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  Table of Contents  
Year : 2014  |  Volume : 32  |  Issue : 4  |  Page : 387-390

Possibility of scrub typhus in fever of unknown origin (FUO) cases: An experience from Rajasthan

Department of Microbiology and Immunology, Sawai Man Singh Medial College, Jaipur, Rajasthan, India

Date of Submission19-Jun-2013
Date of Acceptance12-Jan-2014
Date of Web Publication4-Oct-2014

Correspondence Address:
R Bithu
Department of Microbiology and Immunology, Sawai Man Singh Medial College, Jaipur, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0255-0857.142241

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 ~ Abstract 

Purpose: Fever of unknown origin (FUO) has multiple causes. Scrub typhus is less known cause of FUO in India. The present study reports a recent epidemic of scrub typhus amongst cases of FUO from different areas of Rajasthan, India. There was high mortality in undiagnosed cases of FUO which lead to the diagnosis of scrub typhus. Objective: To study the possibility of scrub typhus as a causative factor in FUO cases by qualitative detection of IgM antibodies with ELISA. Materials and Methods: From September 2012 to December 2012, 271 serum samples of FUO cases were analysed for IgM antibodies to Orientia tsutsugamushi along with dengue, malaria, typhoid, tuberculosis and brucellosis. Results: Scrub typhus IgM antibodies by ELISA were detected in 133 (49.1%) patients. Scrub typhus positivity was significantly higher among female in comparison to males (P < 0.05). Maximum positivity of scrub typhus was found in females of 46-60 years age group. The laboratory parameters were abnormal in most of the patients as evident by thrombocytopenia (63%), deranged liver functions (56%) and renal functions (25%). Conclusion: The present study emphasises the importance of scrub typhus among cases of FUO especially after rainy season and during early cooler months. The study also highlights the significance of ELISA method for rapid and early reporting and ruling out scrub typhus in FUO cases.

Keywords: ELISA, Fever of unknown origin, Orientia tsutsugamushi, Scrub typhus

How to cite this article:
Bithu R, Kanodia V, Maheshwari R K. Possibility of scrub typhus in fever of unknown origin (FUO) cases: An experience from Rajasthan. Indian J Med Microbiol 2014;32:387-90

How to cite this URL:
Bithu R, Kanodia V, Maheshwari R K. Possibility of scrub typhus in fever of unknown origin (FUO) cases: An experience from Rajasthan. Indian J Med Microbiol [serial online] 2014 [cited 2020 Nov 30];32:387-90. Available from:

 ~ Introduction Top

Fever of unknown origin (FUO) is defined as temperature of more than 38.3 o C for a period of more than 1 week, usually longer, or often 3 weeks without elucidation of a cause or one week of intelligent and invasive ambulatory investigations. [1] Although there are multiple causes of FUO but infections such as enteric fever, malaria, dengue, tuberculosis,  Brucellosis More Details are among most common causes. [2] Scrub typhus (ST), a rickettsial disease caused by Orientia tsutsugamushi, is a very less-known cause of FUO. It is underdiagnosed in India due to its non-specific clinical presentations, low index of suspicion amongst clinicians, limited awareness and limited diagnostic facilities. The present study is based on diagnosis of ST in the recent out break of FUO with high mortality in Rajasthan.

 ~ Materials and Methods Top

During the month of August 2012 there was reporting of sudden spurts in cases of FUO from different areas of Alwar district of Rajasthan. These patients were investigated for dengue, malaria, typhoid, tuberculosis and brucellosis but the cause of FUO was not ruled out. There were 22 sudden deaths from one small geographic location within a span of 6 weeks. It triggered the urgent need of exact diagnosis of the cause of FUO and the serum samples were sent to National Centre for Disease Control (NCDC), New Delhi. Around 58 serum samples were sent, out which 15 samples came out positive for ST.

As more cases of FUO were reported from different areas of Alwar district of Rajasthan, necessitating an urgent need of diagnosis, a testing centre was set up in clinical microbiology section, central laboratory of SMS Medical College and Hospital, Jaipur with the facility of diagnosis of ST along with other routine causes of FUO.

The kit for detection of ST by ELISA was introduced at this centre. It was procured from InBios International Inc. Seattle, WA, USA. It is a qualitative test for the detection of IgM antibodies to Orientia tsutsugamushi in the serum sample. In this test, wells of each plate were coated with recombinant antigen of O. tsutsugamushi. Patient's serum samples were tested by ELISA method for IgM antibody for O. tsutsugamushi. The data was statistically analysed on SPSS 16 software by using Chi-square (X 2 ) test. In statistical analysis by Chi-square test, the probability value (P value) of less than 0.05 was considered significant.

 ~ Results Top

A total of 271 patients of FUO reported to the SMS hospital from September 2012 to December 2012. ST IgM antibodies were detected in 133 (49.1%) patients by ELISA. Among these 133 diagnosed cases ST, 80 (62.7%) were females and 53 (37.3%) were males as shown in [Table 1]. Positivity for ST was significantly higher among female who were suffering from fever of unknown origin in comparison to males (P < 0.05).

The age of the patients ranged between 2 and 80 years. Among females with FUO, positivity for ST IgM antibody was highest in 46-60 years (100%) followed by 31-45 years of age group (68.4%). In males highest positivity was seen in 0-15 years (41.9%). On statistical analysis, the difference in positivity for ST in different age group of female was significant (P < 0.05) and insignificant in males (P > 0.05) as shown in [Table 1].
Table 1: Age and sex - wise distribution of fever of unknown origin cases

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The laboratory parameters thrombocytopenia, deranged liver function and renal function test were seen in 63%, 56% and 25%, respectively. Total leucocyte count was raised in 52 patients (39.09%) as shown in [Table 2].
Table 2: Laboratory parameters of scrub typhus cases

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Most of the patients were from rural areas belonging to Alwar, Dausa, Bharatpur and Karauli districts of Rajasthan. Maximum numbers of cases were seen after the rainy season and during early cooler months i.e. between September and October as shown in [Figure 1].
Figure 1: Month-wise positive cases of scrub typhus from September to December 2012

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All the cases of FUO diagnosed as ST were followed up and among these 133 positive cases 13 (9.7%) deaths were reported; however, on statistical analysis it was non-significant. All the deaths were because of acute respiratory failure attributed to ST. There was no any other underlying cause of death in these cases.

 ~ Discussion Top

Scrub typhus is a rickettsial disease caused by O. tsutsugamushi which is a Gram negative, intracellular bacterium. It is transmitted by the bite of mite belonging to the genus Leptotrombidium (L. delienis) in India. [3]

Scrub typhus, originally found in Scrub jungles, has also been found in a variety of habitats like sandy beaches, rice fields, mountain deserts, equatorial rain forests and even in semidesert. [4] Previous to this study, there are certain reports of ST from Himachal Pradesh (2003) belonging to hilly areas and Pondicherry (2006) belonging to sandy beaches of India. [5],[6] The present study is the first report from the semidesert area Rajasthan in India.

In the study of present outbreak, most of the patients were from rural background. Maximum numbers of cases were reported from the month of September to October. This is because the mites are more active during or at the end of rainy season which coincides with the months of August to September in India. Earlier reports from India indicate similar period of disease occurrence. [5],[6]

The study shows more positivity of ST in females particularly above 30 years of age. Vivekanandan M et al. also reported female preponderance in their study. [6] This could be due active involvement of females as field and farm workers in Rajasthan.

The present study reports 9.7% mortality in concurrence with previous studies. [7],[8],[9],[10] The most common cause of death in our study was acute respiratory failure as most of cases presented with fever, cough and dyspnoea showing bilateral interstitial pneumonia in high-resolution computerised tomogram.

In the laboratory parameters, the most important abnormality noticed was thrombocytopenia (63%). Other laboratory findings include elevation of liver enzymes, serum urea and serum creatinine. Similar abnormalities have been observed by Vivekanandan M et al. in their study. [6]

The central pathophysiological derangements of thrombocytopenia, liver function and renal function in ST is because of wide spread vasculitis and perivasculitis of these organs. This is due to multiplication of the organism in the endothelial cells lining the small blood vessels and consumption of platelets in the process of intravascular microthrombosis. [11]

Weil-Felix test is widely used in the diagnosis of rickettsial diseases but this test is neither sensitive nor specific in the diagnosis of these diseases. [12] Its results may be negative during early stage of disease because the agglutinating antibodies are detectable only during second week of onset of illness. [13] Therefore, it has been replaced by more accurate and sensitive immunological tests. Among these specific immunological tests, microimmunoflourescence test is considered the best approach followed by latex agglutination (LA), indirect haemagglutination (IHA), immunoperoxidase assay (IPA) and ELISA. [14] These specific immunologic tests are not easily available in India. The isolation of the organisms in animals or cell culture is difficult because of lack of containment facilities and handling these high-risk group pathogens. [15]

The various studies from India used mainly Weil-Felix test [4],[5],[6] and a very few studies used ELISA technique [16],[17] for the detection of scrub typhus IgM antibody. It is the latest technique in India in comparison to Weil-Felix test. Our study emphasises the importance of ELISA technique as a rapid and more accurate diagnostic tool than Weil-Felix test. It has better specificity because standardised r56 recombinant antigen which is a 56-kDa major outer membrane protein of Orientia tsutsugamushi. [18],[19] It also has an advantage to provide positive results within 3-4 days after the onset of disease. [13]

The present study is different from all previous studies done in India in the major context that in the earlier studies using ELISA technique, the sample size was very small (not larger than 44 cases). [16],[17] However, in our study the number of total cases was 271 out of which 133 (49.1%) cases were positive. Thus, the sample size was large enough to make it statistically more valid than the other studies for IgM antibody detection of ST by ELISA method.

Our study was solely based on ELISA method and the results were not compared to any other method. A future study can be done comparing various diagnostic techniques and their feasibility for the diagnosis of scrub typhus.

 ~ Conclusions Top

Scrub typhus is prevalent but an underdiagnosed disease in India. It should be considered in the differential diagnosis of patients suffering from acute febrile illness especially with pneumonitis, thrombocytopenia, elevation of liver enzyme, serum urea and serum creatinine. This is particularly important after the rainy season and early cooler months, i.e. between August and October months. Rapid and specific diagnostic methods using ELISA can be carried out timely for early diagnosis of scrub typhus in patients with FUO in developing countries like India. An early empiric therapy can be given to reduce serious complications and mortality.

 ~ References Top

1.Bleeker-Rovers CP, van der Meer JW, Oyen WJ. Fever of unknown origin. Semin Nucl Med 2009;39:81-7.  Back to cited text no. 1
2.Schneidewind A, Ehrenstein B, Salzberger B. Infections as causes of fever of unknown origin. Internist (Berl) 2009;50:659-67.  Back to cited text no. 2
3.Tamura A, Ohashi N, Urakami H, Miyamura S. Classification of Rickettsia tsutsugamushi in a new genus, Orientia gen. nov., as Orientia tsutsugamushi comb. nov. Int J Syst Bacteriol 1995;45:589-91.  Back to cited text no. 3
4.Mahajan SK. Scrub typhus. J Assoc Physician India 2005;53:954-8.  Back to cited text no. 4
5.Sharma A, Mahajan S, Gupta ML, Kanga A, Sharma V. Investigation of an outbreak of scrub typhus in himalayan region of India. Jpn J Infect Dis 2005;58:208-10.  Back to cited text no. 5
6.Vivekanandan M, Mani A, Priya YS, Singh AP, Jayakumar S, Purty S. Outbreak of scrub typhus in Pondicherry. J Assoc Physicians India 2010;58:24-8.  Back to cited text no. 6
7.Wang CC, Liu SF, Liu JW, Chung YH, Su MC, Lin MC. Acute respiratory distress syndrome in scrub typhus. Am J Trop Med Hyg 2007;76:1148-52.  Back to cited text no. 7
8.Yen TH, Chang CT, Lin JL, Jiang JR, Lee KF. Scrub typhus: A frequently overlooked cause of acute renal failure. Ren Fail 2003;25:397-410.  Back to cited text no. 8
9.Thap LC, Supanaranond W, Treeprasertsuk S, Kitvatanachai S, Chinprasatsak S, Phonrat B. Septic shock secondary to scrub typhus: Characteristics and complications. Southeast Asian J Trop Med Public Health 2002;33:780-6.  Back to cited text no. 9
10.Cracco C, Delafosse C, Baril L, Lefort Y, Morelot C, Derenne JP, et al. Multiple organ failure complicating probable scrub typhus. Clin Infect Dis 2000;31:191-2.  Back to cited text no. 10
11.Seong SY, Choi MS, Kim IS. Orientia tsutsugamushi infection: Overview and immune responses. Microbes Infect 2001;3:11-21.  Back to cited text no. 11
12.Pradutkanchana J, Silpapojakul K, Paxton H, Pradutkanchana S, Kelly DJ, Strickman D. Comparative evaluation of four serodiagnostic tests for scrub typhus in Thailand. Trans R Soc Trop Med Hyg 1997;91:425-8.  Back to cited text no. 12
13.Isaac R, Varghese GM, Mathai E, J M, Joseph I. Scrub typhus: Prevalence and diagnostic issues in rural Southern India. Clin Infect Dis 2004;39:1395-6.  Back to cited text no. 13
14.Coleman RE, Sangkasuwan V, Suwanabun N, Eamsila C, Mungviriya S, Devine P, et al. Comparative evaluation of selected diagnostic assays for the detection of IgG and IgM antibody to Orientia tsutsugamushi in Thailand. Am J Trop Med Hyg 2002;67:497-503.  Back to cited text no. 14
15.Batra HV. Spotted fevers and typhus fever in Tamil Nadu. Indian J Med Res 2007;126:101-3.  Back to cited text no. 15
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16.Mathai E, Rolain JM, Verghese GM, Abraham OC, Mathai D, Mathai M, et al. Outbreak of scrub typhus in southern India during the cooler months. Ann N Y Acad Sci 2003;990:359-64.  Back to cited text no. 16
17.Narvencar KP, Rodrigues S, Nevrekar RP, Dias L, Dias A, Vaz M, et al. Scrub typhus in patients reporting with acute febrile illness at a tertiary health care institution in Goa. Indian J Med Res 2012;136:1020-4.  Back to cited text no. 17
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18.Ching WM, Wang H, Eamsila C, Kelly D, Dasch GA. Expression and refolding of truncated recombinant major outer membrane protein antigen (r56) of Orientia tsutsugamushi and its use in enzyme-linked immunosorbent assays. Clin Diagn Lab Immunol 1998;5:519-26.  Back to cited text no. 18
19.Land MV, Ching WM, Dasch GA, Zhang Z, Kelly DJ, Graves SR, et al. Evaluation of a commercially available recombinant-protein enzyme-linked immunosorbent assay for detection of antibodies produced in scrub typhus rickettsial infections. J Clin Microbiol. 2000;38:2701-5.  Back to cited text no. 19


  [Figure 1]

  [Table 1], [Table 2]


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