· web viewstrains). a ≥ 4-fold increase in titre or a single high antibody titre ≥640 to...

Appendix 6. Data extraction forms

Table 1. Scrub typhus studies

Source (first author, year of publication, journal)

Quality Country, region (study site), Time-frame

Type of Rickettsiosis (MSF / ATBF / ST)

Study design: original and after inclusion in review

Study objective

Methods of selectionClinical judgement / Complete approach

Laboratory methods used and cut-off values

Number of included patients

Eschar rates

Other findings relevant for this review (e.g., demographics)

Notes by reviewer

BangladeshMiah MT et al., 20071

Mymensingh Med J 2007 Jan; 16(1); 85-88

4/7Unclear / Medium risk of bias? / +

Bangladesh, Mymensingh, Mymensingh Medical College

2003 - 2005

ST Prospective cohort study

Case series

To describe the distribution and outcome of Rickettsial fever admitted in MMCG, Mymensingh.

Clinical / UnclearPatients were suspected as rickettsial cases, who initially presented with fever with rash & those diagnosed as typhoid or malaria initially and treated with ciprofloxacin/anti-malarials respectively but did not respond. Cases were diagnosed by clinical suspicion., Exclusions of other common febrile illness like typhoid, UTI, malaria, kala-azar, TB and by positive Weil-Felix test.

Weil-Felix test (details NR) 19 0% All above 12y, male > femaleBut demographics NR for ST subgroup.

ChinaHe et al.20142

Zhonghua er ke za zhi. = Chinese journal of pediatrics. 52 (9) (pp 683-687), 2014

1/7Unclear / High risk of bias? / -

China, Wenzhou, Wenzhou Medical College, Yu Ying Children’s Hospital

June 2007 – July 2013

ST Retrospective case series

To analyse the clinical manifestations and intervention against fulminant scrub typhus-associated hemophagocytic syndrome.

Clinical / unclearMedical records of scrub typhus patients were reviewed for onset time of the hemophagocytic syndrome, clinical course, chest radiographic findings, laboratory data, antibiotic therapy, clinical outcome and prognosis.

IFA (details NR)4 patients clinical diagnosis alone.

19 12/19 = 63.2%

Male 9 (47.4%), female 10

Children, age NR.

7 patients had an ulcer (possible eschar?)

Hu et al. 20153

3/7 Unclear /

China, south-central Jiangsu

ST Outbreak investigation

In light of the outbreak of scrub typhus in

ClinicalCoincidence of three or more ofthe following items constituted a

Confirmed cases were clinical cases with a positive result (OD>0.5) in immunoglobulinM

187 165/187 = 88.2%

Not reported for this group (n=187 laboratory confirmed cases)

PLoS ONE 10(5): e0125999. doi:10.1371/journal.pone.0125999

Medium risk of bias? / +

Province, Jingjiang City

October 18, 2013 – December 11, 2013

Case series

2013,we launched an investigation on scrub typhus in Jingjiang City, in order to describe its epidemiological and clinical characteristics, identify risk factors and provide a basis for taking scientific countermeasures

clinical case of scrub typhus:(1) a field exposure history 1–3 weeks before illness onset;(2) symptoms including high fever, lymphadenopathy, skin rash, splenomegaly, hepatomegaly, or multiorgan dysfunction;(3) typical cutaneous leisions (eschars or ulcers);(4) rapid defervescence with appropriate antibiotics; and(5) Weil-Felix OX-K agglutination titre 1:160.Confirmed cases were clinical cases with a positive result (OD>0.5) in immunoglobulinM (IgM) or immunoglobulinG (IgG) by enzyme linked immunosorbent assay (ELISA) or nested polymerase chain reaction (PCR) test targeting a 56-kDa gene of O. tsutsugamushi

(IgM) or immunoglobulinG (IgG) by enzyme linked immunosorbent assay (ELISA) or nested polymerase chain reaction (PCR) test targeting a 56-kDa gene of O. tsutsugamushi

Lee, Ip et al. 20084

Am. J. Trop. Med. Hyg., 78(6), 2008, pp. 973–978

4/7Medium risk of bias+

Hong Kong, two major acute general hospitals

1995 - 2005

ST Retrospective analysis Case series

To examine risk factors for life-threatening rickettsial infections

ClinicalCases were identified through the hospitals’ computerized clinical management system (searching ICD-9 codes for rickettsioses, spotted fevers,and typhus), and the laboratory information system of the microbiology laboratories. Cases were included foranalysis if the diagnosis was confirmed by immunofluorescence assay (IFA), or if supportive serologic findings were available. In the latter situation, cases should also include a febrile illness characterized by eschar (tache noir) formation and/or skin rash, and with no alternative diagnosis. Sevencases were excluded because of no serologic support.

Paired acute-phase and convalescent-phase serum samples collected two weeks apart (median = 13 days, interquartile range [IQR] = 9–15 days) were tested using the Weil-Felix test and an IFA for specific IgM and IgG antibodies against rickettsial antigens. The tests included antigens from species in the three major biogroups (spotted fever group = R. Australis, R. honei, and R.conorii; typhus group=R. prowazekii and R. typhi; scrub typhus group = O. tsutsugamushi strains). A ≥ 4-fold increase in titre or a single high antibody titre ≥640 to either of the spotted fever group, typhus group, or scrub typhus antigens, or a positive IgM result for scrub typhus antigens were considered indicative of current rickettsial infection. A reactive/positive IFA result that

34

(37.0% of 92 cases of rickettsial infection)

61.8%(21 cases)

Demographics NR for ST group

“Patients with scrub typhus were less likely to develop a rash (38.2% versus 81.4%; P < 0.001), but more likely to have an eschar (61.8% versus 40.5%; P = 0.065)”

did not satisfy these criteria, e.g., titre ≥320, and/or 4-fold increase in titre by the Weil-Felix test, were regarded assupportive evidence for current rickettsial infection.

Liang et al.20145

Clin Lab.2014;60(1):63-8.

2/7High risk of bias -

China, Guandong province, 3 hospitals: Afifiliated Hospital of Jinan University, People’s Hospital of Yuebei, People’s Hospital of Guangzhou

January 1999 – December 2010

ST Retrospective case-control study

Case series

To investigatethe incidence of abnormal liver function in scrub typhus and the significance of hepatic impairmenton the outcome of patients with scrub typhus.

ClinicalWe retrospectively reviewed a total of 143 cases with scrub typhus. The diagnosis of scrub typhus was confirmed with three and/or more of the following conditions. Firstly, history of outdoor activities in vegetated areas. Secondly, acute-onset fever and eschar or ulcer. Thirdly, enlarged lymph node, maculopapular skin rashes. Fourthly, a positive Weil-Felix test (an OXK titre ≥ 1:160, a four-fold or a greater rise in titre).The patients with chronic liver disease, chronic renal failure and/or dysfunction, chronic heart disease, hematologicdisorders, and inflammatory bowel disease were excluded.

The Weil-Felix test was considered positive with an OXK titre ≥ 1:160, a four-fold or a greater rise in titre.

143 Total:98/143 = 68.5%

F: 72, M: 71 (49.7%)Median age = 48y (range 18 – 77)

Liu et al.20096

BMC Infectious Diseases. 2009;9:82


China, Shandong province, Feixian county, five hospitals (Fangcheng,Wanggou, Huyang, Xinqiao, and Shangye)

1995 - 2006

ST Case series

Case series

“In this study, we summarize the clinical characteristics ofhuman infections by autumn-winter type scrub typhus in Feixian county, south of Shandong province, northernChina.”

Clinical“Between 1995 and 2006, patients who were admitted to the five townships hospitals, had acute undifferentiated fever and clinical manifestations indicative of scrub typhus were enrolled in the study as suspected cases. The clinical manifestation included acute fever, eschars, local lymphadenopathy, and maculopapular rashes on the trunk and proximal limbs.”

“Acute and convalescent blood samples and eschars from suspected cases were collected for subsequent IFA and PCR analyses. For each suspected case, the serum was assayed by IFA for detecting the IgM and IgG antibodies against pooled Karp, Kato, and Gilliam strains of O. tsutsugamushi antigens. A confirmedscrub typhus case was defined as (1) IgG titre ≥ 4-fold increase in paired serum specimens; and (2) IgM titre ≥1:80 or IgG titre ≥ 1:400 in a single serum sample. PCR method became available in 2001 and was usedfor detection and genotyping of O. tsutsugamushi connected with RFLP and nucleotide

480 425/480 = 88.5%

F: 211, M: 269 (56.0%)(range 1 – 81 yo)

“Of 480 confirmed scrub typhus cases, 88.5% (425/480) exhibited one eschar, of which 89.2% (240/269) was found in male while 87.7% (185/211) was observed in female patients. None of confirmed cases showed two or more eschars.”

https://www.ncbi.nlm.nih.gov/pubmed/24600976

sequences analyses since then.”Wei et al.20147

Parasites & vectors. 2014;7:513


China, 24-86y)

1 May 2012 – 20 June 2012

ST Retrospective case – control study

Case series

To identify source and risk factors of an outbreak of scrub typhus in Xiaogang Park.

ClinicalA case was defined as any scrub typhus patient reported between 1 May and 20 June in Haizhu district. The diagnostic criteria for scrub typhus were based on a guidebook published by the Chinese Center for Disease Control and Prevention (China CDC). Patients with two of the following were defined as clinically diagnosed cases: (i) field exposure history 1–3 weeks prior to onset of symptoms, (ii) sudden high fever accompanied by characteristic eschar or ulcer, (iii) enlarged lymph nodes, skin rash, splenomegaly, or hepatomegaly.

“ The confirmed scrub typhus case was defined as: agglutination titre >1:160 in the Weil– Felix test using the OX-K strain of Proteus mirabilis , or a positive 56-kD nested polymerase chain reaction (NPCR) test. For the NPCR test, DNA was extracted from blood clots using a blood DNA extraction kit (Invitrogen, China). The Orientia tsutsugamushi 56-kDa protein gene was amplified by nested PCR.”

29 28/29=96.6%

F: 15, M: 14 (48.3%)Median age = 58 yo (range 24-86)

Mortality rate: 4/29 (all > 70 yo)

Zhao, Wang et al. 20168

Int J Antim Ag 48 (2016) 317-320

2/7High risk of bias-

China, Jiangsu Province, Nantong, Affiliated Hospital of Nantong University

August 2013 - January 2016

ST Retrospective analysis

Case series

To compare the efficacy ofazithromycin with that of minocycline, an analogue of doxycycline,for the treatment of mild scrub typhus.

Clinical / UnclearThis study was performed retrospectively from data collected atthe Affiliated Hospital of Nantong University, a 2016-bed tertiarycare university hospital located in Jiangsu Province, northern China.Clinical examination was performed by four authors (MZ, TW, XY and YS).Patients with organ failure were excluded from the analysis. Organ failure was assessed using the Sepsis-related Organ Failure Assessment (SOFA) score. Patients were randomly assigned to treatment with oral minocycline (Wyeth Pharmaceuticals Inc., Suzhou, Jiangsu,China; 200 mg initially, followed by 100 mg every 12 h for 7 days) or intravenous (i.v.) azithromycin (Shenyang No. 1 Pharmaceutical Inc., Shenyang, Liaoning, China; 500 mg once daily for 5 days). Intravenous azithromycin was chosen because oral azithromycin isnot available in the Affiliated Hospital of Nantong University.

Diagnosis of scrub typhus was confirmed by immunoglobulinM(IgM) enzyme-linked immunosorbent assay (ELISA) using a recombinant 56-kDa protein to detect specific IgM produced in scrub typhus infections. The assay was performed on serum samples using a Scrub Typhus Detect IgM ELISA Kit (InBios Inc., Seattle,WA) as per the manufacturer’s instructions. An optical density (OD) above the mean OD plus three times the standard deviation of healthy donor serum was considered positive.

74

Minocycline group: n = 40

Azithromycin group: n = 34

74/74 = 100.0%

Male: 39/74 = 53.7%Age NR for overall group (median age 67 (17-80) for Minocycline group, and 71y (19-86) for Azithromycin group

Minocycline group (n = 40):Sex: female: 20, male: 20

Azithromycin group (n = 34):Sex: female: 15, male: 19

All patientsin this study were hospitalised and treatment compliance was supervised by nurses. Oral temperature was monitored every 2 h. Patients were discharged when defervescence had been achievedand maintained for ≥48 h. Patients were contacted by telephone 1 month after discharge to check for symptoms of relapse.

Zhang et al.20079

The Southeast Asian journal of tropical medicine and public health. 2007;38(3):482-486


China, Henan Province, Huaibin County, Xinyang city, Dadong Village

September 26, 2005 – November 10, 2005

ST Case series (outbreak investigat§ion)

Case series

To obtain knowledge of the genetic characteristics and types of the epidemic strains of Orientia tsutsugamushi in the first outbreak of scrub typhus in Henan Province.

Complete / Unclear“Thirty-two patients with scrub typhus in the outbreak in Dadong Village, Huaibin County, Xinyang City, Henan Province from September 26-November 10, 2005 were recruited.”“As scrub typhus was not suspected in the early phase of the outbreak, eschar was only found in 2 patients through inquiry of disease history. Patients were not sensitive to treatment with penicillin or ampicillin, and improved with cefoperazone, reduction of fever and detoxification, and through symptomatic management. Most patients were observed for 10-14 days. Some patients were discharged from the hospital before laboratory tests could be conducted for scrub typhus, and only 5 patients provided samples for Weil-Felix test for O. tsutsugamushi. In the second blood collection, 19 whole blood samples were obtained, including 15 patients in recovery phase (10-40 days) and 4 patients in acute phase (1-7 days).

1. Serological Weil-Felix reaction was conducted according to the conventional method, using diagnosing reagents purchased from Shanghai Institute for Biological Products, OX2, OX19, and OXK. Results of ≥1:160 were consideredpositive.2. Indirect immunofluorescent test(IFA) was conducted according to the method of Philip et al (1976), and antigen-glass slides of Gilliam, Karp, and Kato strains of O. tsutsugamushi were provided by WHO Cooperation Center of Rickettsiae (Mediterranean University, Marseille, France). Fluorescence-labeled anti-human antibodies (IgM and IgG) were purchased from Sigma. The results were considered positive when a titre of ≥1:80 was obtained.3. DNA was extracted from coagulatedblood by using a kit purchased from Qiagen (Qiagen, Hilden, Germany). Genus-specific and type-specific primers of O. tsutsugamushi 56 kDa envelope protein gene were those of Liu et al (2004).

32 2/32= 6.3%

F: 21, M: 11(34.4%)Mean age = 36.3y (range 3 – 75y)

Zhang et 3/7 China, ST Surveillance “To identify Clinical “Confirmed cases were clinical 102 88/102 Demographics NR.

al.201210

Am J Trop Med Hyg. 2012;87(6):1099-1104

Medium risk of bias+

Shandong Province, five districts (Gangcheng, Laicheng, Xintai, Yinan, and Yiyuan)from the inland and four districts (Jimo, Jiaonan, Donggang,and Wendeng) from coastal areas

2006 - 2011

report & retrospective case series

Case series

changes in epidemiology and clinical profile, clarify current diagnostic issues of scrub typhus, arouse clinical awareness, and facilitate its diagnosis and prevention.”

Surveillance data, including demographic information and onset place and date of reported cases of scrub typhus from 2006 to 2011, were obtained through SDRIS to describe the epidemiological characteristics of scrub typhus. Coexistence of more than or equal to three of the following items can be used to diagnose a clinical case of scrub typhus:(1) a field exposure history 1–3 weeks before onset;(2) symptoms including high fever, lymphadenopathy, skin rash, splenomegaly, hepatomegaly, or multiorgan dysfunction;(3) typical cutaneous leisions (eschars or ulcers);(4) rapid defervescence with appropriate antibiotics; and(5) Weil–Felix OX-K agglutination titre 1:80.

cases with a positive result in immunoglobulinM (IgM) or IgG using a rapid immunochromatographic immunoassay or nested polymerase chain reaction (PCR) test targeting 56-kDa gene of O. tsutsugamushi.”

= 86.3%

Zhang et al.201411

IJID 2014;29:203-207


China, Shandong Province

January 1, 2010 – December 31, 2013


Case series

To identify risk factors associated with severe scrub typhus, in order to provide a reference for clinical decision-making.

Clinical“Patients with clinically suspected scrub typhus presenting to hospitals were identified. Patients who had three or more of the following items could be diagnosed as a case of scrub typhus: (1) a history of field exposure 1–3 weeks before symptom onset,(2) symptoms including high fever, lymphadenopathy, skin rash, splenomegaly, hepatomegaly, or multiorgan dysfunction,(3) typical cutaneous lesions, such as eschars or ulcers,(4) rapid defervescence with appropriate antibiotics, and(5) Weil–Felix OX-K agglutination titre ≥1:80. Patients were confirmed by nested PCR test targeting the 56-kDa gene of O. tsutsugamushi or by rapid

1. Weil–Felix OX-K agglutination titre ≥1:80.2. Patients were confirmed by nested PCR test targeting the 56-kDa gene of O. tsutsugamushi or by rapid immunochromatographic immunoassay with a positive result for IgM or IgG.

240 Total:194/240 = 80.8%

37/46 = 80.4%

157/194 = 80.9%

TotalF: 115, M:125 (52.1%)Mean age = 54.1y46 x 57.3 = 2635.8194 x 53.4 = 10359.62635.8 + 10359.6 = 12995.412995.4 / 240 = 54.1 yo

Severe scrub typhus (n = 46):F: 25, M: 21Mean age = 57.3y 17.7y

Non-severe scrub typhus (n = 194):F: 90, M: 104Mean age = 53.4 19.1 y

immunochromatographic immunoassay with a positive result for IgM or IgG.14 Scrub typhus patients with one or more of the following manifestations were defined as severe scrub typhus cases: bronchopneumonia, meningoencephalitis, toxic hepatitis, acute nephritis or renal failure, acute gastritis, gastrointestinal bleeding, myocarditis, shock, and death. Controls in this study were scrub typhus patients without the severe complications listed above..

IndiaAbhilash et al. 201612

J Global Infect Dis [serial online]. 2016;8(4):147-54.

6/7Low risk of bias++

India, Tamil Nadu, Vellore, Christian Medical College

October 2012 – September 2013


Case series

To determine the prevalence and epidemiology of the causative pathogens of acute undifferentiated febrile illness to develop protocols for empiric antibiotics.

Complete“This prospective observational study was conducted in a tertiary hospital in South India. All adult patients presenting with acute undifferentiated febrile illness of 3-14 days duration were evaluated for etiology, and the differences in presentation and outcome were analysed.”“Diagnostic criteria for scrub typhus include eschar + scrub IgM ELISA positive or scrub IgM ELISA positive with other serological and blood culture negative or scrub typhus IgM ELISA seroconversion on convalescent sera.”

A serological test for scrub typhus (IgM ELISA) was done on or after the 7th day of fever if tests for malarial parasites and blood cultures were negative. Convalescent serological testing after 2 – 4 weeks was performed if the initial serological diagnosis was unclear and if the patient was willing. A 4-fold increase in titre from acute to convalescent sample, or a result change going from negative to positive, was considered indicative of seroconversion.

452 262/452 = 57.9%

452 x 0.579 = 262 patients with an eschar

F: 266, M: 186 (41.2%)Mean age = 42.7y 15.1

Agarwal et al. 201413

Asian Pac J Trop Dis 2014; 4(Suppl 2): S666-S673


India, Telangana, Hyderabad, Yashoda hospital


ST Case series

Case series

To document the clinical and laboratory findings of scrub typhus infection and to determine the prognostic factors of the disease.

Clinical“Patients diagnosed with scrub typhus and admitted in Department of Medicine, Yashoda Hospital Malakpet, Hyderabad, were included in this study. Yashoda Hospital is a referral center in South India, the states of Andhra Pradesh and Telangana. Scrub typhus was diagnosed based on the modified definition given by the World Health Organization. We collected the data retrospectively.”

Weil-Felix test was performed in all patients, and immune-chromatographic test (ICT) was performed in 85 (88.5%) patients.

96 20/96 = 20.8%

M: 47 (49.0%)Median age = 39 y (15 – 70y)

Anitharaj et al. 201614

J Clin Diagn Res 2016 Nov, Vol-10(11): DC07-DC10


India, Tamil Nadu, Puducherry, Mahatma Gandhi Medical College and Research Institute

November 2015 – June 2016

ST Prospective case series

Case series

To evaluate the performance of InBios Scrub Typhus Detect IgM Rapid Test against ImmuneMed Scrub typhus Rapid and the nonspecific but routinely used Weil-Felix test.

CompleteConsecutive patients with: 1) high grade fever with or without chills and rigour; 2) fever with rash, eschar, hepatosplenomegaly, jaundice, lymphadenopathy, or thrombocytopenia; 3) fever with constitutional symptoms like malaise, myalgia, nausea, vomiting; 4) fever with capillary leak syndrome; or 5) fever with bleeding diathesis/fever with shock, were prospectively enrolled.“In our hospital, ST is routinely screened by ST Rapid ICT test followed by other serological tests for Fever of Unknown Origin (FUO) patients.”

“In our present study, ST serology included the following tests:1. ST Detect IgM ELISA (InBios International, Seattle, U.S.A) (Conventional ELISA) Cut-off value = Average of the Normal Human Sera (NHS) + three times SD of NHS. The samples with OD values above the Cut-off (0.560) were considered positive and those below the Cut-off were taken as negative. Borderline samples were tested in triplicate.2. ST Detect IgM Rapid Test (InBios International, Seattle, U.S.A); (yes/no test)3. ImmuneMed ST Rapid kit (ImmuneMed, Chuncheon, Gangwon-do, South Korea);4. WF Test – Proteus OXK (Plasmatec, South El Monte, California, USA). A single OXK titre of ≥ 1:320 was considered as suggestive of ST.”

140 34/140=24.3%

Children (0-14 y): n = 61Adults ( 15 y): n = 79

Mean/median age NR

Attur et al. 201315

Clin Exp Nephrol (2013) 17:725–729


India, Karnataka, Udupid District

Jan 2009 – Dec 2010


“We studiedthe incidence, urinary abnormalities, course, severity and the predictors of AKI in patients with scrub typhus.”

CompleteThe case records of consecutive patients with scrub typhus admitted to a tertiary care hospital in South India from January 2009 to December 2010 were studied prospectively. Scrub typhus was confirmed in patients with acute febrile illness by (see next box). Demographic, clinical and laboratory variables were recorded in all patients. All patients had a detailed clinical history and examination, a standard set of investigations including complete blood counts, liver function tests, serum creatinine, urea, electrolytes, creatinine phosphokinase (CPK), chest radiograph, peripheral blood smears for malaria, urinalysis and a standard set of serological investigations for leptospirosis,

Scrub typhus was confirmed in patients with acute febrile illness by either a positive IgM ELISA for scrub typhus (InBios International Inc., Seattle, WA, USA; OD value[1.0) or a positive Weil-Felix test. The Weil-Felix Proteus agglutination assay (Proteus Vulgaris, OX-19, OX-2, OX-K strain agglutination; Wellcome, Dartford, UK) was performed in dilutions 1:20 to 1:1280. A single Weil Felix titre of C1:160 or a four-fold rise in titre from 1:40 was considered positive for scrub typhus.

259 51/259=19.7%

Male: 139 (53.7%) (median age 38)Female 120 (median age 40)Overall median age = 39 y

The mean duration of hospital stay was 9 days. Out of 259patients 2 patients died and both were in the failure categoryof AKI. Urinary abnormalities were present in 151 patients (58.3 %)

dengue and scrub typhus. Patients with concomitant infections like leptospirosis, malaria, and dengue in addition to scrub typhus were excluded from the study.

Bhat N.K. et al. 201416

J Ped Inf Dis 9 (2014) 93–99


India, Uttarakhand, Dehadrun, Himalayan Institute of Medical Sciences

Jan 2013 – Dec 2013

ST Prospective observational study

Case series

To determine the profile of children presenting with scrub typhus at our institution and whether it is different from that reported previously.

ClinicalScrub typhus was suspected in all children up to 18 years of age who presented with a fever for more than 5 days without an identifiable infection and one or more of the following clinical features: rash, edema, hepatosplenomegaly, lymphadenopathy and an eschar.

Provisional serological diagnosis was made by a rapid immuno-chromatographic assay (SD Bioline Tsutsugamushi test from Standard Diagnostics, Inc. Hagal-dong, Kyonggi-do, Korea)and confirmed by IgM ELISA test (Scrub typhus detectTMIgM ELISA system from In BiOS International, Inc. Seattle USA). For IgM ELISA test local cut-off values were calculated using 30 normal human sera. The samples were tested in duplicate and those with borderline OD values were tested in triplicate.

62 14/62 = 22.6%

Male 42 (67.7%), female 20 (32.3%)

Mean age 8.6y (1.5 months – 18y)

Bhat et al.201417

Iranian Journal of Pediatrics, Volume 24 (Number 4), August 2014, Pages: 387-392


India, Uttarakhand, Dehradun, Himalayan Institute of Medical Sciences



Case series

“We conducted a prospective observational study at a teaching hospital in north India, to study the clinical features and therapeutic outcomes of pediatric scrub typhus. The research objective was to determine the profile of children presenting with scrub typhus at our institution and whether it is different from that reported previously.”

Clinical“Scrub typhus was suspected in all children up to 18 years of age who had a fever for more than 5 days without an identifiable infection and one or more of the following clinical features: rash, edema, hepatosplenomegaly, lymphadenopathy and an eschar. Common infectious conditions that could clinically mimic scrub typhus were ruled out by performing the following tests: peripheral smear and rapid antigen test for malaria, Widal test, Dengue (NS1 antigen and IgM antibody) test, urine and blood cultures. Tuberculin test, leptospira serology and an HIV-ELISA were performed when clinically indicated. Cardiac evaluation and cerebrospinal fluid (CSF) analysis was performed for selected cases with suspected myocarditis or meningoencephalitis respectively. A favorable clinical response to

“Serological diagnosis was made by a rapid immunochromatographic assay (SD Bioline Tsutsugamushi test from Standard Diagnostics, Inc. Hagal-dong, Kyonggi-do, Korea) and/or IgM ELISA test (Scrub typhus detect TM IgM ELISA system from In BiOS International, Inc. SeattleUSA).”

66 13/66 = 19.7%

F: 27, M: 39 (59.1%)

Mean age = 8.8y (range 8 months – 18 years)

antibiotics (defervescence within 48 h) was considered additional evidence of the disease”.

Das et al.201518

BJMMR, 10(10): 1-10, 2015; Article no.BJMMR.19822


India, Sikkim, Sikkim Manipal Institute of Medical Sciences

May 2013 – October 2013

ST Cross-sectional survey

Case series

“This study was conducted to determine various infectious etiologies of acute febrile illness with their clinical presentations, complications, and mortality with special emphasis to scrub typhus.”

Clinical / unclear:This study included a total of 205 patients admitted with acute febrile illness. Acute febrile illness was defined as at least 2 consecutive days of fever ≥ 38°C. Clinically suspected cases of scrub typhus were confirmed by IgM antibody against O. tsutsugamushi in their serum. Presence of eschar was considered as a characteristic finding in case of scrub typhus.Consecutive febrile episodes separated by a symptom free (i.e fever free) interval of more than 14 days wereregarded as separate episode and not included in this study. Patients presented with fever but later diagnosed as confirmed cases of tuberculosis were not included in this study. Detailed clinical examination including a careful search for eschar was done in all patients. Basic laboratory tests were done in all cases. Additional investigations were performed to establish the cause of fever.

IgM antibody for Scrub typhus was detected by Scrub typhus DetectTM IgM ELISA System (InBios International, Inc) according to manufacturer's instructions. An optical density (7OD) >0.5 was considered positive.

74(out of 205 febrile patients)

44/74 = 59.5%

F: 32, M: 42 (56.8%)

Mean/median age NR

Dass et al. 201119

Indian J Pediatr (November 2011) 78(11):1365- 1370


India, Northeast, Meghalaya, Shillong(North EasternIndira Gandhi Regional Institute of Health and MedicalScience)

October 2009 – January 2010


Case series

To identify and report a recent outbreak of scrubtyphus cases recorded from October 2009 to January 2010in the state of Meghalaya, India.

ClinicalChildren showing a significant clinical history and/or eschar and a positive Weil Felix test (with titre >1:160) during that period were included for the purpose of the study(A total number of 31 children admitted during the period and diagnosed as either ‘scrub typhus’ or ‘rickettsial fever’, were identified from the discharge summaries and inpatient records. Their charts were retrieved from the medical records department and reviewed thoroughly. All cases had a compatible clinical

Weil Felix test (with titre >1:160)

24 10/24 =41.7%

Male n=13 (54.2%)Female n= 11 (45.8%)The average age of presentation was 9.4 years.

picture but Weil Felix (WF) test was not done in 3 cases and 4 cases shows OXK titre <1:80.)

Devarajan et al. 201520

Infect Dis Clin Pract 2015;23: 89–90


India, Tamil Nadu, Chennai, Apollo Speciality Hospitals

January 2011 – June 2012


Case series

NR Clinical / unclearMedical records of children admitted with scrub typhus were retrospectively reviewed. Cases were defined as patients with a compatible clinical presentation and a positive Dectect TM immunoglobin M (IgM) ELISA.

Detect TM immunoglobulin M (IgM) enzyme-linked immunosorbent assay (In Bios International, Inc)that detects IgM antibodies to O. tsutsugamushi–derived recombinant antigen (56-kDa antigen, PanBio).

12 4/12 = 33.3%

F: 5, M: 7 (58.3%)Mean age = 8.25 y (range 2 – 14)

Farhana et al. 201621

J Clin Diag Res 2016 May, Vol-10(5): DC24-DC26


India, Jammu, Srinagar, Govt Medical College/Hospital

March 1, 2015 – October 31, 2015

ST Cross sectional survey

Case series

“To find out the extent to which scrub typhus contributes to Pyrexia of Unknown Origin (PUO) in patients admitted to or attending the OPD of our tertiary hospital.”

CompleteSamples from patients suffering from PUO were processed for the detection of scrub typhus.Patients who did not conform to the definition of classical PUO, those who were on antibiotics or immunosuppressive and/or immunomodulatory drugs, those with immunodeficiency were excluded from the study.The patients had no history of travel to an area where scrub typhus is endemic.The samples were simultaneously tested for typhoid fever (Widal tube agglutination test) and brucellosis (tube agglutination test).

1. Weil-Felix agglutination assay using OX-K strain (Omega Diagnostics) as per manufacturer’s instructions [11]. The serum samples were diluted 1/20 to 1/640 and a titre of ≥1:160 was taken as positive. Base line titre for Weil-Felix test was ascertained by screening 100 blood samples taken from healthy donors from the blood bank at our hospital. A value of 1:20 was seen in 8, 1:40 in 53 and 1:80 in 39 samples from healthy donors.2. IgM and IgG antibodies by ELISA (In Bios International Inc. USA), performed as per the instructions on the kits.

37

(of 162 samples analysed)

0/37 = 0%

F: 16, M: 21 (56.8%)

Majority of ST patients were in the age group 30 – 49 years (n = 24)

Gurung et al. 201322

Indian J Med Microbiol. 2013;31:72-74.

3/7Unclear/ Medium risk of bias? / +

India, North East Himalaya region, Sikkim

Jan – Dec 2011

ST Prospective cohort study (hospital based)

Case series

To estimate the prevalence of scrub typhus and correlate the demographic profile of the patients.

CompletePatients attending the medicine and paediatric departments during January 2011 to December 2011 diagnosed with PUO were evaluated.

All samples were screened using Weil-Felix agglutination test containing a Proteus vulgaris antigen suspension OX19, OX2, and a Proteus mirabilis antigen suspension OXK (Tulip Diagnostics (P) Ltd. Verna, Goa, India), immunochromatography (ICT) test (Standard Diagnostics Inc., Kyonggi-do, Korea) containing a major surface protein 56-kDa antigen representative of O. tsutsugamushi (Karp, Kato, Gilliam). The ICT test detected IgA, IgM, and IgG. Samples with a titre of >320 or a positive ICT result were considered

63 12/63 = 19.0%

Adults: 2/36 = 5.6%

Children:10/36 = 37.0%

42 males and 21 females; 36 were adults patients (age above 13 years) and 27 were from the pediatric age group, the youngest being 2 years

42/63 = 66.7% males

positive. Positive samples were further confirmed by indirect IgM ELISA (InBios International, Seattle, WA, USA) that used recombinant antigens to detect antibodies.

Jain & Jain201223

J. Nepal Paediatr. Soc. 2012; 32(2):187-92.


India, Uttarakhand, Dehradun, Himalayan Institute of Medical Sciences and Research Hospital

2010 - 2011

ST Case series

Case series

To describe paediatric scrub typhus cases at a teaching hospital

ClinicalWe reviewed 19 paediatric cases with confirmed scrub typhus admitted, (Cases in whom all common causeswere excluded (malaria/typhoid/UTI/Dengue) to ourhospital in 2010-2011. The cases were con rmed by positive serology with an immuno uorescence antibody test (an IgM titer for scrub typhus) or a positive result with polymerase chain reaction (PCR). Epidemiological variables included in the analysis were gender, age, and city of residence. Clinical manifestations were fever, cough, rash, poor appetite, headache, vomiting, drowsiness, neck stiffness, lymphadenopathy, jaundice, eschar, abdominal pain, ascites, hepatomegaly, splenomegaly, and cholecystitis. Laboratory data were CRP, AST, ALT, and albumin levels, and white blood cell count in the blood and cerebrospinal uid. The presence or absence of proteinuria was also documented.

The cases were confirmed by positive serology with an immunofluorescence antibody test (an IgM titre for scrub typhus) or a positive result with polymerase chain reaction (PCR).

19 9/19 = 47.4%

F: 9, M: 10 (52.6%)Age NR.

Jamil et al. 201424

J Ass Physicians India, 63, Dec 2014


India, Northeast, Maghalaya, Shillong

7 Jan 2013 – 6 Jan 2014

ST Hospital based prospective observational study

Case series

To study the different clinical manifestations and complications associated with scrub typhus

CompleteAll patients with acute febrile illness above 18 years were subjected to a battery of investigations as per the institute protocol and also special investigations for particular cases were done according to the institute protocol.

Inclusion: All patients with acute febrile illness above 18 years of

Weil- Felix test (PROGEN, Tulip Diagnostics (P) Ltd.) and lateralflow-format immunochromatographic test (ICT) for the detection of O. tsutsugamushi IgM, IgG and IgA antibodies (SD Bioline Tsutsugamushi, Standard Diagnostic, Inc. Korea)Diagnosis of scrub typhus has been made if patient fall in any of the following three groups:

59 17/59 = 28.8%

Male patients 35(59.3%); female patients 24(40.7%) (include three pregnant women one of whom had spontaneous abortion)Majority of the patients were young belong to age group 18-30 years (42.37%) and 31-40 years (28.81%).

Almost all patient who having eschar had single

age admitted to the department of general medicine from 7th January 2013 to 6th January 2014 with diagnosis of scrub typhus.

Exclusion: Patients diagnosed with an associated infection. Patient having co-morbid condition like chronic renal failure, chronic liver disease, patient with known neoplastic disease etc.

Group A: Acute febrile illness with eschar specific for scrub typhus plus serological test positive for scrub (in Weil-Felix test titre for OXK more or equal to 1:160 or immunochromatographic card test (IgM, IgG and IgA) positive for scrub typhus).Group B : Acute febrile illness + Weil-Felix test titre for OXK more than or equal to 1:320.Group C: Acute febrile illness highly suspicious of scrub typhus plus Weil-Felix test titre for OXK equal to 1:160 or immunochromatographic card test (IgM, IgG and IgA) positive for scrub typhus plus response to doxycycline.

except two (3.39%) whom had multiple eschars, one had multiple eschars at inguinal region and other had eschar at two different site.

Kamarasu et al. 200725

Indian J Med Res 126, August 2007, pp 128-130


India, Tamil Nadu, 32 health centres in 11 districtsof 15 health units


ST Cross-sectional survey

Case series

To evaluate the distribution of spotted fevers and typhus in southern India.

CompleteBlood was collected from patients with fever for more than 10 10 days. Serum samples of patients who were smear negative for malaria were tested by Weil-Felix test for scrub typhus.

Diagnosis was confirmed by Weil-Felix test. Titres of 80 or more were considered as a positive result.

N = 80

2004: 1152005: 89

80 patients with sufficient clinical information

0/80 = 0.0%

NR for group analysed here.

2004:F: 35, M: 80

2005:F: 41, M: 48

Karanth et al. 201426

Asian Pac J Trop Dis 2014; 4(Suppl 2): S674-S678


India, Karnataka, Manipal, Kasturba hospital

May 2012 – April 2013

ST Case-control study

Case series

To identify the risk factors that would predict a severe outcome in scrub typhus so as to facilitate prompt and aggressive therapy.

Clinical“A prospective study of 255 consecutive patients who were admitted with scrub typhus over one year period between May 2012 to April 2013 were included in the study. Patients above 18 years with acute febrile illness with eschar or maculopapular rash or possibility of scrub typhus were included.”

Definitive diagnosis wasobtained by positive ELISA for scrub IgM or using indirect immunofluorescent antibody assay (IFA) IgM titre against O. tsutsugamushi. IFA titres of ≥1:80 or four fold or more rise in titres was considered diagnostic for scrub typhus.

220

Severe: n = 116

Non-severe: n = 104

Total: 64/220 =29.1%

Severe group:22/116 = 19.0%

Non-severe group:42/104 =

Total:F: 76, M: 144 (65.5%)Mean age = 38.0y116 x 39.2 = 4547.2104 x 36.7 = 3816.84547.2 + 3816.8 = 83648364 / 220 = 38.0 yo

Severe group:F: 50, M: 66Mean age = 39.20 15.04 yo

Non-severe group:F: 26, M: 78

40.4% Mean age = 36.70 11.50 yo

Khan et al.201727

Emerg Infect Dis. 2017;23(1):148-50.


India, Assam, Dibrugarh, Assam Medical College

2013 - 2015


Case series

To determine the contribution of Orientia tsutsugamushi, the agent of scrub typhus, as a cause of acute encephalitis syndrome (AES) in India.

CompleteWe conducted a retrospective study of patients exhibiting symptoms of AES. Serum samples of patients with AES were tested for scrub typhus infection.

1. Serum samples underwent serologic testing with InBios ST Detect IgM ELISA kit (InBios International, Seattle, WA, USA). An optical density of >0.5 was considered positive.2. Nested PCR (56-kDa gene of Orientia, targeting a 483-bp fragment)

104 0/104 = 0.0%


53 of 104 patients completed follow-up; 26 (49%) had died.

Krishna et al. 201528

Indian J Pediatr (June 2015) 82(6):537–540


India, Tamil Nadu, Chennai, Kanchi Karmakoti CHILDS Trust Hospital

September 2010 – June 2011


Case series

To document the epidemiological, clinical and laboratory profile of all children with scrub typhus at a tertiary care centre in Chennai.

Clinical / UnclearThe study analysed case records of all patients diagnosed to have scrub typhus between September 2010 and June 2011 at Kanchi Kamakoti CHILDS Trust Hospital, a pediatric tertiary care centre in Chennai.

IgM ELISA to a 56 kDa antigen. Case definitions / cut-off titres NR.

52 35/52 = 67.3%

F: 22, M: 30 (57.7%)Age: range (7 months – 16 years)

The referral diagnosis was not scrub typhus or Rickettsisal infection in any of the cases: 25 were referred as dengue fever. Scrub typhus was in the differential diagnosis at admission in 41 children.

Kumar et al. 201229

J Inf Pub H (2012) 5, 82—88


India, South, Tamil Nadu, Puducherry

Feb 2010 – Feb 2011


Case series

To determine whether the profile of children presenting with scrub typhus at our institution is different from that reported previously.

ClinicalThe study was carried out in children up to age 12 years old who had a fever for more than 5 days without an identifiable infection.Rickettsial disease was suspected in patients who had a fever for more than 5 days without an identifiable infection and one or more of the following clinical features: rash, edema, hepatosplenomegaly, lymphadenopathy, an eschar, and a tick bite or tick exposure.

The Weil-Felix (WF) test was performed for all of the cases. The WF Proteus agglutination assay (P. vulgaris, OX-K strain agglutination) was performed on each sample by diluting the serum 1:20 to 1:1280. A WF titre of 1:80 (OX-K) or more was considered a positive result.All children who were clinically suspected of having rickettsial infection because they had one or more of the above-mentioned features and who tested positive by the Weil-Felix test (OX-K 1:80 or more) were defined as having scrub typhus

35 4/35 = 11.4%

The age of the patients ranged from 1.5 to 12 years with a mean age of 6.3 years. Children between 5 and 10 years of age accounted for 60% of all cases. There were 20 males (57.1%) and 15 females (42.9%).

Kumar et al. 201430

PLoS NTD


India, Punjab, Chandigarh, Nehru Hospital of


Case

To study the pattern of kidney involvement and its impact

CompleteAll patients referred with unexplained fever and/or multisystem involvement were tested for O. tsutsugamushi.

1. A nested PCR (targeting gene encoding for the 56-kDa antigen of Gilliam strain of O. tsutsugamushi) on DNA isolated from buffy coat of blood.

49

(from 201 included)

9/49 = 18.4%

F: 20, M: 29 (males constituted 59.2% of the PCR positive cases: 0.59 x 49 = 29)

8(1): e2605.

Postgraduate Institute of Medical Education and Research

September 2011 – November 2012

series on the outcome in scrub typhus patients who were diagnosed by using a strict NAT based case definition.

All patients also underwent at least three blood cultures for bacterial growth, three peripheral blood film examinations for malarial parasite and malarial antigen detection in blood byimmunochromatographic rapid card test. In addition, dengue virus NS1 antigen, dengue virus IgM antibody and leptospiral IgM antibody were tested in blood samples of all patients.

2, IgM ELISA kit (InBios International, Inc., USA). The test was considered to be positive if the antibody was present at dilution of ≥1:100 as defined by the manufacturer.A confirmed case of scrub typhus was defined as the one with positive nested PCR, with no other evidence of any other infection.

Mean age = 34.1y 14.4y (range, 11 – 65)

Mathai et al.200331

Ann N Y Acad Sci. 2003;990:359-364.


India, Tamil Nadu, Vellore, Christian Medical College Hospital

October 2001 – February 2002

ST Case series

Case series

“From October 2001 to February 2002, several patients presented to our hospital with acute febrile illness associated with diverse signs and symptoms and were found to have positive scrub typhus serology. This manuscript describes our experience with this recent outbreak.”

CompleteAdult patients admitted to Christian Medical College Hospital with acute febrile illness are routinely evaluated for common causes of fever, like leptospirosis, dengue fever, malaria, typhoid fever, urinary tract infection, and pneumonia. During October 2001 to February 2002, approximately 300 patients had fever and other associated features requiring admission to our hospital. Etiological diagnosis was established for about 50% of these patients. Clinical and laboratory data were collected from the case records.In the initial part of the outbreak, serum samples were tested for rickettsial illnesses only after excluding other febrile illnesses.

Sera were tested using the Weil-Felix (WF) test with OX-19, OX-2, and OX-K antigens with a positive cut off of 1:80. Positive and a few negative serum samples were then sent to Unité des Rickettsies Marseille, France, for specific microiimunofluorescence assay (MIF) using whole-cell antigens of O. tsutsugamushi serotypes Karp, Kato, Gilliam, and Kawasaki. Sera were also tested with a large panel of other antigens including Bartonella Henselae, Rickettsia typhi, Francisella tularensis, Coxiella burnetii, R. Felis, R. Japonica, R. Helvetica, R. Conorii, R. Honei, and R. Heilongjangii. Positive cutoff values were greater than or equal to 1:128 for IgG and greater than or equal to 1:64 for IgM.

28 1/28 = 3.6%

Sex ratio NR for whole group analysed.Mean age = 38.9 y (range 16-65)

60% were farmers belonging to low income groups

Misra et al.201532

J Neurol, Neurosurg and Psych. 2015;86(7):761-766.


India, Uttar Pradesh, Lucknow, Sanjay Gandhi Post GraduateInstitute of Medical Sciences

2012 - 2013

ST Cross-sectional study

Case series

To report the neurological manifestations in patients with scrub typhus along with their EEG and MRIfindings.

Complete / unclear“Consecutive patients admitted with febrile illness attributed to scrub typhus in the neurology service were included. Other known causes of febrile illness with systemic manifestations such as dengue, leptospira and chikungunya were ruled out by serum IgM ELISA. On admission, blood cultures, falciparum/vivax card test and Widal test were performed in all patients.”

“Scrub typhus was diagnosed based on the detection of antibodies by a solid phase immunochromatographic assay and/or Weil Felix test.”

37 17/37 = 45.9%

F: 19, M: 18 (48.6%)Median age = 37.7 (range 3-71)

“Patients with an eschar had significantly lower platelet counts (r=0.5; p=0.001) than those without an eschar.”

Narvencar et al. 201233

Indian J Med Res. 2012;136(6):1020-1024.


India, Goa,Goa Medical College

June 2009 – October 2010

ST Propective cohort study

Case series

To assess the aetiological agent of cases with ictero-haemorrhagic fever or fever with hepatorenal syndrome in Goa.

Complete“All consecutive adult patients presenting with febrile illness from June 2009 to October 2010 were evaluated. Other likely diagnoses such as malaria, leptospirosis, dengue fever, viral pharyngitis, enteric fever, urinary tract infection were ruled out by history, clinical examination and appropriate laboratory investigations. The patients were subjected to a battery of investigations such as urine analysis, complete blood count, platelet count, renal function tests and liver function tests, smear for malarial parasite, rapid antigen test for malaria, serology for leptospirosis and dengue haemorrhagic fever, blood widal and culture.”

Patients having were tested using a commercial ELISA kit (InBiOS International Inc. USA).. Patients with IgM antibodies against O.tsutsugamushi in their serum samples were diagnosed as having scrub typhus.

15 2/15 = 13.3%

F: 10, M: 5 (33.3%)Age (range 22 – 65)

Ramyasree et al. 201534

Indian J Med Micr. 2015; 33; 1, p68-72

2/7Unclear/ High risk of bias? / -

India, Andra Pradesh, Tirupati, Sri Venkateswara Institute of Medical Sciences

January 2013 - March 2013

ST Cross-sectional study Case series

To know the seroprevalence of scrub typhus in clinically suspected patients and to compare a rapid test which is simple, and economic test with IgM ELISA for the diagnosis of scrub typhus.

Clinical / unclear“This is a cross-sectional study carried out on serum samples from clinically suspected cases received over a period of 3 months extending from January to March 2013. The samples were processed for the detection of IgM antibodies for the diagnosis of scrub typhus by ELISA and Rapid test. Samples were also tested for dengue fever, typhoid fever and leptospirosis, tuberculosis and malaria.”

Detection IgM antibodies by ELISA- was done using In Bios International TM IgM ELISA.Detection of IgM antibodies by Rapid method was done using SD Bioline Tsutsugamushi, one-step scrub typhus antibody test.

39

(positive by ELISA or RDT)

0% NR (for positive group included here)

Rathi et al 201135

Indian Ped 48; Nov 2011


India, Maharashtra, Akola, Rathi Children’s Hospital and Maternity Home



Case series

To report a series of cases of rickettsialinfections in children / adults < 20y from central India and to develop a clinical scoring system for its early detection.

ClinicalInclusion criteria: Age <20 years; hospitalized with fever without a source; presence of one or more of the following clinical features: rash, edema, hepatospenomegaly, lymphadenopathy, eschar, and tick bite or tick exposure.Exclusion criteria: The cause of fever known at the time of admission; and patients treated on an outpatient basis.

ELISA for scrub typhus IgM antibody(InBios International, Seattle, USA). Weil-Felix test (Tulip DiagnosticsPvt Ltd. Goa, India) was done in 157 cases and a titre of 1:80 or more was considered as a positive test.Positive ELISA for IgM antibody and a titre of 1:64 or more was considered as a

23 5/23 = 21.7%

Male: 19/23 = 82.6%Age (median): 8 (8m-20y)

positive test. The serological tests were performed more than 7 days after the onset of the disease.

Razak et al.201036

Trop Doc 2010;40(3):149-151


India, Karnataka, Manipal, Kasturba Hospital



Case series

To examine the clinical and haematological profiles of patients suffering from rickettsial fever and their outcomes after admission to our hospital.

Clinical / unclear“Medical records of cases with serologic evidence of infection were reviewed and their clinical manifestations, investigations and outcomes were analysed.”

The WF proteus agglutination assay (Proteus vulgaris, OX-19, OX-2, OX-K strain agglutination; Wellcome, Dartford, UK) was performed on each sample according to the manufacturer’s instructions by diluting each serum 1/20 to 1/1280. A single WF titre of 1:160 or rise of fourfold or more in titres on repeat testing, starting from 1:40, wasaccepted as a positive result

29 2/29 = 6.9%

F: 11, M: 18 (62.1%)

Rose et al. 201637

J Trop Ped, 2016, 62, 415-420





Case series

To presentour data on the distribution of eschars in children<15 years with confirmed scrub typhus.

Clinical / Unclear:We retrospectively reviewed the records after institutional review board approval of all children who were admitted with a diagnosis of scrub typhus fromJanuary 2010 to December 2014 in the Pediatric department at the Christian Medical College, Vellore, India.

Diagnosis was based on the detection of IgM in serum to O. tsutsugamushi-derived recombinant antigenperformed using the InBios Scrub Typhus Detect TM IgM ELISA kit or a positive Weil Felix test with an OX K titre >80

431 176/431 = 40.8%

Male 237/431 = 54.9%Female: 194/431 45.0%Mean age 6.6y (0.17 – 15y)

Comparison was made between those with and without eschar with regards to their demographic, clinical and outcome measures (Table 1). The median age of those with an eschar was 5 years comparedwith a median age of 7 years in those without an eschar [OR: 0.90 (0.85–0.94); p< 0.001]. With regards to clinical symptoms, breathing difficulty [OR: 2.92 (1.76–4.86); p< 0.001] and hepatomegaly [2.26 (1.24–4.13); p ¼ 0.007] were more common in those with an eschar, whereas headache [0.48 (0.26–0.88); p ¼ 0.016] and vomiting [OR: 0.54 (0.35–0.81); p ¼ 0.003] were less common in those with an eschar. Those with an eschar were also less wasted [OR: 0.50

(0.32–0.79); p ¼ 0.003].ARDS was more common in those with an eschar [OR: 2.92 (1.69–5.05); p <0.001], whereas meningitis was less common in those with an eschar [OR:0.34 (0.18–0.63); p < 0.001]. There was no difference in mortality between the two groups.

Sahoo et al. 201638

Ind J Crit Care Med 2016 (20); 8


India, Telangana, Hyderabad,Apollo Hospital, Jubilee Hills

June 2013 – December 2014


Case series

To investigate the risk factor, clinical course, and outcomeof scrub typhus patients complicated with ARF.

Complete / Unclear:All consecutive adult patients with a diagnosis of scrub typhus, which was based on the detection of antibodies by a solid phase immunochromatographic assay, were studied.“The diagnostic workup for other acute febrile illness such as dengue, leptospira, Q-fever, malaria, and typhoid were also performed.”

“diagnosis of scrub typhus was based on the detection of antibodies by a solid phase immunochromatographic assay”

55 8/55 = 14.5%

Age 41.36 ±14.38Male: 26/55 = 47.3%

Sarangi et al. 201639

Ped Polska 91;2016; 308-311


India, Odisha, Bhubaneswar, Siksha O Anusandhan University, IMS & SUM Hospital

July – December 2015


Case series

To study the clinical profile, laboratory parameters, complications and efficacy to therapy in scrub typhus

ClinicalChildren under 14 years admitted to pediatric ward with acute undifferentiated febrile illness of more than 5 days without an identifiable cause and with one or more presenting features like lymphadenopathy, organomegaly, headache, edema, rash and eschar were enrolled in the study.

The Weil-Felix test and IgM ELISA were done in all 71 cases. The WF Proteus agglutination assay (Proteus vulgari, OX-K strain) was performed on each sample by diluting serum 1:20 to 1:1280. A titre 1:80 or more was considered as a positive result. Detection of IgM antibody in ELISA (in Bios, international inc.) for O. tsutsugamushi in their serum sample and optical density (OD) more than 0.5 was considered to be positive result for typhus.

26 8/26 = 30.7%

Male: 17/26 = 65.3%Mean age 6.5 (11m-12y)

Sharma et al. 200540

Jap J Inf Dis 2005;58(4):208-210.


India, Himachal Pradesh, Shimla, Indira Gandhi Medical College and Hosptial

ST Case series

Case series

To evaluate the epidemiology and magnitude of scrub typhus infections.

CompleteMore than 100 cases of fever of unknown origin (FUO) were admitted and investigated using all routine diagnostic tests and cultures.

Serum samples were tested using the Weil-Felix test. Patient sera were tested by the tube agglutination method with a doubling method of 1:20 to 1:640, and a titre of 1:80 or a fourfold rise in titre was considered positive.

45 3/45 = 6.7%

Age and sex NR for whole group analysed.

September 2003 – April 2004

Sharma et al. 201441

J Ass Phys India; 62; Dec 2014


India, Rajasthan, Jaipur, SMS Hospital

2012 -2013

ST NR

Case series

To describe the diversity of clinical manifestations, laboratory findings and outcome of scrub typhus in hospitalised patients of SMS Hospital, Jaipur during 2012 and 2013.

CompleteAll patients admitted with acute febrile illness and thrombocytopenia to SMS Hospital, Jaipur were evaluated. Patients were included in the study group whose Scrub typhus IgM serology was positive.Detailed history and clinical examination followed with a meticulous search for presence of Eschar.

“Scrub typhus ELISA IgM serology”Details NR.

125 22/125 = 17.6%

The mean age was 38 years. There were 80 (64.0%) female patients.Male: 45 (36.0%)

Sivarajan et al. 201642

Inf Dis Poverty. 2016;5(1):91.


India, Meghalaya, Shillong

September 2011 – August 2012

ST Longitudinal study (Prospective cohort study)

Case series

“The present study aimed to describe the clinical andparaclinical profile, complications and predictors ofoutcome among 90 cases of scrub typhus in a hospital of north-eastern India from Sept 2011 to Aug 2012.”

CompleteAll consecutive patients, aged 18 years and above, presenting with febrile illness were evaluated. Detailed clinicalexamination, including a careful search for eschar was made in all the patients. All of them were evaluated for other endemic febrile diseases, i.e., malaria, typhoid fever, dengue, leptospirosis, and pneumonia by relevant laboratorytests.

A suspected case of scrub typhus was confirmed by SD Bioline Tsutsugamushi (Standard Diagnostics, Inc., Gyonggi-do, Korea) rapid diagnostic test for IgG, IgM or IgA antibodies and a dramatic response to doxycycline. SD Bioline Tsutsugamushi test is a solidphase immune-chromatographic assay for the rapid, qualitative detection of IgG, IgM or IgA antibodies to Orientia tsutsugamushi in human serum, plasma or whole blood.

90 10/90 = 11.1%

Sex: F: 43 (47.8%), M: 47 (52.2%)Mean age = 36.3 13.4 yo

Subbalaxmi et al. 201443

J Ass Phys India 2014;62(6):490-496


India, Andhra Pradesh, Hyderabad, Nizam’s Institute of Medical Sciences

August 2011 – December 2012


Case series

“We present our experience on clinical and laboratory features of patients with scrub typhus.”

Clinical / unclear“Data of clinical and laboratory features of patients aged more than 12 years, with fever, and confirmed diagnosisof scrub typhus was collected and analysed.”

“Scrub typhus cases confirmed by the Weil Felix test with a titre of 1 in 80 and a positive immunochromatography test were included in the study.The Weil Felix reagents used are Progen OX K WeilFelix reagent (Tulip Diagnostics, India). The other reagents are Progen OX 2 and Progen OX 19. Any sera sample tested positive for agglutination with positive with OX K reagent, was retested by the scrub typhus

176 23/176=13.1%

F: 71, M: 105 (59.7%)Mean age = 41.0 16.0y

immunochromatography test card test. The ICT consists of a filter paper strip coated with the cultured somatic antigens of O. tsutsugamushi (Gilliam, Karp and Kato strains).”

Tilak et al.201144

Indian J Public Health. 2011;55(2):92-99


India, Darjeeling, Kurseong, Kurseong hospital

2005 - 2007

ST Case series (outbreak investigation)

Case series

1) To undertake epidemiological analysis of existing data of the scrub typhus cases, 2) to conduct an entomological survey in an outbreak area to determine the vector speicies, its abundance and distribution,3) to determine Rickettsial activity amongst rodents in the proposed study areas,4) to analyse factors contributing to vector abundance and man-vector contact, and5) to recommend preventive and vector control strategies.

Clinical“Cases were reported especially during rainy season, when many patients were admitted to Kurseong hospital with fever of unknown origin. It was because of the fever associated with eschar that a clinical diagnosis of scrub typhus was considered .”

Blood samples were sent for testing to NCDC, Delhi for confirmation by Weil Felix and / or IgM testing.

120 suspected cases,

61 laboratory confirmed cases

92/120 = 76.7% .

Out of 120 suspected cases:M: 47 (39.2%), F:73Median age = 30y (range 2.4 – 74y)

Usha et al. 201445

Asian J Pharm Clin Res, Vol 7,


India, Andra Pradesh, Tirupati, tertiairy care hospital

April 2011 –

ST NR

Case series

To identify the prevalence of scrub typhus by using serological methods and analyze their

CompleteBlood samples of the patients submitted to Microbiology Department, tertiary care hospital, Tirupati, Andhra Pradesh and reported negative for Typhoid, Malaria, Leptospirosis,

Weil-Felix test. Antigens were prepared in-house following standard protocol. A doubling dilution of 1:20 to 1:320 was used and a titre ≥ 1:80 or fourfold rise in titre was considered positive.

158 3/158 = 1.9%

NR for subgroup

Suppl 1, 2014, 19-21

December 2012

demographic profiles.

Chikungunya and Dengue was used for this study.

Samples were also analyzed by commercially available lateral-flow-format immunochromatographic test (SD Bioline tsutsugamushi assay, Inc., Korea.) and indirect IgM ELISA

Vaz & Gupta, 200646

MJAFI, Vol. 62, No. 4, 2006


India, Kashmir, Jammu

July – October 2002


Case series

Outbreak investigation in local military hospital

CompleteAll cases of fever occurring during July to October 2002 formed the study group. A thorough clinical examination andinvestigation including blood counts, urine analysis, peripheral blood smear exam, chest radiograph, electrocardiogram (ECG) . Widal and Weil Felix tests were carried out in all cases.

Widal and Weil Felix tests werecarried out in all cases. The diagnosis of scrub typhus was based on a single titre of 1:160 or greater of Weil Felix OX-K

12

(of 24 febrile soldiers)

1/12 = 8.3%

Demographics NR(All male?)

Varghese et al. 200647

J Infect 2006; 52(1):56-60.





Case series

To derive a clinical algorithm for diagnosing scrub typhus and to determine predictors of bad prognosis among hospitalized patients with febrile illness.

CompletePatients above the age of 12 years hospitalized with febrile illness of 5–30 days duration were recruited. These patients were evaluated for common febrile illnesses like malaria, typhoid fever, dengue fever, leptospirosis,urinary tract infection, pneumonia and sepsis syndrome by conducting appropriate laboratory investigations.

Sera were tested in batches for IgM and IgG antibodies to O. tsutsugamushi using a commercial ELISA kit (Panbio, Brisbane, Australia). The kit uses a specific 56kDa recombinant antigen of O. tsutsugamushi and has a sensitivity and specificity of above 90%. Weil Felix (WF) test was also performed on the sera using OX-19, OX-2, and OX-K antigens by standard methods, to initiate treatment.

50 4/50 = 8.0%

Sex NR.Median age = 36.5 yo (range 12 – 75)

Varghese et al. 201448

IJID 2014; 23:39-43


India, Vellore, Tamil Nadu, Christian Medical College

2005-2010


Case series

To provide a detailed panel of clinical aspects of this disease based on a large patient population, thus to create a better clinical and laboratory profile of this reemerging disease for clinicians to work with. We also set out to

Clinical“Patients over the age of 16 years admitted with scrub typhus to the Christian Medical College, Vellore, a 2700-bed medical college hospital, between 2005 and 2010, were included in this retrospective study. The diagnosis was confirmed through serum IgM ELISA scrub typhus and/or presence of an eschar with PCR confirmation.”

IgM ELISA was performed on serum samples using the Scrub Typhus Detect test (InBios International, Inc., Seattle, WA, USA) as per the manufacturer’s instructions. An optical density (OD) >0.5 was considered positive.Eschar samples were used for PCR. Bacterial DNA, extracted using a QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) in accordance with the manufacturer’s instructions, was used as the template for the PCR. A standard PCR targeting the 56-kDa protein was carried

623 Total:271/623 = 43.5%

98/212= 46.2%

173/411= 42.1%

Total:F: 323, M: 300 (48.2%)Mean age = 45 15 yo

Multiorgan dysfunction present (n = 212)F: 116, M: 96

Multiorgan dysfunction absent (n = 411)F: 207, M: 204

study the trend in mortality over time.

out as reported previously

Vikrant et al. 201349

Renal failure. 2013;35(10):1338-1343


India, Himachal Pradesh, Shimla, Indira Gandhi Medical College

July 2011 – December 2011


Case series

“To describe the clinical characteristic, laboratoryparameters, complications and outcome of scrub typhusinducedAKI.”

Complete“This study was a retrospective analysis on patients who were hospitalized with acute febrile illness and were diagnosed scrub typhus associated with acute kidney injury (AKI) over a period of 6 months (July-December 2011). All patients were subjected to The Scrub Typhus Detect IgM ELISA test”

“All patients were subjected to The Scrub Typhus Detect IgM ELISA test which is a qualitative ELISA for the detection of IgM antibodies in human serum to O. tsutsugamushi (OT) derived recombinant antigen (In Bios International, Inc., Seattle, WA), and were performed as per the manufacturer’s instructions. The cut off value was calculated using geographically relevant serum samples and a value of > 0.468 was considered positive.”

174 32/174=18.4%

F: 132, M: 42 (24.1%)Mean age = 41.4 15.9y (range 6-78)

Viswanathan et al. 201350

PLoS One. 2013;8(6):e66595


India, Tamil Nadu, Puducherry, The Puducherry Institute of Medical Sciences

February 2011 – January 2012


Case series

To compare scrub typhus cases with meningitis versus scrub typhus cases without meningitis.

Clinical / unclear“We did a retrospective analysis of all adult cases ( 16 years) of scrub typhus that were admitted in the hospital between February 2011 and January 2012. Computerized records of the Medical Records Department were searched using the terms, “scrub typhus”, “typhus”, “scrub typhus meningitis”, and “rickettsial meningitis”.”

“Confirmed cases of scrub typhus were selected based on a positive scrub IgM ELISA (Scrub Typhus DetectTM IgM ELISA, InBios India, detecting IgM antibodies to Orientia tsutsugamushi derived recombinant antigens), a positive Weil-Felix test (WFT), the presence of an eschar or a combination of the three in a patient with an acute febrile illness.”

65 Total:13/65= 20.0%

10/48=20.8%

3/17= 17.6%

TotalF: 32, M: 33 (50.8%)Mean age = 41.4 yo41.3 x 48 = 1982.441.8 x 17 = 710.61982.4 + 710.6 = 26932693 / 65 = 41.4

Without meningitis (n = 48):F: 25, M: 23Mean age = 41.27 14.64 y

With meningitis (n = 17):F: 7, M: 10Mean age = 41.82 17.67 y

JapanOgawa et al. 200251



Japan, countrywide

1998

ST Retrospective survey

“In the present study, scrub typhus patients reported in 1998 were analyzed for epidemiologic information and clinical features”

ClinicalThe working group for scrub typhus surveillance of Japan developed a questionnaire about scrub typhus in 1998. The questionnaire was filled by doctors in hospitals, and the staffs of health centers and public health laboratories in the prefectures of Japan. The questionnaire included

Not clearly reported (varying):“Four hundred-eight cases (88%) were confirmed by serologic tests after the provisional diagnosis by clinicians, while 54 cases (12%) were diagnosed by clinicians based on clinical symptoms only.

452 391/452 = 86.5%

Mean age and sex NR for group analyzed here.Of total group (n = 462):Male: 232 (50.0%)Female: 230 (50.0%)Mean or median age NR

questions about patients’ 1) demography: age and sex; 2) epidemiologic data: date, places (prefectures and areas), and activities at the time of infection; 3) clinical signs and symptoms: eschar, fever, rash, lymphadenopathy, malaise, headache, myalgia, hepatomegaly, and disseminated intravascular coagulation (DIC); 4) laboratory findings: CRP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), white blood cell(WBC) counts, proteinuria and occult blood in urine; and 5) diagnosis: methods and results of serologic tests.

Tai et al.201452

Journal of clinical microbiology. 2014;52(6):1938-1946


Japan, Wakayama Prefecture, Tanabe City

2003 - 2009

ST Prospective case – control study

Case series

To measure the concentrations of several cytokines and chemokines in patients with Tsutsugamushi Disease (TD) and Japanese Spotted Fever (JSF) before and after administration of minocycline and to compare the levels in the acute phases of JSF and TD.

Clinical / unclear“Serum cytokine and chemokine levelswere examined in 53 Japanese patientswith confirmed rickettsial disease, which included 32 patients with confirmed O. tsutsugamushi infection diagnosed between 2003 and 2009 in Tanabe City, Wakayama Prefecture, Japan, and 21 patients with confirmed R. japonica infection diagnosed between 2007 and 2008 in the mountainous region of Misen, Shimane Prefecture, Japan.”

“The diagnosis of rickettsiosis wasbased on a rise in serum IgM antibody titre or a 4-fold rise in serum IgG antibody titre to strains of O. tsutsugamushi or R. japonica using an indirect immunoperoxidase antibody test performed on paired serum samples collected during the acute (1 to 7 days after disease onset) and convalescent phases (14 to 21 days after onset).

32 28/32 = 87.5%

Demographics NR

South KoreaChin et al.201753

Korean J Intern Med. 2017:23.


Korea, Daejeon, Eulji University Hospital

October 2005 – May


Case series

“Therefore, predictors for associated myocarditis is needed to provide a timely and appropriate

ClinicalWe retrospectively analyzed data from 91 patients who were consecutively admitted to the ICU, Division of Infection, at Eulji University Hospital, a 3rd referral center, and diagnosed with severe and complicated scrub

When an immunofluorescent antibody assay (IFA) titre against O. tsutsugamushi increased more than four times or an indirect IFA IgM titre against O. tsutsugamushi was ≥ 1:80, scrub typhus was confirmed.

89

Myocarditis group: n = 13

Without myocardi

Overall:20/89 = 22.5%

Myocarditis group

Overall:Sex: F: 54 (60.7%), M: 35 (39.3%)Mean age: 69 ± 12 yo

Myocarditis group (n = 13):Sex: F: 7 (53.8%), M: 6 (46.2%)

2015 diagnosis and to reduce the mortality rate of complicated scrub typhus; therefore, we did this study to evaluate predictors of acute myocarditis in patients with scrub typhus admitted to 3rd referral center in the intensive care unit (ICU), retrospectively.”

typhus between October 2005 and May 2015. The diagnosis of scrub typhus in patients was based on the World Health Organization’s criteria.

tis group: n = 76

(n = 13):2/13 = 15.4%

Without myocarditis group (n = 76):18/76 = 23.7%

Mean age = 69 ± 13 yo

Without myocarditis group (n = 76):Sex: F: 47 (61.8%), M: 29 (38.2%)Mean age = 69 ± 12 yo

Choi et al. 200054

Clinical Radiology (2000) 55, 140–144


Korea, Suji-Gu, Dankook University College of Medicine

Period NR


To describe the radiological and clinical findings of scrub typhus.

Clinical / unclearWe retrospectively reviewedchest radiographs and thin-section CT in 75 patients with scrub typhus. The subjects were collected among the consecutive hospitalized patients from two institutes, who had an acute febrile episode during the late fall epidemic period for last 2 years.

The diagnosis was established serologically by indirect immunofluorescent antibody test (n = 73) or by the presence of the typical eschar (n = 2).

75 56/75 = 75.0%


Ho et al.201455

Korean J Pediatr Infect Dis 2014;21:104-113


Korea, Jeonju, Department of Pediatrics, Presbyterian Medical Center


ST Case – control study

Case series

To compare the clinical characteristics, laboratory findings, and complications of scrub typhus between children and adults.

ClinicalThe diagnosis of tsutsugamushi disease was made either clinically or serologically. Clinical diagnostic criteria are characteristic clinical findings (fever, rash, headache, etc.) along with the onset season, outdoor outings and skin confirmation.

Serological diagnostic criteria were indirectimmunofluorescent antibody test, IFA, and the antibody titre was 1:40 or more.

768

719 adults49 children

Total: 631/768 = 82.2%

Adults:583/719 = 81.1%

Children:48/49 = 98.0%

Total:F: 473, M: 295 (38.4%)

AdultsF: 450, M: 26962.28 ± 14.42 y

ChildrenF: 23, M: 26Mean age = 5.55 ± 3.59 y

Hwang et al. 201756

BMJOpen

3/7Unclear / Medium risk

Korea, Jinju, Gyeongsang National University Hospital


Case series

“The aim of the present study was to evaluate the incidence, risk

ClinicalThis study enrolled 510 patients with scrub typhus who were admitted to Gyeongsang National University Hospital from January

A high initial indirect immunofluorescent antibody (IFA) titre. If the initial titre was low, a fourfoldincrease in titre was considered

510

AKI group: n = 183

Overall:200/510 = 39.2%

Overall:Sex: F: 265 (52.0), M: 245 (48.0%)Mean age = 57.9 ± 18.9 y

2017;7:e013882.

of bias? / + January 2001

– November 2003

factors and clinical outcomes of AKI according to the RIFLE (risk, injury, failure, loss, end-stage kidney disease) classification in a large series of patients with scrub typhus.”

2001 to November 2003. A diagnosis of scrub typhus was made when patients had a scab (eschar), acute febrile illness, skin rash, headache, muscle aches, lymphe node swelling, hepatosplenomegaly and a high indirect immunofluorescent antibody (IFA) titre.

signifi cant.Non-AKI group: n = 327

AKI group (n = 183):80/183 = 43.7%

Non-AKI group (n = 327):120/510 = 36.7%

AKI group (n = 183):Sex: F: 86 (47.0%), M: 97 (53.0%)Mean age = 64.5 ± 15.3 y

Non-AKI group (n = 327):Sex: F: 179 (54.7%), M: 148 (45.3%)Mean age = 54.3 ± 19.7 y

Jang, Kim, et al. 201457

Archives of Gerontology and Geriatrics 58 (2014) 196–200

3/7 Medium risk of bias+

South Korea, Gwang-ju, Chonnam National University Hospital

2001-2011


Case series

To identify differences in the complicationfrequency between elderly and non-elderly people, along withclinical predictors of complications in elderly scrub typhus patients

ClinicalA diagnosis of scrub typhus was made based on typical clinical manifestations and the results of a serologic test.(Complicated scrub typhus was defined by the following conditions: (i) shock, defined by a systolic blood pressure of <90mm Hg or a fall in systolic blood pressure of >40 mm Hg; (ii) acute kidney injury, defined by a serum creatinine increase of >2.0-fold or a glomerular filtration rate decrease of>50% from baseline; (iii) pneumonia with parenchymal lung lesions on a chest radiograph and cough or dyspnea;(iv) acute respiratory distress syndrome, defined by a ratio of arterial partial oxygen tension as a fraction of inspired oxygen of <200 mm Hg in the presence of bilateral infiltrates on a chest radiograph; (v) meningoencephalitis with neurologic symptoms and evidence of infection of the central nervous system, based on imaging studies or cerebrospinal fluid (CSF) counts of >5

Serologic testing was performed using a passive haemagglutination assay (PHA) against indirect O.tsutsugamushi antigen. A positive result was defined as a titre of ≥1:80 in a single serum sample or by a ≥4-fold increase in the follow-up titre. The PHA was performed using Genedia Tsutsu PHA II test kits (GreenCross SangA, Yongin, Re-public of Korea).

615 569/615 = 92.5%

Elderly:298/328 = 91.7%

Non-elderly:271/287 = 95.8%

Male n=264 (42.9%)Female n= 351 (57.1%)

Mean age:Elderly (n= 328):Mean age = 73.4 ± 5.8 yo

Non-elderly (n = 287):Mean age = 52.0 ± 10.7 yo

Total (n = 615)328 x 73.4 = 24075.2287 x 52.0 = 1492424075.2 + 14924 = 38999.238999.2 / 615 = 63.4 yo

leukocytes/mm; (vi) gastrointestinal bleeding; and (vii) cholecystitis, defined by the presence of Murphy’s sign and radiological evidence of gallbladder inflammation.

Jung et al. 201558



South Korea, Kangwon Province, Chuncheon, Kangwon National University School of Medicine



Case series

We investigated the etiologic spectrum in adult patients presenting with acute undifferentiated fever at the emergency department of a non-tropical scrub typhus-endemic area. In addition, we tried to develop a prediction rule toidentify suspected cases of scrub typhus in patients with acuteundifferentiated fever using predictors derived from a multipleregression model

ClinicalInformation from all patients who presented with fever or history of a fever at the emergency department fromJanuary of 2009 to December of 2013 was retrieved from the administrative registry. From these data, adult patients(≥18 years old) who were hospitalized with acute undifferentiated fever were included in this study. To evaluate the etiology of acute undifferentiated fever, IFA for Orientia tsutsugamushi or hantavirus; microscopic agglutination test for Leptospira species; immunochromatographic test forO. tsutsugamushi, hantavirus, or Leptospira species and other testing, have been performed according to the clinical judgment of the physicians caring for the patients. Consequently, final diagnosis of cases with acute undifferentiated fever was estimated based on the etiologic evaluation.

Patients who showed IFA antibody titre with a ≥fourfold increase in paired sera were defined as havingdefinite scrub typhus. Patients who showed either an IFA antibody titre of ≥1:160 in a single serum or a positive result of an immunochromatographic test for O. tsutsugamushi were defined as possibly having scrub typhus.

Immunochromatographic test was performed in each hospital to detect antibodies against 56-kDa major surface protein antigens from representative strains using commercial kits (SD BiolineTsutsugamushi Assay; Standard Diagnostics, Yongin, Korea).

41 23/41 = 56.1%

Male: 14/41 = 34.1%Female: 27/41 = 65.9%

Mean age 69.2 ± 10.5y

Kim et al. 200259

J Korean Acad Fam Med Vol 23, No 1, January 2002,


Korea, Jeongeuop, Asan Medical Center, Dept. of Internal Medicine and general Surgery

1 October


Case series

To describe the developmental stage, symptoms, and epidemiologic distribution.

Clinical / unclear31 patients were hospitalized for acute febrile illness – 15 were excluded because of clinical and serological problems (details NR).

PHA (Green Cross Co., Ltd). A titre of 1:1280, or 4x increase in convalescent sample was considered positive.

16 13/16 = 81.3%

Male 9 (56.3%), Female 7 (43.8%)

Age 40 – 73 years (mean/median NR)

p87-95 2000 – 30 November 2000

Kim et al.200460

Clinical Infectious Diseases 2004; 39:1329–35


Korea, Daejeon, Chungnam National University Hospital


ST Prospective randomized trial

Case series

To evaluate the efficacy or a single dose of azithromycin for the treatment of scrub typhus, compared with doxycycline.

ClinicalEligible patients were those 18 years of age who exhibited documented fever (oral temperature, ≥38.0C) together with eschar or a maculopapular skin rashand ≥2 of the following symptoms: headache, myalgia, generalizedweakness, coughing, nausea, and abdominal discomfort. Patients who were unable to take oral medications, those who were pregnant, and those with a history of hypersensitivity to macrolides or tetracyclines, severe scrub typhus-related complications, or indications of the presence of a febrile illness unrelated to scrub typhus were excluded.

O. tsutsugamushi infection was confirmed if specific IgM was detected at a dilution of 1:10 or if 4-fold increased titres were demonstrated with paired serum specimens in an indirect immunofluorescence antibody (IFA) test. IFA was performed with Gilliam (ATCC VR-312), Karp (ATCC VR-150), Kato (ATCC VR-609), and Boryong strains.

93 Total: 90/93 = 96.8%

Azithromycin: 46/47 = 97.9%

Doxycyclin: 44/46 = 95.7%

Total:F: 55, M: 38 (40.9%)Mean age = 62.0 y.47 x 62.9 =2956.346 x 61.1 = 2810.62956.3 + 2810.6 =5766.95766.9 / 93 = 62.0

Azithromycin (n = 47):F: 27, M: 20Mean age = 62.9 14.1 yo

Doxycycline (n = 46)F: 28, M: 18Mean age = 61.1 13.5 yo

Kim, Chung, et al. 201361

Am. J. Trop. Med. Hyg.,89(6), 2013, pp. 1206–1211


South Korea, Gwang-ju, Chosun University Hospital

September 1, 2004 – December 31, 2008

ST Retrospective case control study (within prospective cohort study)

Case series

To analyze the factors associated with meningitis and meningoencephalitis by comparing cases and controls.

ClinicalWe enrolled patients who presented with acute febrile illness and we enrolled those ≥18 years of age who had escharsor maculopapular skin rashes, or were diagnosed clinically as having scrub typhus by a specialist in infectious diseases.

The diagnosis of scrub typhus was confirmed when a positive nested polymerase chain reaction (PCR) using O. tsutsugamushi-specific primers targeting 56 kDa surfaceprotein antigen encoding genes was obtained, or the indirect fluorescent antibody titre against O.tsutsugamushi increased 4-fold or more.

325 304/325 = 93.5%

Males 111/325 = 34.2%Females 214/325 = 65.8%Mean age = 62.4y

Meningitis or meningoencephalitis group (n = 22):Mean age = 70 y

No meningitis or meningoencephalitis group (n = 302): 62 years

Total:22 x 70 = 1540302 x 62 = 187241540 + 18724 = 2026420264 / 325 = 62.4 y

Kim et al.201762

Japanese Journal of


Korea, Jeonju, Chonbuk National University Hospital

ST Retrospective study

Case series

“The purpose of the present study is to describe the CT findings and clinical features of

ClinicalThis retrospective study was approved by our institutional review board, and the requirement for informed patient consent was waived. We searched our institutional database for patients

Positive serology was defined by a titre of passive hemagglutination assay (PHA) against O. tsutsugamushi of ≥ 1:80 in a single serum sample or by a four-fold or greater increase of titre

78 52/78 = 66.7%

Sex: F: 45, M: 33 (42.3%)Mean age = 63.1 ± 16.1 yo (range 20 – 87)

Radiology. 2017;35(3):101-8.

October 1, 2010 – December 31, 2013

abdominopelvic involvement in scrub typhus.”

diagnosed with scrub typhus from October 1, 2010 to December 31, 2013. Scrub typhus diagnoses were established serologically by indirect immunofluorescent antibody and on the basis of clinical manifestations (fever, skin rash, eschar).

upon follow-up.

Lee, Lee et al. 200363

Pediatr Infect Dis J,2003;22:130–3


South Korea, Seoul, CatholicUniversity of Korea, Daejeon St. Mary’s Hospital

1991 - 2000


Case series

To evaluate theeffect of roxithromycin on tsutsugamushi disease in children bycomparing clinical and laboratory findings of children who had been treated with doxycycline or chloramphenicol in the past.

ClinicalWe retrospectively analyzed the medical records of 39 children treated for scrub typhus at the Catholic University of Korea, Daejeon St. Mary’s Hospital, from 1991 through 2000. The diagnosis of scrub typhus was made by clinical manifestations according to seasonal attack, rash and the characteristic eschar and the serologic test.

The qualitative passive hemagglutinin test using sheep red blood cells was performed. The antigens of the passive hemagglutinin test were from the Gilliam, Karp and Kato strains until 1996, and from 1997 an antigen from the Kato strain was replaced with one from the Boryong strain.

39 36/39 = 92.3%

Male n=29 (74.4%)The mean age was 6.1 ±3.4 years (range, 6 months to 13 years),Fever and rash in 100% of cases

Lee et al. 200764

J Korean Acad Fam Med 2007; 28: 774-781


Daejeon and Chungnam, Chihan University Hospital Family Medicine Department


ST Case series Case series

To analyze the clinical characteristics of Tsutsugamushi Disease and the factors affecting the disease.

Clinical / UnclearInclusion criteria remain unknown. 102 patients were diagnosed with ST, partly (n = 10) based on the clinical presentation.

Indirect immunofluorescent antibody test (details NR)

10292 with positive IFA

92/102 = 90.2%

F: 69 (67.6%), M: 33 (32.4%)Mean age = 57.4 ± 16.3 years (range 18 – 97)

Lee et al. 200965



South Korea, Jeonju, Chonbuk National University Hospital

1 Jan 2000 – 31 Dec 2006


Case series

To identify the risk factors of the fatal outcomein patients with scrub typhus, the medical records of patients admitted to this tertiary

Clinical“Patients with acute febrileillness were routinely checked serologically for scrub typhus,leptospirosis, and Haantan virus.”And:Among the serologically tested 1,855 patients, 302 adult patients (age ≥ 18 years) who had positive serology, and history of fever with either eschar or a

A definite case of scrub typhuswas defined by a titre of passive hemagglutination assay (PHA) against Orientia tsutsugamushi of ≥ 1:80 in a single serum sample or by a 4-fold or greater increase in the follow-up titration. The PHA was performed at the NeoDIN Medical Institute in Seoul,

297 198/297 = 66.7%

Total:Sex: male n = 112 (37.7%)Mean age = 63.6 y18 x 67.1 = 1207.8279 x 63.4 = 17688.61207.8 + 17688.6 = 18896.418896.4 / 297 = 63.6

Age not given for overall group.

educational hospital for the last 7 years were analyzed retrospectively

maculopapular skin eruption and more than two symptoms (such as headache, malaise, myalgia, coughing, nausea, and abdominal discomfort) werediagnosed scrub typhus

Korea using Genedia Tsutsu PHA II test kits (GreenCross SangA, Yongin-shi Kyunggi-do, Korea). Genedia Tsutsu PHA II is a test kit for the qualitative and quantitative detection of antibodies against O. tsutsugamushi in human serum based on the PHA. For the kit, we used sheep erythrocytes that were sensitized by Karp and Gilliam strains, including the Boryong strain found in Korea.

The mean (SD) age of the fatal case was 67.1 (±12.8) years and the non-fatal case was 63.4 (±12.4) (Of these, 18 (6.1%) cases died and these were classified as the fatal case. The rest, 279 patients, were used as the non-fatal case. )

Lee et al.200966

BMC Infectious Diseases 2010, 10:216


South Korea, Geumam-dong, Jeonju, Chonbuk National Univeristy Hospital



Case series

To evaluate the significance of hypoalbuminemia on the outcome of patients with scrub typhus.

ClinicalThe clinical records of patients diagnosed with scrub typhus were reviewed retrospectively. Patients (age ≥ 18 years) who were admitted with fever with either eschar or a maculopapular skin eruption and more than 2 vague symptoms (such as headache, malaise, myalgia, coughing, nausea, and abdominal discomfort) were serologically titrated and diagnosed as scrub typhus.

The diagnosis of scrub typhus was made on clinical manifestations and passive hemagglutination assay(PHA) against O. tsutsugamushi. A definite case of scrub typhus was defined by an increased titre of PHA against O. tsutsugamushi (≥ 1:80) in a single serum sample or by a 4-fold orgreater increase of titre in the follow-up. PHA was performed at the NeoDIN Medical Institute in Seoul, Korea using Genedia Tsutsu PHA II test kits.

246 Total: 173/246 = 70.3%

Group 1: 42/57 = 73.7%

Group 2: 131/189 = 69.3%

Total:F: 162, M: 84 (34.1%)Mean age = 63.2 y57 x 71.4 = 4069.8189 x 60.7 = 11472.34069.8 + 11472.3 = 15542.115542.1 / 246 = 63.2

Group 1: serum albumin of<3.0 g/dL (n = 57):F: 35, M: 22Mean age = 71.4 ± 10.6

Group 2: serum albumin of ≥ 3.0 g/dL (n = 189):F: 127, M: 62Mean age = 60.7 ± 12.2

Lee et al. 201367

Jpn. J. Infect. Dis., 66, 232-234, 2013


Korea, Iksan, Wonkwang Universiry Hospital

Sep 2008 – Dec 2011


Case series

To determine the optimal cutoff value of serum adenosinedeaminase (ADA) activity for diagnosing scrub typhus in acute febrile patients.

ClinicalIn this study, the optimal cut-off valueof serum ADA activity were determined for diagnosing scrub typhus inacute febrile patients.Patients were diagnosed with acute scrub typhus if they had a history of fever with either an eschar or a maculopapular skin eruption and 2 vague symptoms (e.g., headache, malaise, myalgia, coughing, nausea, and abdominal discomfort).

Scrub typhus was defined as anincreased titre in the indirect immunofluorescence antibody (IFA) test against O. tsutsugamushi (Æ1:256) in a single serum sample or a Æ 4-fold increased titre in thefollow-up

286 219/286 = 76.6%

Mean age 63.5 yearsFemale: 59.1% (n=169)Male: 40.9% (n=117)

Park et al.

4/7Mediu

Korea, Seoul, Korea


Our study was conducted

ClinicalClinical scrub typhus was defined

Confirmed case was defined as positive serological result for

16 13/16 = 81.3%

Mean age = 58 yo (range 45 – 69)

201568

PLoS NTD 2015;9(5):e0003814.

m risk of bias+

Centers for Disease Control and Prevention

2010 – 2013

Boramae Medical Center

2010 - 2012

Case series

to investigate the status of indigenous urban scrub typhus and its clinical characteristicsin Seoul at more northern latitude.

as a case with typical eschar and at least two of the following manifestations: fever, maculopapular skin rash, regional lymphadenopathy, headache, myalgia,cough, and abdominal discomfort. Acute therapeutic response to doxycycline or azithromycin with no other alternative diagnosis was a basic component of the clinical scrub typhus.

O . tsutsugamushi . The positive serologywas as a four-fold or greater change in the titre of paired sera, or a single cut-off titre of IgM antibody 1:160 from an indirect immunofluorescence antibody assay against a mixture of O. tsutsugamushi antigens (Gilliam, Karp, Kato and Boryong) in clinical scrub typhus patients.

(Clinical cases (n = 10) were not included in analysis because eschar-positive cases only were defined as clinical cases)

F: 8 (50%), M: 8 (50%)

Park, Kim et al. 201469

Jpn. J. Infect. Dis., 67, 458–463, 2014


South Korea, country wide

2008-2012

ST Retrospective cohort study (through national surveillance data)

Case series

To describe the epidemiology ofscrub typhus and the distribution of eschars amongpatients in South Korea.

Clinical/unclear:Data associated with confirmed scrub typhus cases from 2010 to 2012 wereobtained through epidemiologic investigations. Each case of scrub typhus that was reported through NNDSS was investigated by the respective public health centre via a standardized questionnaire. The standardized scrub typhus questionnaire comprised information regardingclinical manifestations, including eschars, and activities 3 months prior to the onset of symptoms. A patient with a confirmed diagnosis was considered tohave engaged in activities related with exposure to O.tsutsugamushi, including occupational farm work, transientfarm work, or leisure activities. Patients with multiple or no activities were classified as having indeterminableactivities.

In South Korea, scrub typhus cases are reported by physicians to the Korea Centers for Disease Control and Prevention (KCDC) throughthe National Notifiable Diseases Surveillance System (NNDSS). These reported cases are classified as ``confirmed'' according to the results of 1 of the following laboratory tests performed by KCDC or the Institute of Health and Environment of each province: (i) an increase in the IFA IgM titre against O. tsutsugamushi to ≥1:16; (ii) an increase in the IFA IgG titre against O. tsutsugamushi to ≥1:256; and (iii) a ≥4 fold increase in the IFA titre against O. tsutsugamushi. A case was considered `suspected'' if the clinical presentation was consistent with scrub typhus but was not accompanied by laboratory test results.

7353 5798/7353 = 78.9%

Demographic characteristics for cases with eschar information NR.

“Among the verified cases, 73.5% of patients had 1 eschar, and 5.4% had 2 or more eschars.”“Eschars were reported more frequently among women (80.1z) than among men (76.8z; P ＜0.001). Patients aged 50–59 years had the highest proportion of eschars (81.8z), whereas those aged ≥70 years had the lowest proportion of eschars (76.2z).”

Park, Lee, et al. 201570

Pak J Med Sci


South Korea, Changwon, Samsung Changwon Hospital

ST Retrospective cohort study

Case series

To investigate abdominal CTfindings in patients who had scrub typhus with

ClinicalThe diagnosis was made if any one of the following criteria were met: (1) history of outdoor exposure, (2) pathognomonic eschar, and (3) single

The serologic test for scrub typhus was conducted using a commercial immunochromatographic test (ICT) (Tsutsugamushi assay; SD Bioline,

349 245/349 = 70.2%

Male: 145 (41.5%)Female: 204 (58.5%)Mean age 63.7+- 16.2

2015;31(2):295-299.

July 2008 – December 2013

abnormal aminotransferase activity.

measurement of serology at the initial visit.The exclusion criterion was a history ofpreviously known liver disease (e.g. chronic viral hepatitis, liver cirrhosis, or malignancy of liver).Ten of 359 patients diagnosed with scrub typhuswere excluded due to liver cirrhosis (n=4), chronic hepatitis B (n=4), chronic hepatitis C (n=1), and Klatskin tumor (n=1).

Youngin, Korea), with a positive or negative result.

Song, Kim et al. 200471

J Korean Med Sci 2004; 19: 668-73


Korea, Uijongbu, Uijongbu St. Mary’s Hospital

January1993 - May 2003

ST Retrospective analysis of ST patient-records

Case series

To study the relationshipbetween IP and the clinical parameters representingseverity of scrub typhus.

ClinicalThe diagnosis of scrub typhus was made on the basis of their clinical manifestations (fever, skin rash, eschar)and the results of an indirect immunofluorescence antibody test against the organism Orientia tsutsugamushi. The patients with chronic liver disease, chronic renal failure, chronic heart disease, hematologic disease and inflammatory bowel disease were excluded.

Indirect immunofluorescence antibody test against the organism Orientia tsutsugamushi

Cut-off values NR

101 65/101 = 64.4%

Sex: F: 67 (66.3%), M: 34 (33.7%)Mean age: 56 ± 15 yr (range: 9-86 yr).

LaosDittrich et al. 201572

Lancet Glob Health 2015;3: e104–12


Laos, Vientiane, Mahosot Hospital

Jan 10, 2003 – Nov 25, 2011


Case series

To assess whether Scrub typhus (caused byOrientia tsutsugamushi), murine typhus (caused by Rickettsia typhi), and leptospirosisare important causes of CNS infections in Laos

CompleteInpatients of all ages were recruited if adiagnostic lumbar puncture was indicated on the basis of altered consciousness or neurological findings by the attending physicians, and if there were no contraindications.

1. We tested for rickettsial antibodies (IgM and IgG) with batched indirect immunofluorescenc assays for scrub typhus2.qPCR for O. tsutsugamushi3. Culture

30

(all patients n = 1112)

2/30 = 6.7%

Demographics NR for group with eschar information.Male 22/31 = 71%Age 16 (0.3 – 76)Age < 15y 14/31 = 45%

Patients with O. tsutsugamushi also presented late in their illness and had a high frequency of rash (20%). 81% fulfilled the WHO meningitis criteria (figure 2) with a significantly higher median GCS score and the highest reported preadmission antibiotic use (86%) of investigated groups

Paris et al. 201273

Clin Microbiol Infect 2012; 18: 1221–1228


Laos, Vientiane, Mahosot Hospital

Date NR

ST Case control study

Case series

To compare in vivo levels ofcoagulation and inflammation markers in patients with acute murine typhus and acute scrub typhus in order to understandthe roles of early vasculopathic changes accompanyingthese disease states.

Clinical / Unclear:A total of 248 non-pregnant patients with clinical suspicion of scrub typhus or murine typhus were prospectivelyrecruited at Mahosot Hospital, Vientiane, Lao PDR. Of these, 121 patients with paired positive dynamic serology findings were randomly selected, including 55 patients with scrub typhus, 55 patients with murine typhus, 11 ‘febrile controls’with clinical suspicion of typhus, but negative paired serology and PCR results for scrub and murine typhus, and 51 local contemporary blood donors as healthy controls.

The definitive diagnoses of scrub typhus and murine typhus were based on a ‡4-fold dynamic rise in IgM and IgG IFA titres for paired serum samples, which represents the cur-rent serological reference standard [4]. Slides prepared and standardized by the Australian Rickettsial Reference Laboratory were used for anti-O. tsutsugamushi antibody detection(using pooled Karp, Kato and Gilliam antigens) and anti-R. typhi antibody detection (R. typhi Wilmington strain antigens).On admission, bacteraemic patients were identified by realtime PCR, targeting the groEL gene for scrub typhus, as previously described, with modification of the endpoint visualization by intercalating SYBR green. DNA templates wereextracted from 200 lL of buffy coat collected from EDTAanticoagulatedfull blood samples (Qiagen Mini Blood kit; Qiagen, Germantown, MD, USA).

54 23/54 = 42.6%

Median age 26 (5-75)Sex NR

MalaysiaTay et al. 200274

SouthEast Asian J Trop Med Public Health 33; 4; Dec 2002


Malaysia, Slim River, SlimRiver Health Center

December 1997

ST Cross sectional survey

Case series

To attemptisolation of various species of rickettsiae frompatients’ blood and rodent samples, collectedfrom areas with high antibody prevalence of

Complete / UnclearClinical samples were whole blood samples collected from febrile patients attending Slim River Health Center, Malaysia in December, 1997.

Indirect immunofluorescence assay (IFA)Sera having titres of ≥ 1:40 were considered positive.Indirect immunoperoxidase (IIP) assay.To determine the presence of rickettsial antibody in the patients’ blood samples from Slim River Health Center, IIP assay was performedas described by Kelly et al (1988).

12 0% Male 9/12=75.0%Mean age NR

human rickettsial infections.

Sri LankaLiyanapathirana and Thevanesam 201175

BMC Infectious Diseases 2011, 11:328


Sri Lanka, countrywide


ST Surveillance data with retrospective collection of additional (clinical) data

Case series

To map rickettsialinfections in selected localities of Sri Lanka by using serologicaltesting and to describe the clinical profiles ofpatients with laboratory confirmed rickettsial infections

ClinicalClinicians of selected hospitals were informed about the study through letters and workshops conducted in collaboration with the Epidemiology Unit and were requested to send serum samples from patients in whom a clinical diagnosis of rickettsioses was being considered according to the surveillance case definition given by the Epidemiology Unit of Sri Lanka.

Samples were tested using scrub typhus IgM and IgG ELISA kits (Panbio, Australia), IFAkits donated by the Rickettsial reference laboratory, Geelong,Australia and IFA kits prepared using antigens donated by the Rickettsial reference laboratory in Marseille,France.A titre of over 1/128 was considered as positive for IgM and IgG using IFA. Positivity for either IgM or IgG or both was taken as being seropositive. Clinical data from patients whose serum was seropositive for both spotted fever and scrub typhus by ELISA was not considered for clinical profiling.

168 101/168 = 60.1%

Male 48.8% (n=82)Mean age 15.4 ± 18.1

TaiwanJim et al. 200976

Pediatr Neonatol 2009;50(3):96−101


Taiwan, Southeast, Taitung Branch of Mackay Memorial Hospital



Case series

To analyzethe clinical manifestations, laboratory data and outcomesof pediatric scrub typhus in eastern Taiwan.

Clinical / unclearTheir medical records were reviewed to verify the diagnosis, which requiredat least one of the following criteria: (1) a four-fold rise in the indirect immunofluorescent antibody (IFA) test for O. tsutsugamushi measured in acute and convalescent paired sera (test material provided by National Institute of Preventive Medicine, Department of Health, Executive Yuan, Taiwan); (2) an IgM antibody titre against O.tsutsugamushi> 1:80; or (3) a positive PCR test for O. tsutsugamushi (available since 2002).Not described if any other criteria were used for the classification of ST.

(1) a four-fold rise in the indirect immunofluorescent antibody (IFA) test for O. tsutsugamushi measured in acute and convalescent paired sera (test material provided by National Institute of Preventive Medicine, Department of Health, Executive Yuan, Taiwan); (2) an IgM antibody titre against O.tsutsugamushi> 1:80; or (3) a positive PCR test for O. tsutsugamushi (available since 2002).

39 27/39=69.2%

Male n=26 (66.7%)Female n=13 (33.3%)

The mean age of the children was 7.6 ± 4.6 years (range, 1−18 years)

Lai et al. 200977

IJID (2009) 13, 387—393


Taiwan, South, Kaohsiung County, E-Da Hospital

April 2004 - December 2007


Case series

This study was conducted to further identify the differences between acute Q fever and scrub typhus.

CompleteA prospective observational study was conducted in which serological tests for acute Q fever and scrub typhus were performed simultaneously regardless of which disease was suspected clinically.

Serologic assessments using indirect immunofluorescence antibody assay (IFA) were performed in the contract laboratory of Taiwan CDC. Scrub typhus was diagnosed by either an antibody titre of IgM 1:80 or a four-fold or greater rise of total antibody (IgG + IgA + IgM) titre in paired sera for Karp, Kato, and Gilliam strains of O. tsutsugamushi.

40 22.5% (=9/40)

Male 26/40 = 65.0%Mean age 42.9 +/- 15.3

Lee et al.200278

J Formos Med Assoc2002;101:385–92


Taiwan, Tainan,National Cheng Kung University Hospital

October 1992 – July 2000


Case series

To describe the clinical manifestations and complications of cases of rickettsial infection treated at a medical center in Southern Taiwan.

CompleteSerum samples were collected for serologic study from patients with acute febrile illness with or without shock but without a clinical diagnosis of localizedbacterial infection after a preliminary work-up at National Cheng Kung University Hospital.

Serologic assessment was performed using indirect immunofluorescence antibody assay (IFA). Scrub typhus was confirmed by either a four-fold or greater rise in total titre of immunoglobulin G (IgG) + IgA + IgM in paired sera with a peak titre of at least 1:320, or a total titre of IgG + IgA + IgM of at least 1:320 and IgM of at least 1:80 in a singleserum specimen.

16 6/16 = 37.5%

F: 9, M: 7 (43.8%)Mean age = 44.9y ± 17.1y

1/16 ST patients was German.

Lee, Wang et al. 200679

Jpn. J. Infect. Dis., 59, 235-238, 2006


Taiwan, East, Hualien County and Taitung County

ST Surveillance data with retrospective collection of additional (clinical) data

Case series

To update the status of scrub typhus in eastern Taiwan in theyears 2000-2004 to improve our understanding of the spread of this disease.

ClinicalPhysicians in Taiwan are under obligation to report scrub typhus to their local health bureau based on the clinical symptoms of fever, headache, back pain, chills, sweating, lymphadenopathy, skin rashes after 1 week, and eschar. Samples of patient blood were collected in the acute phase (within 7 days of the day of onset) and convalescent phase (14 days after the day of onset) and sent to the Center for Disease Control (CDC) laboratory or its contract laboratory for confirmation by pathogen isolation, and indirect immunofluorescence assay (IFA). A confirmed case was defined by the positive isolation of O.tsutsugamushior a fourfold increase of antibodies by IFA testing. When the local health bureau received a

Samples of patient blood were collected in the acute phase (within 7 days of the day of onset) and convalescent phase (14 days after the day of onset) and sent to the Center for Disease Control (CDC) laboratory or its contract laboratory for confirmation by pathogen isolation, and indirect immunofluorescence assay (IFA). A confirmed case was defined by the positive isolation of O.tsutsugamushi or a fourfold increase of antibodies by IFA testing.

121 28/121 = 23.1%

Sex and age not given for subgroup analyzed here.Rash 21.6%Fever 90.1%

report of this disease, including data on clinical symptoms, a questionnaire survey was carried out. Patients answered the questionnaireretrospectively. The questionnaire included items on patient background (age, sex, onset date, location, and occupation) and possible infection sites (activities at the time of infection, i.e., 1 month before the day of onset).

Su, Liu et al. 201680

J Micr Imm Inf (2016) 49, 941-946


Taiwan, Kinmen Island, Kinmen Hospital

1 January 2005 – 31 December 2010


Case series

To evaluate theassociated factors and clinical implications of serumaminotransferase elevation in scrub typhus, especially in patients without eschar.

Clinical / UnclearWe retrospectively included all clinically suspected cases of scrub typhus notified to Taiwan CDC by Kinmen Hospital, Kinmen, Taiwan between January 1, 2005 and December 31, 2010.

As the standard procedure of Taiwan CDC, serum and whole blood were collected in the acute and convalescent phases (within 7 days and 14 days after symptoms onset, respectively) from each patient, and were sent to the laboratory of Taiwan CDC for serological or molecular assays. The indirectimmunofluorescence antibody assay with antigens of major strains of O. tsutsugamushi (Karp, Kato, Kawasaki,and Gilliam strains) was used. Scrub typhus was diagnosed as an initial immunoglobulin M titre of >1:80 or a greater than four-fold rise of immunoglobulin G titre in pairedserum. In addition, a positive polymerase chain reaction of specific primer for 56-kDa-type-specific antigen gene of O.tsutsugamushi was used to confirm the diagnosis andfor genotyping as described elsewhere

288 263/288 = 91.3%

Mean age: 42 yMale 210/288 = 72.9%

Tsai et al.201081

IJID 2010; 14(1):e62-67


Taiwan, Buddhist Tzu Chi General Hospital

August 2001 – July 2007

ST Retrospective case-controlStudy

Case series

To evaluate the efficacy of levofloxacin for the treatment of scrub typhus.

Clinical / unclear“Patients diagnosed to have scrub typhus by serologic or molecular methods were enrolled in this study. Their medical records were reviewed and data including demographic characteristics, medical history, medications,

“Serologic testing for O. tsutsugamushi was performed by determining the presence of immunoglobulin M (IgM)- and immunoglobulin G (IgG)-specific antibodies using an indirect immunofluorescence assay. The O. tsutsugamushi

132 Total:67/132=50.8%

31/71= 43.7%

36/61=

Total:M: 74 (56.1%), F: 58Mean age = 50.5 y71 x 51 = 362161 x 50 = 30503621 + 3050 = 66716671 / 132 =50.5

laboratory data, andoutcome were collected for analysis. Those patients with positive serologic tests for other acute infections or positive blood cultures were excluded.”

antigens (Gilliam, Karp, and Kato) used were cultured in L cells. The titres of IgM and IgG were determined in acute- and convalescent-phase sera. IgM 1:80 or IgG increased four-fold in the convalescent phase was considered a positive result. In the molecular method, the genomic DNA of O. tsutsugamushi was extracted using the QIAamp Blood Mini Kit (QIAGEN, Hilden, Germany). O. tsutsugamushi was identified by 56-kDa gene nested PCR.”

59.0%Levofloxacin (N = 71):F: 31, M: 40Mean age = 51 13.8 yo

Tetracycline (N = 61):F: 27, M: 34Mean age = 50 19.3 yo

Wang et al.200782

Am J Trop Med Hyg. 2007;76(6):1148-1152


Taiwan, Kaohsiung Chang Gung Memorial Hospital

January 1998 – August 2006


Case series

“To investigate the clinical course and outcome of scrub typhus patients with ARDS and to identify the relativerisk factors for acquiring ARDS in scrub typhus patients..”

Clinical / unclear“This study retrospectively reviewed the medical records of 72 patients diagnosed with scrub typhus.”

“Quality assurance procedures for diagnostic tests for the 72 scrub typhus patients were conducted by the Center for Disease Control (Taipei, Taiwan) based on a polymerase chain reaction (PCR) or serologic analysis for indirect microimmunofluorescent antibody (IFA) for O. tsutsugamushi. Diagnostic IFA results were positive for O. tsutsugamushi if the total antibody titre for the Karp, Kato, and Gilliam strains of O. tsutsugamushi showed a ≥ 4-fold increase in paired positive serum samples or the antibody titre for IgM was 1:80.”

72 5/8= 62.5%

42/64= 65.6%

Total:47/72= 65.3%

Total:F: 29, M: 43 (59.7%)Mean age = 47.7 y8 x 55.4 = 443.264 x 46.7 = 2988.8443.2 + 2988.8 = 34323432 / 72 = 47.7

With ARDS (n = 8):F: 5, M: 3Mean age = 55.4 ± 21.5 yo (range 24–75)

Without ARDS (n = 64):F: 24, M: 40Mean age = 46.7 ± 17.5The mortatlity rate in the ARDS group was 25% (2 out of 8).

Wang et al.201383

Vector Borne Zoonotic Dis. 2013;13(3):154-159


Taiwan, Penghu, Triservice General Hospital

2006 - 2010


Case series

To assess the epidemiology of scrub typhus in Penghu, Taiwan.

Clinical / Unclear“This retrospective study was conducted at the Penghu branch of the Triservice General Hospital, which is a 200-bed teaching hospital in Penghu. From 2006 to 2010, 126 patients were treated for scrub typhus.”

“Confirmation required fulfillment of at least 1 of the following criteria: (1) A positive PCR result for O. tsutsugamushi; (2) a 4-fold increase in the indirect IFA for O. tsutsugamushi as measured in acute and convalescent paired sera; or (3) an immunoglobulin M (IgM) antibody titre against O. tsutsugamushi greater than 1:80.”

126 78/126= 61.9%

F: 65, M: 61 (48.4%)Age NR

The axilla was the most frequent site of eschars (n = 17, 21.8%), followed by the inguinal region (n = 10, 12.8%), chest (n = 8, 10.3%), abdomen (n = 8, 10.3%, and back (n = 8, 10.3%).

Wu, Wu et al.

2/7High

Taiwan, Mackay


Not clearly reported:

Clinical / unclear:From January 2001 to December

Indirect microimmunofluorescent

136 82/136 =

Male: 95/136 (69.9%)The mean age of all the

200984

Int J Gerontology Dec 2009; 3; 4

risk of bias-

Memorial Hospital, Taitung Branch

January 2001 - December 2007

Case series “A high

clinical suspicion and familiaritywith the various radiologic findings of scrub typhus areimportant in providing early diagnosis and proper treatment,and thus helping to reduce patient morbidity”

2007 in Mackay Memorial Hospital, Taitung Branch, 136 cases of scrub typhus were diagnosed. The diagnosis of scrub typhus was made from patients’ blood samples based on serology using either the indirect microimmunofluorescent antibody for O. tsutsugamushi or polymerase chain reaction at the Center for Disease Control in Taiwan. We retrospectively studied the medical records from the patients infected with scrub typhus.

antibody for O. tsutsugamushi or polymerase chain reaction at the Center for Disease Control in Taiwan.

60.3% subjects was 40.7 ±21.5 years (range, 2–87 years)

ThailandAung-Thu et al. 200485

Southeast Asian J Trop Med Public Health 35; 4; Dec 2004

5/7Medium / unclear risk of bias+

Thailand, Nakhon Ratchasima Province, Maharat Hospital

12 Nov 2002 – 4 Jan 2003

ST Cross sectional study

Case series

“The current study was conducted in order to discover the gastrointestinal manifestations of septic patientswith scrub typhus and to compare these manifestations with those in non-scrub typhus patients”

CompleteWe conducted the study, in this hospital’s medical wards and ICU for 7 weeks, among 80 septic patients. The inclusion criteria for study subjects were: all patients, both male andfemale, who were admitted to the medical wards or ICU unit at Maharat Hospital during the study period, age≥ 14 years, and septic, by clinical evi-dence and who met two or more of the following conditions: T >38ºC or T< 36ºC, tachypnea (RR > 20 breaths/minute), tachycardia (HR >90 beats/minute), PaCO2 <32 mmHg (<4.3 Kpa), white blood cell count >12,000 cells/mm3 or <4,000 cells/mm3 or 10% immature forms. Pregnant women and patients who stayed in hospital <24 hours werenot included in this study.

IFA serology for scrub typhus was performed by a trained laboratory techincian at the hospital.IgM ≥ 400 or IgG ≥ 1,600 was defined as scrubtyphus infection.

20 8/20 = 40.0%

Median age 57.5 (30-77) yearsThe proportions of females to males were 60.0% (n=12) vs 40.0% (n = 8)

Bhengsri 5/7 Thailand ST Retrospective “We assessed Complete Frozen sera were sent on dry ice 22 0/22 = F: 8, M: 14 (63.6%)

et al. 201686



Chiang Rai (northern Thailand): 2002 – 2005

Khon Kaen (northeastern Thailand): 2002 – 2004

Nakhon Phanom (northeastern Thailand): 2004 - 2005

analysis of samples collected in prospective cohort study

Case series

the seroprevalence as a measure of past infection in the population and frequency of acute infection of sennetsu neorickettsiosis (SN), spotted fever group rickettsiosis (SFG), murine typhus (MT), and scrub typhus (ST), among patients with acute febrile illness in Thailand.”

Patients aged 7 years presenting with a history of fever for less than 2 weeks and a documented temperature of > 38C at the time of evaluation. Patients were excluded if they had an apparent focal infection or a specific viral infection that could be diagnosed clinically, had received blood products in the previous 6 months, or required immediate transfer to a larger hospital. Research nurses collected blood at enrollment and at the convalescent visit 3–5 weeks later.

to the French National Reference Center for Rickettsiosis in 2013 where immunofluorescent assays (IFA) were performed to detect anti-rickettsial antibodies as previously described. The IFA was considered positive if IgG titres were ≥ 128 and/or IgM titres were ≥ 64 in either acute or convalescent sera. A seroconversion including a rise in IgG or IgM antibody titres between acute and convalescent sera was considered as a serologically confirmed acute infection.

(of 1603 febrile patients tested)

0%Median age = 24.5 y

Chanta & Chanta 200587

J Med Assoc Thai 2005; 88 (12): 1867-72


Thailand, Chiang Rai, Chiang Rai Regional Hospital

June 2003 – December 2003

ST Case series

case series

“The purpose of this study is to present the clinical manifestations, laboratory findings, and therapeutic outcomes of pediatric scrub typhus.”

CompleteSerum samples from children who presented with fever for more than 5 days and without obvious causes were tested for antibody against O. tsutsugamushi. Diagnosis was confirmed by IFA result. Children with the diagnosis of scrub typhus were enrolled and followed prospectively by the same physician. Complete blood count (CBC) and peripheral blood smear for malarial parasite, liver function test (LFT), Widal test, Weil Felix test and chest x-ray (CXR) were done on the first day of admission in all patients and repeated periodically if necessary.”

The diagnosis of scrub typhus in the present study was based on the presence of a single indirect immunofluorescent antibody (IFA) titre against O tsutsugamushi of > 1:400(6) or positive result by the INDX Dip-s-ticks scrub typhus test(7) (INDX® Dip-s-ticks®. O tsutsugamushi. PANBIO INDX, Inc Baltimore, MD 21227 USA).

20 15/20 = 75.0%

F: 7, M: 13 (65.0)

Mean age = 6.45y (range 1.25 – 14)

3 cases were (mis)diagnosed as dengue virus infection before admission.

14 patients had 1 eschar, 1 patients had 2 eschars.

Chanta & Phloenchaiwanit 201588

J Med Assoc Thai 2015; 98


Thailand, Chiang Rai, Chiangrai Prachanukroh Hospital, Pediatric Ward

June 2010 –

ST Prospective randomized trial

Case series

“The objective of this study was to evaluate the efficacy of azithromycin compared to doxycycline or chloramphenicol in the

ClinicalAll hospitalized children age less than or equal to 15 years who presented with fever more than or equal to 38°C for more than five days were screened and enrolled. Inclusion criteria were 1) clinical history and physical examination compatible with scrub typhus

Positive result by dipstick test for scrub typhus (SD Bioline® tsutsugamushi test).

57 Total: 23/57 = 40.4%

Azithromycin:12/29 = 41.4%

Total: F:19, M: 38(66.7%)Mean age = 6.4 y29 x 6.6 = 191.428 x 6.2 = 173.6191.4 + 173.6 = 365365 / 57 = 6.4

Azithromycin (n = 29):F: 11, M: 18

(8): 756-60

May 2013 treatment of uncomplicated pediatric scrub typhus.”

such as high fever, headache, lymphadenopathy, myalgia, and eschar, and 2) laboratory finding showed positive result by dipstick test for scrubtyphus (SD Bioline® tsutsugamushi test).

Doxycycline or chloramphenicol:11/28 = 39.3%

Mean age = 6.6 3.4y

Doxycycline or chloramphenicol (n = 28): F: 8, M: 20Mean age = 6.2 4.0y

Chinprasatsak et al. 200189

Southeast Asian J Trop Med Public Health 32;1;March 2001


Thailand, Nakhon Ratchasima Province, Maharat Hospital

(mid) Nov 1995 – (early) Jan 1996


Case series

To prospectively evaluate a dipstick test using a dot blot immunoassay forthe serodiagnosis of scrub typhusin patients presenting to hospital with acute febrile diseases.

CompleteInpatients and outpatients aged 14 years or older with an oral temperature of at least 37.8ºC were included in the study (“acute FUO”)

The diagnosis of scrub typhus was made if there was either a four-fold or greater rise in IIP titre to at least 1:200, or if a single IIP test detected IgM antibody titres of ≥1:400 and/or IgG antibody titres of≥1:1,600

30 13 / 30 = 43.3%

Male n = 20 (66.7%)Female n = 10 (33.3%)Mean age 42 (14-69)

IP serotesting was not performed on convalescent sera in 15 patients.

McGready et al. 201490

PLoS NTD. 2014;8(11):e3327.


Thailand, Mae Sot, Shoklo Malara Research Unit

2004 - 2006


Case series

To undertake a detailed analysis ofST and MT (murine typhus) cases from a previously published fever cohort and ofthe published literature to provide further detail on pregnancyoutcomes in relation to treatment.

Complete“Febrile (aural temperature .37.5uC)pregnant women following the antenatal clinics of Shoklo Malaria Research Unit (SMRU) were offered a fever screen. None of the ST and MT results were available for the patient as these were initially stored and later analyzed off-site. Women were admitted and treatment was initiated according to the clinical examination and available laboratory test results. This impliespatients may have been treated for other infections such as malaria because the result was immediately available and consistent with the clinical picture. ST or MT may not have treated as it was not suspected and the laboratory result was unavailable.”

Typhus was confirmed by PCR and/or in vitro isolation of Rickettsia spp. and/or positive reference serology measured by four-fold rise in paired sera IFA to define acute infection as MT (Rickettsia typhi) or ST (Orientia tsutsugamushi).

Additional cases:Additional cases were tested with a rapid diagnostic test, which is nonspecific testing IgG, IgM and IgA Orientia tsutsugamushi antibodies. Acute and convalescent serum was collected. ST was confirmed by PCR and/or positive reference serology measured by four-fold rise in paired sera IFA.

11 2/11 = 18.2%

F: 11.Mean age = 27 7 (range 17 – 38)

Live born: 7/11

Silpapojakul et al. 200491

Tr RSoc of Trop Med Hyg2004;98(6):354-359


Thailand, Songkla, Hat-yai, Hat-yai Hospital

April 1985 – May 2002


Case series

To evaluate the clinical and laboratory manifestations, hospital course, treatments, and outcomes of children with scrub typhus.

Clinical / unclearPatients with laboratory-confirmedscrub typhus were identified through a search of laboratory records of the rickettsial serological tests done between April 1985 and May 2002.

“ A serologically-confirmed case was defined as a child with a single high (≥ 1:400) titre or a four-fold or greater increase in serum antibody titre against pooled Karp, Kato, and Gilliam strains of O. tsutsugamushi antigens by either indirect fluorescent antibody (IFA) or indirect immunoperoxidase (IIP) antibody testing.”

69 5/69 = 7.2%

NR for subgroup with information on eschar presence.

Sirisanthana et al. 200392

Ped Inf Dis J.2003;22(4):341-345


Thailand, Chiang Mai, Chiang Mai University Hospital



case series

To describe the epidemiological, clinical and laboratory features of scrub typhus in Thai children.

Complete“All pediatric patients (age 15 years) who had obscure fever for > 5 days were tested for antibody against O. tsutsugamushi, Rickettsia typhi (the causative organism of murine typhus), Leptospira spp., Mycoplasma spp., and Salmonella spp. (Widal test).” Children with the diagnosis of scrub typhus were enrolled and followed prospectively.

“Scrub typhus was diagnosed on the basis of either a single indirect immunofluorescent antibody (IFA) titre against O. tsutsugamushi of 1/400 or a 4-fold or greater rise in IFA titre to at least 1/200. The antigens used were pooled Karp, Kato and Gilliam strains of fibroblast (L 929)-propagated O. tsutsugamushi prepared at the Department of Medical Sciences of the MOPH.

30 21/30 = 70.0%

Mean age = 6.8 y (range 1.25 – 13)F: 7, M: 23(76.7%)

Only 1 patient reported a definite history of mite bite.

Twenty patients had one eschar each, and 1 patient had two adjacent eschars.

Sonthayanon et al. 200693



Thailand, Udon Thani, Udon Thani Hospital

October 2000 -December 2001


Case series

To compare PCR amplification of a region of the 16S rRNA geneof O. tsutsugamushi for the early diagnosis of 183 cases of scrub typhus in an endemic area of Thailand.

Complete:Patients were enrolled into the study if they were ≥15 years of age, had fever (> 37.8°C) of unknown cause, had given written informed consent to participate, and agreed to out-patient follow-up and a further blood test at 2 weeks. Patients with a blood smear positive for malaria parasites or other definable infections such as pneumonia or urinary tract infection were excluded. Blood was drawn on admission for aerobic bloodculture, serologic testing, and molecular diagnostics. A second (convalescent) serum sample was taken at ∼2 weeks after presentation.

The IFA assay was used as the reference standard for the diagnosis of scrub typhus. This was performedon paired (acute and convalescent) sera at Siriraj Hospital using established methodology.10 In brief, pooled antigens of O. tsutsugamushi strain Karp, Kato and Gilliam were spotted on a glass slide kindly provided by The National ResearchInstitute of Health (NIH), Ministry of Public Health, Thailand.Initial screening was performed using a dilution of 1:50, after which positives were assayed using 2-fold serial dilutions from 1:100 to 1:6,400. Antibody binding was determined using a fluorescent microscope (Olympus BX50, Olympus

183 11/183 = 6.0%

Demographics NR

Corporation, Tokyo, Japan). Known positive and negative control sera were run with each experiment. A positive result for scrub typhus infection was defined as a single IFA IgM titre against O. tsutsugamushi of ≥1:400 or a 4-fold or greater risein IFA IgM titre,11 and/or a single IgG titre ≥ 1:800 or a 4-fold or greater rise in IgG titre.

Sriwongpan et al. 201394

Risk Man Healthcaree Pol 2016;6 43-49


Thailand, Chiang Rai and Chiang Mai hospitals

2004 – 2010


Case series

To explore clinical risk characteristics that may be used to forecast disease severity under routine clinical practice

ClinicalPatients were those diagnosed with scrub typhus, registered in two university-affiliated tertiary care hospitals in Chiang Rai and Chiang Mai, in the north of Thailand, from 2004 to 2010. The guidelines for diagnosis used by the two hospitals followed the modified World Health Organization recommended sur-veillance standards:

- Patients with both exposure to chiggers (stayed or went into risk areas with 2 weeks before onset symptoms) and reported acute fever (within 2 weeks of onset of symptoms)

- Accompanied by at least one: headache/myalgia/profuse sweating/cough/conjunctiva injection/lymphadenopathy.maculopapular rash

- Also accompanied by at least one: Presence of eschar or positive immunochromatographic test for scrub typhus

“Positive immunochromatographic test for scrub typhus” Details NR.

526 290/526 = 55.1%

Male: 291/526 = 55.3%Mean age = 29.3 y357 x 25.0 = 8925100 x 32.6 = 326069 x 46.7 = 3222.38925 + 3260 + 3222.3 = 15407.315407.3 / 526 = 29.3

Non-severe (n = 357):Mean age = 25.0 20.6 yo

Severe (n = 100):Mean age = 32.6 21.8 yo

Deceased (n = 69):Mean age = 46.7 20.2 yo

Suttinont et

4/7Mediu

Thailand, Maharat


To investigate the causes of

CompleteThe adult patients who presented

Scrub typhus was diagnosed using a micro-

135 41/135 =

Demographics NR for ST subgroup.

al.200695

Ann Trop Med Para 2006;100(4):363-370.

m risk of bias+

Nakhon Rachasima Hospital, Loei Hospital, Banmai Chaiyapod Hospital, Chumphon Hospital, and Ratchaburi Hospital

July 2001 – June 2002

Case series

undifferentiated febrile illness in rural Thailand.

at any of the hospitals with acute febrile illness (<15 days’ duration) in the absence of an obvious focus of infection were prospectively investigated. Only patients with malaria and those with clinically obvious dengue-virus infection, who met the World Health Organization’s criteria for diagnosing dengue infection (WHO, 1997), were excluded. Blood samples were taken from all of the patients and checked for aerobic bacteria and leptospires by culture. In addition, at least two samples of serum were collected at different times (on admission and 2–4 weeks post-discharge) from each patient and tested, in serological tests, for evidence of leptospirosis, rickettsioses, dengue and influenza.

immunofluorescence assay with three O. tsutsugamushi strains (Karp, Gilliam, and Kato). Individuals found to have titres of anti-rickettsial antibodies in their convalescent sera that were at least four-fold greater than those seen in their acute sera, and those found to have titres of anti-rickettsial antibodies of at least 1:400 were considered to be confirmed cases of scrub typhus.

30.4%An eschar was detected in 42 patients, including one patient who was culture-positive for leptospirosis (and had a high titre of anti-O. tsutsugamushi antibodies).

Thitivichianlert et al. 200996

Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2009;92 Suppl 1:S39-46.


Thailand, 21 provincial army hospitals (seven in the central region, four in the north-eastern region, five in the northern region and five in the southern region)

June 2005 – October 2006


Case series

To prospectively study the incidence of rickettsial infection in patients with acute fever in rural Thai army hospitals and evaluate the clinical use of the Dot-ELISA test compared to the immunofluorescent assay in the diagnosis of scrub typhus.

CompleteInclusion criteria included patients over15 years from the Outpatient Department of hospitals who presented with acute fever; history of fever not more than two weeks, oral temperature equal to or more than 38°C. Exclusion criteria included patients who had clinical signs and symptoms of localized infection such as skin and soft tissue infection, urinary tract infection; those who had received clinical diagnosis of specific diseases such as acute appendicitis, acute pneumonia, acute pelvic inflammatory disease; and those who were in immunosuppressive states.

After enrollment, the first serum sample were collected and divided into two samples for scrub typhus testing. One sample was tested by the Dot-ELISA for IgG and IgM antibodies to O. tsutsugamushi. A second serum sample was tested for IgG and IgM antibodies to O. tsutsugamushi by immunofluorescent assay. IFA tests were interpreted aspositive if the titre of IgM or IgG antibodies was equal to or more than 1:400. At least one to two weeks after the first serum sample was drawn, the second serum sample was collected and tested similar to the first sample.

10 1/10 = 10.0%

F: 3, M: 7Mean age = 37.4 yo (range 21 – 59). Age was given for 9 out of 10 patients.

Watt et al.200097

5/7Medium risk of bias

Thailand, Chiangrai Regional Hospital


Case

To compare the efficacy of rifampicin with that of

ClinicalMore than 12.800 patients with fever were assessed. Of these, only 2090 patients were serotested

“Serum samples were screened for O tsutsugamushi antibody before enrolment by a dot-blot ELISA rapid test (DipSticks,

78 4/28= 14.3%

3/26=

Total: F: 36, M: 42 (53.8%)

Doxycycline (n = 28):F: 11, M: 17

Lancet. 2000;356(9235):1057-1061

+Unknown period

series standard doxycycline therapy for the treatment of potentially drug-resistant scrub-typhus infections.

for scrub typhus because > 10.710 patients did not have symptoms indicative of scrub typhus. Out of 2090 patients that were tested for scrub typhus, 357 patients were seropositive.

Integrated Diagnostics, Baltimore, MD, USA). O tsutsugamushi infection was confirmed by the indirect immunoperoxidase test if IgM antibody titres were more than 1:400 or if IgG titres were more than 1:1600.

11.5%

3/24= 12.5%

Total:10/78=12.8%

Median age = 31 (range 19 – 65)

600 mg rifampicin (n = 26):F: 11, M: 15Median age = 33 (range 19 – 55)

900 mg rifampicin (n = 24):F: 14, M: 10Median age = 34 (range 18 – 57)

VietnamNadjm et al. 201498

Trans R Soc Trop Med Hyg 2014;108: 739-740.


Vietnam, Hanoi, Bach Mai Hospital (National Hospital of Tropical Diseases)

2001-2003


case series (prospective)

To report the frequency, clinical features and outcome of scrub typhus in patients admitted to a tertiary referral hospital in Hanoi.

ClinicalAdults and children admitted to the Infectious Disease Department of Bach Mai hospital (now the National Hospital of Tropical Diseases), between 2001 and 2003, had serological testing performed for scrub typhus by ELISA (Panbio, Melbourne, Australia) or Tsutsugamushi rapid test (SD Bioline, Kionggi, South Korea), if they presented with either fever with eschar, lymphadenopathy and rash or fever with no signs of pneumonia, urinary infection or other confirmed infections. A positive response (IgG/IgM by ELISA or IgG/IgM/IgA by rapid test) was considered a positive case of scrub typhus.

IgG/IgM by ELISA or IgG/IgM/IgA by rapid test

251

(251/749 were positive)

155/251 = 61.7%

Demographics NR

“Although cases were found in all age groups, only 8 (8/251; 3.2%) confirmed cases were found in children (≥ 15 years).”

Table 2. Data extraction forms Mediterranean spotted fever and African tick bite fever studies

Source (first author, year of publication, journal)

Quality

Country, region (study site), Time-frame

Type of Rickettsiosis (MSF / ATBF / ST)

Study design: original and after inclusion in review

Study objective

Methods of selectionBiased / Ideal

Laboratory methods used and cut-off values

Number of included patients

Eschar rates

Other findings relevant for this review (e.g., demographics)

Notes by reviewer

AlgeriaMouffok et al.200999

International Journal of Infectious Diseases (2009);13(2):227-35.


Algeria, Oran, Oran Teaching Hospital


MSF Prospective cohort study / cross-sectional survey

Case series

NR(“We report herein a prospective study conducted in Oran, the second largest city inAlgeria. This disease has not been properly described in Oran or in other Algerian cities.”)

BiasedAll patients seen at the infectious diseases consultation department of the Oran Teaching Hospital with a suspicion of rickettsiosis (high fever, skin rash, headache, myalgia, arthralgia, and/or eschar) during the period between January 2004 and December 2005 were included in the study.

For each patient, an acute-phase serum sample was obtained within 2 weeks after the onset of symptoms and, when possible, a convalescent-phase serum sample (collected 1 to 2 weeks later) was also obtained. The IF assay was considered positive if: (1) IgG titers were 128 and/or IgM titers 64 for R. conorii and (2) IgG titers were 64 and/or IgM titers 32 for other rickettsial antigens.

Sera were sent to the World Health Organization (WHO) collaborative center for rickettsial diseases in Marseille, France. IgG and IgM antibody titers were estimated by the immunofluorescence (IF) assay, using nine spotted fever group rickettsial antigens (R. conorii conorii, R. conorii israelensis, Rickettsia africae, Rickettsia sibirica mongolotimonae, R. aeschlimannii, R. massiliae, Rickettsia helvetica, Rickettsia

167 123/167 = 73.7%

Mean age = 38.1 2.7 years (range 0—80 years)

Patients with MSF were predominantly male.

103 patients with single eschar, 14 with two eschars and 6 with three eschars.

slovaca, and Rickettsia felis) and a typhus group antigen, Rickettsia typhi. When cross-reactions were noted between several rickettsial antigens, the standard procedure of the Unite´ des Rickettsies was followed. This includes Western blotting and cross-adsorption studies to complement the IF Assay.

BulgariaBaltadzhiev et al. 2012100

Folia Medica 2012; 54(1): 36-43


Bulgaria, Plovdiv region, St. George University Hospital

1993 - 2011

MSF Case series

Case series

To investigate the epidemiological characteristics of the re-emerging MSF in Plovdiv city and its suburbs, in order to update the surveillance and control of the disease.

Biased / Unclear“Our data are based onpatients admitted to the Clinic of Infectious Diseases at St George University Hospital.The total number of patients infected and treated for MSF between 1993 and 2011 was 1254. The disease was diagnosed clinically and etiologically confirmed in 907 patients (72.32%) by IFA.”

The diagnosis of MSF was etiologically confirmed by positive antibodies response to a specific antigen- R. conorii with indirect immunofluorescent assay (IFA), performed by the Referent Rickettsioses Laboratory at MMA, Sofia.

Infected and treated for MSF: n = 1254

Diagnosed clinically and etiologically confirmed:n = 907 (72.3%)

Total: 970/1254= 77.4%

Phase 1 (1993 – 2003) (n = 774):77.04%.774 x 0.7704 = 596 patients with an eschar

Phase II (2004 – 2011) (n = 480):77.91%480 x 0.7791 = 374 patients with an eschar

F: 612, M: 642 (51.2%)Age NR

Single eschar in 72.50% of patientsTwo eschars were observed in 21 patients (4.37%)Three eschars were observed in 5 patients (1.04%)

Pishmisheva et al.

3/7Unclea

Bulgaria,Pazardjik

MSF NR To analyze the clinical

BiasedDiagnosis of MSF was based on

Single-positive antibody titre >128, using

Total: 1510

1029/1510 =

Mean age=41.1y10.6*257= 2724.2

2014101

Ped Inf Dis J 33;5; May 2014

r / Medium risk of bias? / +

Regional Hospital (ID ward)

1995 - 2012

Case series patterns of MSF in children and compare them with disease features in adults.

the following criteria: presence of 2 cardinal signs as fever, “tache noire” and rash and a single-positive antibody titre >128Exclusion criteria were as follows: age>18 years; absence of informed consent; presence of severe disease,defined by neurological signs (stiff neck or seizures), hemorrhagic manifestations or sepsis; alanine-aminotransferase concentration >250 U/L; creatinine concentration >1.5 mg/dL and history of treatment with antibiotics potentially active against Rickettsia species (eg, macrolides, tetracyclines, chloramphenicol or quinolones) 7 days before hospitalization.

immunofluorescence assay (IFA test Rickettsia conorii—Spot IF, BioMerieux, Marcy L’Etoile, France). Diagnostic laboratory confirmation byimmunofluorescence assay was performed at the Military MedicalAcademy in Sofia.

Children: 257

Adults: 1253

68.1%

Children: 187/257=72.8%

Adults: 842/1253= 67.2%

47.3*1253=59266.92724.2 + 59266.9=61991.161991.1/1510 = 41.1

Children mean age: 10.6 (+/- 0.28)Children males: 133 (51.8%)

Adults mean age: 47.3 (+/- 0.42)Adults sex NR

Children: 7 (2.7%) of the children had more than one eschar.

CroatiaPunda-Polic et al. 2008102

Epidemiol. Infect. (2008), 136, 972–979.


Croatia, Split, University Hospital

1982 – 2002

MSF Retrospective cohort study

Case series

To describe the incidence, clinical and epidemiological features of these three zoonoses (rickettsioses) recognized in hospitalized patients in southern Croatia. This study summarizes data collected over 21 years.

BiasedMSF was suspected in patients presenting with two of the following symptoms: fever >38C, headache,eschar (tache noire), and a macular or maculopapular rash

For each patient, an acute-phase serum specimen was obtained; a convalescent-phase serum specimen was obtained at least 2 weeks later. Serum samples were tested prior to 1988 by complement fixation test. After 1988, the indirect immunofluorescence assay (IFA)using commercially available antigens (Rickettsia conorii – Spot IF, bioMérieux, Marcy l’Etoile, France) was performed to detect the titresof IgM and IgG in patient sera. A diagnosis was considered established when characteristic symptoms were present and associated with either a seroconversion or at least a

126 80/126 = 63.5%

Male 79/126 = 62.7%Female: 47/126 = 37.3%(incidence rate 33.88/100 000 inhabitants), and 47 (37.3%) were female (incidence 19.52/100 000)(Table 1). The male:female ratio was 1.7:1 with significantdifference (P=0.0024).The mean age of patients was 33.3 years (S.D.±21.9; range 11 months to 79 years)

fourfold increase in antibody titres

FranceBotelho-Nevers 2011103

J Antimicrob Chemother 2011; 66: 1821–1830


France, countrywide.

January 1999 - December 2009


Case series

To evaluate the epidemiological and clinical characteristics and treatment of MSF cases to identifyrisk factors associated with severe MSF in a retrospective cohort.

Biased:Identification of cases from the French National Reference Centre for Rickettsial Diseases in Marseilles. A ‘confirmed’ MSF case was defined as the presence of signs and symptoms compatible with the disease (e.g.fever, tache noire and rash) and at least one confirmatory laboratory finding.The epidemiological and clinical data were collected retrospectively using a standardized form. For confirmed and probable cases of MSF that were diagnosed between January 1999 and December 2009, the medical charts were reviewed retrospectively to obtain additional data about each case (specifically the epidemiological and demographic characteristics, clinical presentation, time between appearance of signs and treatment, laboratory findings, antibiotic regimen used and outcome data).

Tests were done in French National Reference Centre for Rickettsial Diseases in Marseilles.Positive PCR assay with specific primers for R. conorii conorii from the blood or a skin biopsy of the eschar, or isolation of R. conorii conorii from the clinical specimens. The identification of rickettsial antigens by immunochemistry from the biopsy was also considered confirmatory, as described elsewhere. A ‘probable’ MSF case was defined when a patient had a score of > 25 according to the MSF diagnostic score chart. For the majority of the patients, a serum sample was obtained within 2 weeks following the onset of symptoms, and, when available, a late-phase sample(2 weeks after the onset of symptoms) was obtained. Immunoglobulin (Ig) and IgM antibody estimation was performed with a microimmunofluorescenceassay, which is a reference method for rickettsial diseases, as reported elsewhere. Rickettsia conorii strain Malish was used as the antigen. Titres of 1:64 for IgG and 1:32 for IgM were defined as the cut-off values.

161 109/150 = 72.7

Male: 93 (57.8%)Mean age 50.2 years (range 1–85 years, SD18.9)

Multiple eschars 12/147

Region of acquisition: south of France for 115 of the cases and in the Mediterranean basin by French travellers for the remaining cases (Portugal n¼12 cases, Morocco n¼11, Algeria n¼10, Italy n¼4, Spain¼1 and Tunisia n¼1). MSF was considered confirmed in 41cases and probable in 120 cases and the median diagnostic MSFscore was 36.

GreeceGermanakis 5/7 Greece, MSF Case series To present the Biased Immunofluorescence assay 15 8/15 = F: 5, M: 10 (66.7%)

et al.2006104

Ann. N.Y. Acad. Sci. 1078: 263–269 (2006).


Crete, General Hospital of Sitia

December 2000 – July 2003

Case seriesclinical, epidemiological, laboratory, and therapeutic data of 15 cases of MSF.

Diagnosis of the disease, on the basis of clinical symptoms and signs, was further confirmed by serology. The presumptive clinical criteria for the diagnosis of MSF were the presence of fever, and/or headache, and/or skin rash, and/or aneschar at the tick bite site. Immunofluorescence assay test (IFAT) was performed in acute-phase and convalescent-phase serum samples of patients with suspected MSF

(IFA) (IgM and IgG, (Bio Merieux, Marcy L’Etoile, France). A case was defined positive by either the presence of an IgM titer ≥ 1/100, or a fourfold or higher increase in IgG titers against R. conorii between two assays, or both findings. In the majority of patients, three serum samples were obtained: the first sample on admission, the second within a mean time of 2 weeks after admission, and the third, when possible, approximately 1 month later.

53.3%

53% of 15 patients:15 x 0.53 = 8 patients

Median age = 52 y (range 23 – 76)

Five patients had a history of tick bite, while three reported the presence of ticks in their environment.

ItalyColomba et al.2011105

Le Infezioni in Medicina, n. 4, 248-253, 2011


Italy, Sicily, Palermo, Paolo Giaccone University Polyclinic

January 2007 – August 2010

Giovanni Di Cristina Children’s Hospital:January 1997 – December 2004

MSF Case-control study

Case series

To compare the clinical and laboratory characteristics of Mediterranean Spotted Fever (MSF) in the pediatric and adult population.

Biased / unclearThe analysis included all adult patients with MSF diagnosed at the Institute of Infectious Diseases, Paolo Giaccone University Polyclinic in Palermo, during the period January 2007- August 2010 and all the children diagnosed with MSF at the G. Di Cristina Children Hospital in Palermo during the period January 1997- December 2004.

Diagnosis of MSF was confirmed by indirect immunofluorescence assay, at admission and two weeks later, using a commercial kit (Rickettia conorii-spot; bio-Merieux, Marcy l'Etoile, France). The Rickettsia PCR was carried out on some samples from adult patients.

Total: 473

415 paediatric patients

58 adults

Total: 297/473 = 62.8%

Children:263/415 = 63.4%

Adults:34/58 = 58.6%

Total: M=289 (61.1%)

Paediatric cases (n = 415):F: 170, M: 245Median age = 6y (range 1 month – 15 yo)

Adult cases (n = 58):F: 14, M: 44Median age = 49y (range 15 – 77)

Micalizzi et al.2007106

Infez Med. 2007 Jun;15(2):105-10.


Italy, Sicily, Palermo


MSF Retrospective case series

Case series

The aim of this study is to evaluate the incidence of abnormal liver function in consecutive patients diagnosed with MSF.

BiasedThis is a retrospective study in which patients were diagnosed with MSF based on the clinical presentation (fever, rash, eschar, general malaise, headache) and serological tests.Patients with liver diseaseand pre-existing Rickettsia infection were excluded.

Serological tests include indirect immunofluorescence (IIF) and ELISA. Titres were considered positive if they were 1:40 by IIF or 1:100 by ELISA. For a safe diagnosis was necessary to show a significant increase in antibody titerin at least 2 successive serum samples taken to 15 days apart from each other, the first in the acute phase of the disease, the second convalescent.

49 59.2% (29/49)

F: 21, M: 28 (57.1%)Mean age = 57.1y (range 21 – 83)

“Eighteen patients (36.7%) had both transaminases and AP above the normal limits.”

Vitaliti et al. 2015107

IJID 31 (2015) 35–40ID


Italy, Sicily, Catania, Policlinico-Vittorio Emanuele University Hospital, University of Catania, Paediatric Operative Unit

1987-2010


Case series (only rickettsia positives included here)

Analysis of the incidence of Rickettsioses in childhood and the clinical, immunological and serological parameters of infected patients.

Ideal:All included patients had been admitted to the Operative Unit after 7 days of fever, not responding to common antibiotics, and generalised macular-papular erythematous lesions were included. All patients underwent full routine, metabolic and infective blood analyses, including the coagulation profile, inflammatory indexes, immunological profile, and serologic parameters with serum-diagnosis evaluation. Children between 2 and 11 years of age who were admitted.

Weil-Felix, Vidal-Wright (with 4 R. conorii antigens: OX19, OXK, OX2, OXQ). Serum IgA, IgM, IgG and complement. Cut-off values not clearly reported.

55 16/55 = 29.1%

Sex: F: 26 (47.3%), M: 29 (52.7%)Mean age: 5.6y (SD 3.12)

PortugalCrespo et al.2015108

SpringerPlus (2015) 4:272


Portugal, Coimbra, Centro Hospitalar e Universitário de


To better characterize evolution of MSF between 1989 and 2012

Biased / Unclear“The authors made a retrospective review of the files of the patients followed-up for MSF (as defined by the clinical team that cared for the patient).”

“Serologic confirmation was considered when one of the following criteria was met: IgG >128 in acute phase test, seroconversion or fourfold titre rise between acute and convalescent test. In the cases in

250 151/250 = 60.4%

F: 116, M: 134 (53.6%)Mean age = 58y (range 11 – 92)

Contact with dogs was referred by 34% (n = 85)and only 10% (n = 26)

Coimbra


which this did not happen, clinical evaluation was considered the most important diagnostic criteria.”

noticed a tick bite.

Multiple eschars were found in 2% (3/151)

De Sousa et al.2008109

The Journal of infectious diseases. 2008;198(4):576-85.


Portugal, Portuguese hospitals

1994 - 2006

MSF Prospective case series

Case series

“Because our previous studies were not exhaustive, we conducted a larger study to determine the risk factors for death in Portuguese patients who had a diagnosis of MSF confirmed by identification of the strain causing the infection.”

Biased / UnclearPatients were admitted to Portuguese hospitals with a clinical diagnosis of MSF confirmed by isolation of Rickettsia species from blood or detection of rickettsial DNA in skin biopsy sample by polymerase chain reaction (PCR) at the Portuguese National Institute of Health during 1994–2006.

1. Isolation from blood2. DNA detection in skin biopsies (PCR)3. Serology: the diagnosis of R. conorii infection was confirmed when serum samples obtained from patients with acute infection contained IgM antibodies at a titer of32 and/or IgG titer of 128 or there was a 4-fold increase in titer between serum samples from patients with acute infection and samples from convalescent patients. The cutoff for a positive result for R. conorii infection was established by the Portguese National Institute of Health on the basis of previous studies in the Portuguese population and previous studies of Portugal as a country where MSF is endemic. Serum samples from convalescent patients were collected at least 15 days after samples obtained during acute infection.MSF was confirmed in 93 patients by isolation of Rickettsia species from blood and in 47 patients by detection of R. conorii DNA by PCR. Additionally, serologic analysis was performed on 138 serum samples obtained from patients with acute infection and 53

123

(total of 140 patients, eschar evaluated in 123)

61/123 = 49.6%

Sex: F: 75 (53.6%), M: 65 (46.4%)Median age = 60.5 y

An eschar was observed in a significantly higher percentage of patients infected with the Malish strain (38 [60%]), compared with patients infected with the ISF-strain (23 [38%]).

serum samples obtained from convalescent patients.

Meireles et al.2015110

Acta Med Port. 2015 Sep-Oct; 28(5):62-31.


Portugal, Porto, Hospital de Santo António


MSF Retrospective case-control study

Case series

To re-evaluate the clinical picture of MSF and to identify prognostic factors related to severe disease.

BiasedThis is a retrospective hospital-based study. Patients aged 18 years, who fulfilled the criteria of ICD9 (ICD0-CM 0,82 – 0,839), and who were diagnosed clinically (fever, rash and eschar) and/or serologically (IF or ELISA techniques) and/or histologically with MSF were included in analysis.

Serological test performed were IF and ELISA techniques (details NR).

71 Total:44/71 = 62.0%

Group 1 (general ward) (n = 54):34/54 = 63.0%

Group II (medium/intensive care or death) (n = 17):10/17 = 58.8%

52.1% males (n =0.521x71=37)F = 34

Mean age = 63.3 16.7 yo (range 25 – 92)

RomaniaPitigoi et al. 2013111

Biomed Res Int 2013 ID 395806


Romania, Bucharest, National Institute Infectious Diseases

2000 – 2011


To raise awareness about MSF in certainregions of Romania, which is not a Mediterranean country, and to describe clinical and epidemiological characteristicsin this area.

Biased / Unclear:Retrospective study of patients agedover 14 years, reported as having MSF according to epidemiological,clinical, and laboratory characteristics by the National Institute of Infectious Diseases “Prof.Dr.Matei Bals” between2000 and 2011 was conducted. According to the diagnostic criteria described by Raoult et al., patients were further analysed if they had a diagnosticcriterion score of >25

Paired serum samples collected at10–14 days interval and single serum samples were tested by the indirect immunofluorescence assay method for anti-R.conorii IgG antibody levels. Serum sample dilutions were 1/40and 1/80, and examination of the slides was made on Eurostar III Plus microscope at 400x magnification. The interpretation of the test results was determined by the presenceof apple green fluorescence of cocobacilar morphology, the

171 115/171 = 67.3%

The mean age 52.5 years male to female sex ratio of 1 : 1.06M: 83, F: 88M: 83/171 = 48.5%

fluorescence pattern being the positive and negative controls provided by the kit producer (Rickettsia conorii IFA IgG kit produced by Vircell, Spain). Each positive serum by the screening test was analysed by twofold dilutions up to 1/640.The highest serum dilution with visible fluorescence (positive reaction) was considered the final titre of the serum.

SpainAnton et al. 2003112

Eur J Clin Microbiol Infect Dis (2003) 22:126–128


Sabadell, Barcelona, Spain

1989 - 1999

MSF Prospective inclusion of all with MSF

Case series

To analyze the clinical and laboratory characteristicsof patients diagnosed with MSF at our hospital during the last 11 years.

Biased / Unclear:The diagnostic criteria included the presence of symptoms and signs characteristic of MSF, plus a positive serological result.(NB: “symptoms and signs characteristic of MSF” is not specified)

Indirect immunofluorescence. Seroconversion, a fourfold titre increase between two consecutive samples, or a single titre ‡160.

144 121/144 = 84.0%

Eighty percent of the patients were male (n=115: 79.9%).The mean age was 37.5 years (range, 1–85 years), and 96 of the patients were older than 14 years. Contact with dogs was confirmed for 115 patients.

110 patients had a solitary eschar and 11 having multiple lesions

Bartolomé et al.2005113

Enferm Infecc Microbiol Clin 2005;23(4):194-6


Spain, University Hospital of Albacete

1997 - 2003


Case series

“The aim of this study was to describe the clinical and epidemiological features of spotted fever group rickettsiosis acquired in the province of Albacete, Spain.”

Biased“We retrospectively reviewed the clinical records of patients with a diagnosis of spotted fever grouprickettsiosis and positive serologic results between 1997 and 2003. Criteria for inclusion were as follows:1) seroconversion in IgG to Rickettsia conorii by indirect immunofluorescence, or 2) a single titer of _≥160 with two or three of the following symptoms: fever, eschar, or rash.

Criteria for inclusion were as follows: 1) seroconversion in IgG to Rickettsia conorii by indirect immunofluorescence (BioMérieux, Marcy l'Etoile, France), or 2) a single titer of ≥160 with two or three of the following symptoms: fever, eschar, or rash.

41 38/41 = 92.7%

Mean age = 58 15 y (range 14 – 84)

F: 17, M: 24 (58.5%)

34 patients had 1 eschar, 4 patients had 2 eschars

Juffresa et al. 1997114

An di Med Intern 1997;14;7; p 328-331


Spain, Barcelona, Hospital General Universitario Vall d’Hebron

1986 – 1994


To study the clinical manifestations of 86 patients with Mediterranean Boutonneuse Fever who were admitted in a Univesity General Hospital

Biased“We retrospectively studied the course and evolution of 86 patients diagnosed with MSF”Diagnosis was established by clinical-epidemiological criteria (fever, black spot, exanthema and epidemiological antecedent of contact with dogs) and serologically.

IFA for R. conorii, a positive initial titre > 1/80, and / or seroconversion.

86 52/86 = 60.5%

M: 64 (74.4%), F: 22.Mean age 55y (14-88y).

Six patients had multiple eschars (7.0%)

TunesiaLetaïef et al. 2003115

Ann N Y Acad Sci (2003): 990:327-30


Central Tunisia

1995 - 2001

MSF Case series

Case series

To evaluate a restricted part of the diagnostic scoring system proposed by Roult, considering only clinical and epidemiological parameters, in order to help clinicians diagnose MSF earlier.

Biased / unclear:Sixty-two consecutive charts of patients with suspected MSF (for whom a R. conorii serology was required) were retrospectively reviewed.(NB: “suspicion” is not specified)

MSF was confirmed when antibody titer against R. conorii, detected by indirect immunofluorescence, exceeded 1/128 or if seroconversion was obtained.

45

(N = 60, but 45 with positive serology

60.0% of MSF group (n = 45)

0,59 x 45 = 27 patients with an eschar out of 45

Total group (including 17 patients with negative serology)Sex: M: 41, F: 21Mean age = 39 years

Romdhane et al. 2009116

Clin Mic Inf; 15; Dec 2009


Tunisia, Monastir, Fattouma Bourguiba University Hospital

January 1987 – Decembe

MSF Case series

Case series

To assess the effectiveness of a short course of antibiotic treatment in MSF.

Biased / unclear:All patients diagnosed with MSF at the Department of Infectious Diseases, University Hospital of Monastir, Tunisia, during the period January 1987 to December 2006, were included in this case series. Diagnosis was considered confirmed if the patients had a MSF diagnostic score of >25 according to the scoring system described by Raoult et al.

Indirect immunofluorescence to R. conorii was performed in 194 (97%) cases. Thirty-six patients had two serum samples with four-fold titre elevation within 2 weeks; 73 had a single serum sample with IgG of ‡ 1:128 and IgM of ‡ 1:64; 43 had negative serology both on admission and in convalescence; 42 patients hadnegative serology on admission

200 126/200 = 63.0%

The median age was 38.4 years (range, 15–80 years).Male: 123/200 = 61.5%

r 2006 and did not have another sample taken after 2 weeks. In all patients the diagnosis has been made on the grounds of the Raoult criteria [1].

TurkeyMert et al. 2006117

Journal of Dermatology (2006): 2: 103-107


Turkey, Istanbul

1993 – 2002

MSF Case series

Case series

To (i) determine all cases presenting at the Cerrahpasa University Hospital with MSF between 1993 – 2002; (ii) compare the rate of cases with MSF to the ones admitted with rash and fever; (iii) examine their clinical features; and (iv) to determine the factors predicting MSF in those patients admitted with rash and fever.

Biased / UnclearThe patients admitted with rash and fever between 1993-2002 were determined by their files. The files of the patients with MSF were thoroughly investigated.

The diagnosis of MSF was established according to the epidemiological and clinical features and also by the clinical response to doxycycline therapy within 2 days.Weil-Felix reaction and indirect immunofluorescence assay. Weil-Felix reactions and IFA tests were obtained in 11 and five patients, respectively. The diagnosis of MSF established according to epidemiological and clinical features was confirmed in nine patients with serology.

15 2/15 = 13.3%

Sex: M: 11 (73.3%), F: 4Mean age = 41 (range 17-70)

Four had a history of tick-bite.

Kuloglu et al.2012118

Ticks and Tick-borne Diseases 3 (2012) 297– 303


Turkey, Trakya region

2003 - 2009

MSF Prospective case series

Case series

To evaluate the cases with confirmed diagnosis of MSF in the Trakya region of Turkey.

BiasedA descriptive study was conducted in adult patients (≥12 years) with SFG rickettsioses admitted to the Trakya University Hospital from 2003 to 2009. Patients with high fever, maculopapular rash (involving the palms or soles), and/or a black

In order to obtain acute- and convalescent-phase serum samples, blood samples were collected from each patient on admission to the hospital, and 7–14 days thereafter.An IFA test (R. conorii IFA IgG; Focus Technologies, USA) was considered positive in the

128 90/128 = 70.3%

F: 66, M: 62 (48.4%)Mean age = 52.7 18.4yKulo (range, 12 – 88)

86 patients had a single eschar, 4 had 2 eschars.

inoculation eschar atthe site of the tick bite (tache noire) were included in the study. We used the diagnostic criteria that were proposed in the “Guidelines for the diagnosis of tick-borne bacterial diseases in Europe” developed by The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group on Coxiella, Anaplasma, Rickettsia and Bartonella (ESCAR). According to these criteria, a positive diagnosis was made on the basis of an overallscore of ≥25.

presence of (i) antibodies above the cut-off titres of 1:128 for IgG and 1:64 for IgM; (ii) significant seroconversion; or (iii) a fourfold or greater rise intitre between the acute- and convalescent-phase serum. The sera obtained from 2003 to 2004 were also sent to the World Health Organization (WHO) collaborative centre for rickettsialdiseases in Marseille, France, for confirmation (IFA testing).A PCR (targeting ompA and gltA) was performed on skin biopsy samples; positive samples were sequenced.

Yilmaz et al. 2010119

Trakya Univ Tip Fak Derg 2010;27(2):167-171


Turkey, region NRMay 1987 - July 2007


To evaluate the clinical and epidemiological features of Mediterranean spotted fever cases and their response to treatment with antimicrobial agents

BiasedSixteen cases admitted to our clinic with high fever, maculopapular rash and headache between May 1987 and July 2007 and diagnosed with rickettsioses were evaluated retrospectively.

Indirect immunofluorescence antibody (Rickettsia conorii- Spot IF, BioMerieux, Marcy L'Etoile, France) has been performed, as a serological test and positivity was considered when antibody titers ≥1/40. The diagnosis of MSF was established according to the epidemiological and clinical features and also by the clinical response to doxycycline therapy approximately within two days. Raoult score was also used for diagnosis of the cases.

16 8/16 = 50.0%

Mean age: 38.9±13.0 (range 18 – 64)Male: 12/16 = 75.0%

TravellersJelinek & Löscher 2001120

J Travel Med 2001; 8:57–59.


Germany, Munich

1992 - 1998

MSF and ATBF

Case series

Case series

“In order to identify clinical and epidemiological features in tick typhus among travellers, we

Ideal“Tick typhus was diagnosed in 78 German patients returning from endemic countries who presented to our out-patient clinic. Travel and case histories were analysed for clinical and epidemiological features in the infection.

“The diagnosis was confirmed by serological testing for antibodies to R. conorii (IgG and IgM) by indirect immunofluorescence test (IFT).”

78 68/78 = 87.2%

F: 34, M: 44 (56.4%)Mean age = 34.3 y (range 14 – 71)

Travel to southern Africa accounted for 73% of the infections. All of them had participated in safaris.

investigated travel and medical histories of patients who presented to our out-patient clinic.”

Serological testing for rickettsial infection was performed in all patients who presented with fever on their return from endemic areas, and had other specific febrile diseases excluded (e.g., malaria).”

Only 17.9% of the patients remembered a tick bite at the location of the eschar.

Jensenius et al.2003121

Clinical Infectious Diseases 2003; 36:1411–7


Norway, Oslo, Akurhus, and Sør-Trønderlag (nine travel-medicine clinics)


ATBF Prospective case-control study

Case series

“To estimate the incidence of, identify risk factors for, and describe the spectrum of clinical manifestations in consecutive cases of travel-associated ATBF, we prospectively studied a cohort of Norwegian travellers to rural sub-Equatorial Africa.”

IdealConsecutive attendees who planned to travel to rural areas in continental sub-Equatorial Africa (including Kenya and Uganda) were given oral and written information on ATBF and were asked to participate in the study. Attendees who agreed to participate were mailed a 2-page questionnaire on their return to Norway. The questionnaire included queries about the country visited, travel time frames, the purpose of travel, bush walking, limited or no use of personal protection against arthropod bites (protective, clothing, permethrine, and skin repellents), observed tick bites or ticks on clothes or skin, the use of primitive accommodation (defined as an overnight stay outdoors, in a tent, and/or in a straw hut), and the presence of any flulike symptoms (fever, myalgia, and headache) commencing no later than10 days after leaving the rural area. Only travelers who submitted a completed questionnaire and reported travel to rural areas were included in the study. Travelers with flulike

Methods:1. Suicide PCR (pcnB gene); if positive sequencing2. MIF (7 antigens)3. WB (2 antigens)

Positive serology:definite serological evidence of R. africae infection was considered when:(1) MIF titers of 1:64 for IgG and/or 1:32 for IgM, with the IgG+IgM titers being at least 2 dilutions higher than any of the other tested SFG rickettsial antigens;(2) a WB profile that revealed only R. africae–specific antibodies; or(3) crossadsorption assays demonstrating that the homologous antibodies were directed against R. africae.

Case definition:A case of confirmed ATBF was defined as a flulike illness commencing no later than 10 days after the patient left rural areas in sub-Equatorial Africa and with positive suicide PCR and/or definite serological evidence of R. africae infection.

38

(out of 940 participants)

20/38 = 52.6%

F: 12, M: 26 (68.4%)Mean age = 38.3y

12/38: single eschar8/38: multiple eschars

symptoms commencing no later than 10 days after leaving rural areas were also asked to present to any of the study group’s infectious diseases specialists within24 h. The medical evaluation included a physical examination with special reference to inoculation eschars, regional lymphadenopathy, cutaneous rash and aphthous stomatitis, and blood sampling for serological testing and PCR. All patients with clinically suspected ATBF were offered a follow-up visit within 2–4 weeks for further medical evaluation.

A case of probable ATBF was defined as a flulike illness commencing no later than 10 days after the patient left rural areas in sub-Equatorial Africa, with serological evidence of recent nondeterminable SFG rickettsial infection, and for which at least 1 of the patient’s fellow travelers had similar symptoms and had confirmed ATBF diagnosed.

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