycycline and rifampicin (very low-certainty evidence). Of note, this trial deviated from the protocol after three out of eight patients who had received doxycycline and rifampicin combination therapy experienced treatment failure.Across trials, mild gastrointestinal side effects appeared to be more common with doxycycline than with comparator drugs.
AUTHORS' CONCLUSIONS: Tetracycline, doxycycline, azithromycin, and rifampicin are effective treatment options for scrub typhus and have resulted in few treatment failures. Chloramphenicol also remains a treatment option, but we could not include this among direct comparisons in this review.Most available evidence is of low or very low certainty. For specific outcomes, some low-certainty evidence suggests there may be little or no difference between tetracycline, doxycycline, and azithromycin as treatment options. Given very low-certainty evidence for rifampicin and the risk of inducing resistance in undiagnosed tuberculosis, clinicians should not regard this as a first-line treatment option. Clinicians could consider rifampicin as a second-line treatment option after exclusion of active tuberculosis.Further research should consist of additional adequately powered trials of doxycycline versus azithromycin or other macrolides, trials of other candidate antibiotics including rifampicin, and trials of treatments for severe scrub typhus. Researchers should standardize diagnostic techniques and reporting of clinical outcomes to allow robust comparisons.

Matched MeSH terms: Scrub Typhus/drug therapy*