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Indian Journal of Medical Microbiology, (2014) 32(4): 387-390

Original Article

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


from Rajasthan
*R Bithu, V Kanodia, RK Maheshwari

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 4660years 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.
Key words: ELISA, Fever of unknown origin, Orientia tsutsugamushi, Scrub typhus

Introduction

Materials and Methods

Fever of unknown origin (FUO) is defined as


temperature of more than 38.3oC for a period of more than
1week, 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 are among most common
causes.[2] Scrub typhus (ST), a rickettsial disease caused by
Orientia tsutsugamushi, is a very lessknown cause of FUO.
It is underdiagnosed in India due to its nonspecific 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.

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.

*Corresponding author(email: <bithu. 7r@gmail.com>)


Department of Microbiology and Immunology(RB, VK, RKM),
Sawai Man Singh Medial College, Jaipur, Rajasthan, India
Received: 19.06.2013
Accepted: 12.01.2014
Access this article online
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PMID:
***
DOI:
10.4103/0255-0857.142241

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. Patients serum
samples were tested by ELISA method for IgM antibody
for O. tsutsugamushi. The data was statistically analysed
on SPSS 16 software by using Chisquare (X2) test. In
statistical analysis by Chisquare test, the probability

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388

Indian Journal of Medical Microbiology

value(Pvalue) of less than 0.05 was considered


significant.
Results
A total of 271patients 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 80years.
Among females with FUO, positivity for ST IgM antibody
was highest in 4660years (100%) followed by 3145years
of age group (68.4%). In males highest positivity was seen
in 015years (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 Table1.
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
52patients(39.09%) as shown in Table2.
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 Figure1.
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
nonsignificant. 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
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]

1XPEHU RI SRVLWLYH FDVHV










6HULHV

6HS

2FW

1RY

'HF







Figure 1: Month-wise positive cases of scrub typhus from September


to December 2012

vol. 32, No. 4

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 30years of age. Vivekanandan M et al.
Table1: Age and sexwise distribution of fever of
unknown origin cases
Age
Male
Female
group (in Total Positive Negative Total Positive Negative
years)
(%)
(%)
(%)
(%)
015
31 13(41.9) 18(58.1) 29 16(55.1) 13(44.9)
1630
64 26(40.6) 38(59.4) 60 37(61.7) 23(38.3)
3145
24
6(25) 18(75) 19 13(68.4) 6(31.6)
4660
13 5(38.4) 8(61.6) 11 11(100) 0(00)
>60
10
3(30)
7(70)
10
3(30)
7(70)
Total
142 53(37.3) 89(62.7) 129 80(62) 49(38)
Chisquare(X)=2.375
Chisquare(X)=12
Degree of
Degree of
freedom(df)=4 P>0.05 freedom(df)=12 P<0.05
Table 2: Laboratory parameters of scrub typhus cases
Investigations
No. of
Percentage
patients
Total leukocyte count
Less than 4.3103/mm3
8
6.00
Between 4.3-103/mm3
43
32.30
More than 10103/mm3
52
39.09
Platelet count below 1.4 lacs/mm3
85
63.90
Liver function tests
Raised SGOT(>40 U/L)
92
69.10
Raised SGPT(>360 U/L)
69
51.80
Raised serum alkaline
65
48.80
phosphatase (>150 IU/L)
Raised Total bilirubin (>1 g/dl)
36
27.10
Renal function tests (mg/dl)
Raised serum urea (>45)
48
36.00
Raised serum creatinine (>1.6)
20
15.00
SGOT: Serum glutamic oxaloacetic transaminase, SGPT: Serum
glutamic pyruvic transaminase

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October - December 2014

Bithu etal.: Scrub Typhus in Fever of unknown origin(FUO) cases

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.[710] 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 highresolution 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 etal. 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]
WeilFelix 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 highrisk group pathogens.[15]
The various studies from India used mainly WeilFelix
test [46] 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 WeilFelix test.
Our study emphasises the importance of ELISA technique
as a rapid and more accurate diagnostic tool than WeilFelix
test. It has better specificity because standardised r56
recombinant antigen which is a 56kDa major outer
membrane protein of Orientia tsutsugamushi.[18,19] It also
has an advantage to provide positive results within 34days
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 44cases).[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

389

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. Afuture
study can be done comparing various diagnostic techniques
and their feasibility for the diagnosis of scrub typhus.
Conclusions
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.
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How to cite this article: Bithu R, Kanodia V, Maheshwari RK. Possibility
of scrub typhus in fever of unknown origin (FUO) cases: An experience
from Rajasthan. Indian J Med Microbiol 2014;32:387-90.
Source of Support: Nill, Conflict of Interest: None declared.

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