Investigations of seasonal outbreaks of acute encephalitis syndrome due to Orientia tsutsugamushi in Gorakhpur region, India: A One Health case study

Abstract

Gorakhpur division consisting of Gorakhpur and neighboring districts Deoria, Kushinagar and Maharajganj in Uttar Pradesh, India, have been witnessing seasonal outbreaks of acute encephalitis syndrome (AES) among children for the last three decades. Investigations conducted during 2005 identified Japanese encephalitis (JE) virus as an aetiology of AES. With the introduction of JE vaccination and other control strategies, the incidence of JE in the region declined, however, outbreaks of acute febrile illness with neurological manifestations continued to occur. Subsequent investigations identified Orientia tsutsugamushi, as the major aetiology of AES outbreaks in the region. This review details clinical, epidemiological, animal and entomological investigations conducted for AES due to O. tsutsugamushi during 2015 and 2017 in Gorakhpur region. Surveillance of acute febrile illness among children attending peripheral health facilities identified scrub typhus as an important aetiology of febrile illness during monsoon and post-monsoon months. Population-based serosurveys indicated high endemicity of scrub typhus. Entomological studies demonstrated natural infection of O. tsutsugamushi in small animal hosts and vector mites. Children acquired this infection through recent exposure to outdoor environment, while playing, or visiting fields or defecating in open fields. A few of the children with scrub typhus progress to develop CNS manifestations. Hence, early administration of appropriate antibiotics is crucial in preventing progression of AFI due to scrub typhus to AES. The investigations conducted by the multi-disciplinary team helped understand the transmission dynamics of scrub typhus in Gorakhpur division and recommend strategies for its control.

Full text

375
© 2021 Indian Journal of Medical Research, published by Wolters Kluwer - Medknow for Director-General, Indian Council of Medical Research
Quick Response Code:
Indian J Med Res 153, March 2021, pp 375-381
DOI: 10.4103/ijmr.IJMR_625_21
Investigations of seasonal outbreaks of acute encephalitis syndrome
due to Orientia tsutsugamushi in Gorakhpur region, India: A One
Health case study
Manoj V. Murhekar1, Jeromie Wesley Vivian Thangaraj1, Candasamy Sadanandane2, Mahima Mittal3,
Nivedita Gupta4, Winsley Rose5, Seema Sahay6, Rajni Kant7 & Mohan D. Gupte1,4
1ICMR-National Institute of Epidemiology, Chennai, 5Christian Medical College, Vellore, Tamil Nadu,
2ICMR-Vector Control Research Centre, Puducherry, 3All India Institute of Medical Sciences,
7ICMR-Regional Medical Research Centre, Gorakhpur, Uttar Pradesh, 4Division of Epidemiology
and Communicable Diseases Division , Indian Council of Medical Research, New Delhi & 6ICMR-National
AIDS Research Institute, Pune, Maharashtra, India
Received March 2, 2021
Gorakhpur division consisting of Gorakhpur and neighboring districts Deoria, Kushinagar and
Maharajganj in Uttar Pradesh, India, have been witnessing seasonal outbreaks of acute encephalitis
syndrome (AES) among children for the last three decades. Investigations conducted during
2005 identied Japanese encephalitis (JE) virus as an aetiology of AES. With the introduction of
JE vaccination and other control strategies, the incidence of JE in the region declined, however,
outbreaks of acute febrile illness with neurological manifestations continued to occur. Subsequent
investigations identied Orientia tsutsugamushi, as the major aetiology of AES outbreaks in the region.
This review details clinical, epidemiological, animal and entomological investigations conducted
for AES due to O. tsutsugamushi during 2015 and 2017 in Gorakhpur region. Surveillance of acute
febrile illness among children attending peripheral health facilities identied scrub typhus as an
important aetiology of febrile illness during monsoon and post-monsoon months. Population-based
serosurveys indicated high endemicity of scrub typhus. Entomological studies demonstrated natural
infection of O. tsutsugamushi in small animal hosts and vector mites. Children acquired this infection
through recent exposure to outdoor environment, while playing, or visiting elds or defecating in
open elds. A few of the children with scrub typhus progress to develop CNS manifestations. Hence,
early administration of appropriate antibiotics is crucial in preventing progression of AFI due to
scrub typhus to AES. The investigations conducted by the multi-disciplinary team helped understand
the transmission dynamics of scrub typhus in Gorakhpur division and recommend strategies for its
control.
Key words Acute encephalitis syndrome - acute febrile illness - One Health - scrub typhus - vector
Review Article
Practice
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]

376 INDIAN J MED RES, MARCH 2021
For the last three decades, Gorakhpur and its
neighbouring districts Deoria, Kushinagar and
Maharajgunj have been witnessing seasonal outbreaks
of acute febrile illness (AFI) with neurological
manifestations such as altered sensorium and new
onset of seizures, among children1,2. Between 2004-
2013, around 1500 - 2000 acute encephalitis syndrome
(AES) patients get admitted every year to BRD
Medical College (BRDMC), Gorakhpur - the tertiary
care hospital in the region3. These outbreaks occurred
in monsoon and post-monsoon (June–October) months
and were associated with high case fatality, in excess of
20 per cent3-5. The region experienced one of the worst
outbreaks in 2005, where more than 5,737 cases of
AES were reported from Gorakhpur and neighbouring
districts, with 23 per cent deaths6. etiological
investigations indicated that this outbreak was due to
Japanese encephalitis virus (JEV)6. Following these
investigations, the Government of India introduced live
attenuated JE vaccine (SA-14-14-2) in the area, initially
as mass vaccination campaigns targeting children aged
1-14 years and subsequently introduced the vaccine
in the Universal Immunization Programme7. In 2013,
a two-dose vaccination schedule was introduced, with
rst dose given at the age of 9-12 months and second
dose at the age of 16-24 months8.
With vaccination and Information Education
and Communication (IEC) campaigns, the incidence
of JE declined5,7, however, outbreaks of AFI with
neurological manifestations continued to occur in
the region. Investigations conducted by a team of
researchers from dierent ICMR institutes; Manipal
Centre for Virus Research, Manipal; Christian
Medical College (CMC), Vellore and Jawaharlal
Institute of Postgraduate Medical Education &
Research (JIPMER), Puducherry identied Orientia
tsutsugamushi, the causative agent of scrub typhus, as
the major aetiology of AES outbreaks in the region9.
It was observed that nearly half of the AES cases had
serological or molecular evidence of O. tsutsugamushi
infection, while JEV and dengue virus accounted for
about 10 and 7 per cent AES cases, respectively9. The
presence of higher levels of O. tsu tsugamushi IgM
and IgG antibodies among AES patients than among
controls further conrmed the role for scrub typhus in
the aetiology of AES in Gorakhpur10.
Scrub typhus is a vector-borne zoonotic disease
with the potential of causing life-threatening febrile
infection in humans. It is transmitted by the bite
of trombiculid mite infected with Gram negative
O. tsutsugamushi. Mites are the vectors and the primary
reservoir for scrub typhus. The infected mite population
is maintained usually by a number of small rodents and
shrews. The disease is endemic in several countries
in Southeast Asia and Western Pacic region11. Scrub
typhus patients with multi-system involvement may
have high case fatality and hence early treatment
with appropriate antibiotic is important12. Following
the diagnosis of O. tsutsugamushi as the major
aetiology of AES outbreaks in Gorakhpur region, the
ICMR recommended administration of intravenous
azithromycin to all hospitalized AES cases at BRD
medical college, in September 2014 (unpublished
data). Considering the zoonotic nature of the illness,
a transdisciplinary team was constituted consisting
of human and animal health experts and a number of
studies were initiated to describe the clinical spectrum
of children with AES due to O. tsutsugamushi infection,
estimate disease burden, understand the transmission
dynamics, and identify risk factors to develop control
strategies. The results of these ndings characterized
the scrub typhus transmission dynamics in the aected
region and recommended appropriate interventions.
Several of these eorts have been documented as
individual research ndings and warrant a composite
presentation to describe the in-depth and multi-faceted
studies done by dierent research teams. This review
details the clinical, epidemiological, animal and
entomological investigations conducted for AES due to
O. tsutsugamushi during 2015 and 2017 in Gorakhpur
region.
Clinical spectrum of AES patients with
O. tsutsugamushi infection (2016)
To strengthen the AES surveillance, the ICMR
established an AES Cell in the department of Paediatrics
in BRD Medical College, Gorakhpur in 2016. This
Cell coordinated collection of clinical details from
AES cases on a standard case report form, collection
and aliquoting of blood and CSF samples and ensured
biochemical, haematological as well as aetiological
investigations of all samples collected. In a case series
of 230 AES cases with O. tsutsugamushi infection
(based on PCR/IgM positivity in serum and/or CSF),
the median age of patients was 61 (IQR: 36-120)
months. All cases were from rural areas and males and
females were equally aected. AES patients developed
CNS manifestations such as seizures (88.7%) and
altered sensorium (69.6%) after a median interval of
six (IQR: 4-9) days after fever onset. Other presenting
symptoms among AES patients included vomiting
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]

MURHEKAR et al: AES IN GORAKHPUR DUE TO O. TSUTSUGAMUSHI 377
(46.5%), headache (13.9%), abdominal pain (15.2%)
and diarrhoea (4.8%). The median Glasgow Coma
Scale (GCS) score at admission was eight (IQR: 8-10).
Important ndings on physical examination included
hepatomegaly (43.5%), peri-orbital oedema (33.0%),
splenomegaly (10.4%) and rash (5.2%). None of these
patients had eschar. Thrombocytopenia, abnormal
liver and kidney functions were the commonest
haematological and biochemical abnormalities. CSF
was clear, with pleocytosis and mildly raised proteins.
Most patients received intravenous azithromycin.
The case fatality ratio (CFR) was lower among AES
patients positive for O. tsutsugamushi infection
(35/230=15.2%) as compared to those negative for OT
infection (51/141=36.2%, P=0.001)13.
Aetiology of AFI among children (2016)
All the studies about the aetiology of AES were
conducted among patients hospitalized at the BRD
Medical College, Gorakhpur. About one fourth of these
patients gave a history of febrile illness for at least a
week before developing neurological manifestations13.
A qualitative study conducted to understand the health
seeking behaviour for febrile illness revealed that
most parents took their children to traditional healers
rst, and parents took the child to BRD Medical
College or district hospital if the child developed
seizures or altered sensorium (unpublished data). It
was therefore, considered worthwhile to nd out the
aetiology of children presenting with AFI attending
peripheral health facilities during monsoon/post-
monsoon months. A facility-based surveillance for
AFI was established in three peripheral health facilities
and all children presenting with fever of four days or
more were enrolled in the surveillance. Analysis of
serum specimen from 224 children with AFI during
August to October, indicated that about one-fourth
had IgM antibodies against O. tsutsugamushi14. Three
children also had eschar, which is pathognomonic
of scrub typhus. The other common aetiologies of
AFI were dengue fever14 (8%), spotted fever group
rickettsiae (SFGR) infection15 (6%) and leptospirosis14
(3%). These ndings indicated that O. tsutsugamushi
infection was the commonest aetiology of AFI among
children during monsoon/post-monsoon months14.
Seroprevalence in the community (2016)
Scrub typhus outbreaks have been reported
in occupational groups with frequent exposure to
outdoor environment, such as military personnel,
agriculture workers, etc16. Most AES cases seen at
the tertiary care hospital in Gorakhpur were children
aged ≤14 years. This age distribution of AES cases
suggested exposure to O. tsutsugamushi infection
during childhood. Population based serosurveys
were conducted to estimate age-specic prevalence
of O. tsutsugamushi infection in dierent villages in
Gorakhpur district reporting AES cases17. The rst
survey was conducted during April-May (n=1085),
and second during October-November (n=906),
corresponding respectively with the lean and epidemic
period. The overall seroprevalence of IgG antibodies
during AES epidemic period was higher (70.8%) as
compared to that of lean AES period (50.6%, P<0.001).
In both survey periods, seroprevalence increased with
age, with higher prevalence among females. The serial
nature of the serosurveys also provided opportunity to
estimate sero-incidence of O. tsutsugamushi infection.
Of the 254 seronegative cases for serological markers
of O. tsutsugamushi infection during April-May, 19.7
per cent seroconverted; more than half of whom had
no history of febrile illness during the intervening
period suggesting subclinical nature of infection. The
sero-incidence of new infection was not dierent by
age-group and sex.
O. tsutsugamushi infection in small animals and
mites (2015)
Although the clinical and laboratory ndings
among AES and AFI patients indicated the role of
O. tsutsugamushi infection, evidence of the presence
of the pathogen in animal hosts and vector mites was
considered conrmatory to its transmission to humans.
A cross-sectional survey of trombiculid mites was
carried out during July and October 2015, in randomly
selected villages in Gorakhpur with recent report of
AES cases18. In the selected villages Sherman live
traps were set in peri-domestic areas to catch rodents/
shrews. Blood sample was collected from the trapped
rodents/shrews and serum samples were tested using
Weil–Felix test for antibodies against three antigens:
OX-19 (Rickettsia typhi), OX-2 (Rickettsia conorii),
and OX-K (O. tsutsugamushi). The trapped rodents
were euthanized and ectoparasites, including chigger
(larval) mites, were collected by combing the animals.
Also, the ears, limbs, and axillary regions of individual
rodents were examined for mite attachment. Based
on the exoskeleton structure, mites were identied to
species level following standard taxonomical keys, and
the tissue samples were pooled and subjected to PCR
assays. Molecular diagnosis of the scrub typhus was
targeted for two dierent gene fragments, groEL and
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]

378 INDIAN J MED RES, MARCH 2021
56 kDa type-specic antigen (TSA) of O. tsutsugamushi,
by conventional PCR and nested PCR, respectively
for rodent/shrew blood samples. Detection of gene
encoding 56 kDa protein, which amplies 483 bp
segments, was carried out by nested PCR for mite
samples18.
Suncus murinus (shrew) was the commonest
animal trapped. More than 80 per cent trapped shrew/
rodent were infested with trombiculid mites, with
Leptotrombidium deliense Walch as the predominant
species. The overall chigger index, dened as the
proportion of shrews/rodents having trombiculid mite
infestation, was highest for S. murinus (21.3%)18.
In the Weil–Felix test, 57 per cent (65/114) serum
samples from the shrews/rodents tested were positive
for antibodies against O. tsutsugamushi, with higher
seropositivity among S. murinus compared to Rattus
sp. On PCR assay, about 20 per cent (25/128) rodent
blood samples were positive for the groEL gene while
one sample was positive for the 56 kDa gene. The
identities of these genes were conrmed as that of
O. tsutsugamushi by DNA sequencing. Seven of the
315 pools of mite tissue samples were positive for 56
kDa gene on nested PCR. All the O. tsutsugamushi
infected L. deliense specimens were from S. murinus.
Phylogenetic analysis conrmed circulation of Gilliam,
Karp, and TA678 serotypes of O. tsutsugamushi in
Gorakhpur. This study provided information on the
relative abundance of small animal hosts, chigger
mite vectors, and the prevalence of the scrub typhus
pathogen, O. tsutsugamushi, in the animal and vector
hosts18.
Seasonal abundance of Leptotrombidium deliense
(2016-17)
A year-round study was conducted in 2016-2017
to examine the seasonal abundance of L. deliense in
rural areas of Gorakhpur district. During the monthly
collections, a total of 903 animals (rodents/shrews)
were collected using 6484 Sherman traps. S. murinus
was predominantly (67%) trapped. A total of 5526 mites
belonging 12 species under nine genera of trombiculids
were collected from the trapped rodents/shrews.
Leptotrombidium (L) deliense was the predominant
species (64.7%) followed by Schoengastiella ligula
(17.4%), the suspected vector of scrub typhus.
The overall chigger index was 5.3 per animal. The
L. deliense index was relatively higher during July
to November with a peak in October (Fig. 1). The
index of S. ligula was very low particularly during this
season. The natural infection of O. tsutsugamushi was
detected only in L. deliense specimens, collected during
rainy months (July - October). Among the 5526 mite
samples tested as 352 pools in nested PCR, four pools
were positive for 56 kDa gene. The peak abundance
of L. delicense coincided with peak incidence of AES
cases in the area (Unpublished data).
Risk factors for scrub typhus infection (2018)
The next step in the investigation was to nd out
household characteristics and behavioural risk factors
associated with scrub typhus infection among children.
In this case control study, 155 febrile children positive
for IgM antibodies against O. tsutsugamushi were
compared with 409 febrile children seronegative for IgM
and IgG antibodies19. Cases, controls and their parents
or guardians were interviewed to collect information
on socio-demographics, household characteristics,
behaviours, and environmental exposures during the
preceding two weeks before fever onset. The ndings
of this study revealed that children residing in houses
within or adjoining agriculture elds and that stored
rewood indoors had higher odds of acquiring scrub
typhus. Children who had a recent exposure to outdoor
environment while defecating in open, playing in or
visiting agricultural elds were also at higher risk of
scrub typhus infection19.
Summarizing the evidence
The ndings of the studies described above provided
data about the transmission dynamics of scrub typhus
in the area. Entomological studies demonstrated natural
infection of O. tsutsugamushi in small animal hosts and
vector mites. Leptotrombidium mites were abundantly
present on shrews during monsoon and post-monsoon
months. High seroprevalence of IgG antibodies
indicated that the population in rural areas of Gorakhpur
division was frequently exposed to O. tsutsugamushi
infection. Children acquired this infection through
recent exposure to outdoor environment, while
playing, or visiting elds or defecating in open elds.
Although most infections were subclinical in nature,
scrub typhus was an important aetiology of febrile
illness among children, accounting for nearly one-fth
of febrile illness attending peripheral health facilities
during monsoon and post-monsoon months. A few of
the children with scrub typhus progressed to develop
CNS manifestations. Hence, early administration
of appropriate antibiotics is crucial in preventing
progression of AFI due to scrub typhus to AES.
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]

MURHEKAR et al: AES IN GORAKHPUR DUE TO O. TSUTSUGAMUSHI 379
Presumptive treatment of AFI with doxycycline or
azithromycin (2018)
There are limited laboratory facilities for diagnosis
of scrub typhus infection at primary care facilities in
Gorakhpur division. The use of rapid diagnostic tests
for all fever patients attending these facilities could be
cost-prohibitive. Moreover, serological tests become
positive only after 5-7 days. In view of this, as well
as considering the risk of progression of AFI patients
to AES which is associated with high case fatality,
and over-burdened public health facilities, treating
children presenting with AFI at peripheral health
facilities during monsoon and post-monsoon months,
presumptively with doxycycline or azithromycin based
on clinical suspicion was considered as a strategy for
reducing incidence and mortality due to AES. The
Government of Uttar Pradesh issued guidelines to the
health facilities of districts in Gorakhpur division for
this presumptive treatment in 201620. A pilot project
conducted in three peripheral health facilities indicated
that presumptive treatment of children with AFI with
doxycycline/azithromycin had about 80 per cent
eectiveness in preventing progression to AES21.
Disability following AES caused by Orientia
tsutsugamushi (2018)
Survivors of infective encephalitis may have
varying degrees of neurologic or neuropsychiatric
sequelae. Little information was available about
neurologic sequelae among scrub typhus patients with
CNS manifestations. A study to estimate the proportion
and spectrum of disability among 146 survivors of AES
due to O. tsutsugamushi indicated that 56 (38.4%) had
mild, whereas 19 (13%) had moderate to severe degree
of disability after median interval of ve months of
hospitalization,. Most patients had impairment in the
domain of cognition and behaviour, while <10 per
cent had impairment in the domain of mobility and
activity limitation in selfcare. The study indicated that
disabilities were frequent among the survivors of AES
caused by O. tsutsugamushi22.
Way forward
The investigations conducted by the multi-
disciplinary team constituted by the ICMR helped to
understand the transmission dynamics of scrub typhus
in Gorakhpur division and recommend strategies for
its control. The decline in the number of AES cases
and deaths in the region (Fig. 2, unpublished data)
observed in the last three years could be due to the
presumptive use of doxycycline/azithromycin for
febrile illness and administration of intravenous
azithromycin for AES patients as well as awareness
campaigns such as Dastak Abhiyan to seek early
treatment for AES and strengthening of peripheral
health facilities to manage AES cases conducted
by the Government of Uttar Pradesh. It is however,
necessary to closely monitor the implementation of
the presumptive treatment strategy during monsoon
and post-monsoon season and ensure adequate supply
of doxycycline and azithromycin at the public health
facilities. Reduction in the AES disease burden would
also require sensitizing clinicians in private sector about
early treatment of suspected scrub typhus cases with
appropriate antibiotics. Further, as part of long-term
approach to facilitate early treatment of scrub typhus
Fig. 1. Reported AES cases and the estimated L. deliense and S. ligula indices in Gorakhpur district, Uttar Pradesh, 2016-2017 (Unpublished data).
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]

380 INDIAN J MED RES, MARCH 2021
at peripheral health facilities, introducing aordable
point of care tests at the primary care level especially
during AES season could help in early diagnosis of
scrub typhus and initiate appropriate treatment23. The
environmental factors are conducive for transmission
of O. tsutsugamushi in the area. Measures to control
vector mites or rodent could be challenging. Hence,
behaviour change communication about avoiding open
defecation and exposure to outdoor environment, as
well as providing household and community toilets
through the Government agship programmes such as
Swachh Bharat Abhiyan could also help reducing such
infections in the region23. Considering the wide range
and magnitude of disability among survivors of AES
patients, it is also necessary to screen all AES patients
to early identify disabilities and initiate appropriate
rehabilitative care in the nearest District Disability
Rehabilitation Centres. Lastly, continued surveillance
for AES in the region is necessary to monitor the trend
as well as impact of dierent control strategies.
Financial support & sponsorship: This review did not
receive any funding.
Conicts of Interest: Authors declare no conict of interest.
References
1. Mathur A, Chaturvedi UC, Tandon HO, Agarwal AK,
Mathur GP, Nag D, et al. Japanese encephalitis epidemic
in Uttar Pradesh, India during 1978. Indian J Med
Res. 1982; 75 : 161-9.
2. Rathi AK, Kushwaha KP, Singh YD, Singh J, Sirohi R,
Singh RK, et al. JE virus encephalitis: 1988 epidemic at
Gorakhpur. Indian Pediatr 1993; 30 : 325-33.
3. Mittal M, Kushwaha KP. AES: Clinical presentation and
dilemmas in critical care management. J Commun Dis
2014; 46 : 50-65.
4. Kakkar M, Rogawski ET, Abbas SS, Chaturvedi S, Dhole TN,
Hossain SS, et al. Acute encephalitis syndrome surveillance,
Kushinagar District, Uttar Pradesh, India, 2011–2012. Emerg
Infect Dis 2013; 19 : 1361-9.
5. Ranjan P, Gore M, Selvaraju S, Kushwaha KP,
Srivastava DK, Murhekar M. Changes in acute encephalitis
syndrome incidence after introduction of Japanese encephalitis
vaccine in a region of India. J Infect 2014; 69 : 200-2.
6. Parida M, Dash PK, Tripathi NK, Ambuj, Sannarangaiah S,
Saxena P, et al. Japanese encephalitis outbreak, India, 2005.
Emerg Infect Dis 2006; 12 : 1427-30.
7. Kumari R, Joshi PL. A review of Japanese encephalitis in
Uttar Pradesh, India. WHO South-East Asia J Public Health
2012; 1 : 374.
8. National Vectorborne Disease Control Program
(NVBDCP), Ministry of Health and Family Welfare,
Govt of India. National Programme for Prevention and
Control of Japanese Encephalitis/Acute Encephalitis
Syndrome Programme. Avaialble from: https://nvbdcp.
gov.in/WriteReadData/l892s/JE-AES-Prevention-Control
(NPPCJA).pdf, accessed on March 28, 2021
9. Murhekar MV, Mittal M, Prakash JAJ, Pillai VM,
Mittal M, Girish Kumar CP, et al. Acute encephalitis syndrome
in Gorakhpur, Uttar Pradesh, India - Role of scrub typhus.
J Infect 2016; 73 : 623-6.
10. Mittal M, Thangaraj JWV, Rose W, Verghese VP, Kumar CPG,
Mittal M, et al. Scrub typhus as a cause of acute encephalitis
syndrome, Gorakhpur, Uttar Pradesh, India. Emerg Infect Dis
2017; 23 : 1414-6. doi:10.3201/eid2308.170025.
11. Koh GCKW, Maude RJ, Paris DH, Newton PN,
Blacksell SD. Diagnosis of scrub typhus. Am J Trop Med Hyg
2010; 82 : 368-70.
Fig. 2. Number of AES patients hospitalized at BRD Medical College, Gorakhpur and case fatality ratio, 2014-2020 (Unpublished data).
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]

MURHEKAR et al: AES IN GORAKHPUR DUE TO O. TSUTSUGAMUSHI 381
12. 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.
13. Mittal M, Bondre V, Murhekar M, Deval H, Rose W,
Verghese VP, et al. Acute encephalitis syndrome in Gorakhpur,
Uttar Pradesh, 2016: Clinical and laboratory ndings. Pediatr
Infect Dis J 2018; 37 : 1101-6.
14. Thangaraj JWV, Mittal M, Verghese VP, Kumar CPG, Rose
W, Sabarinathan R, et al. Scrub Typhus as an etiology of acute
febrile illness in Gorakhpur, Uttar Pradesh, India, 2016. Am J
Trop Med Hyg 2017; 97 : 1313-5. doi:10.4269/ajtmh.17-0135.
15. Khan SA, Bora T, Thangaraj JWV, Murhekar M. Spotted fever
group rickettsia among children with acute febrile illness
in Gorakhpur, India. J Trop Pediatr 2020; fmaa031. doi:
10.1093/tropej/fmaa031.
16. Rahi M, Gupte MD, Bhargava A, Varghese GM, Rashmi Arora.
DHR-ICMR Guidelines for diagnosis & management of
Rickettsial diseases in India. 2015; 141 : 417-22.
17. Kamble S, Mane A, Sane S, Sonavale S, Vidhate P,
Singh MK, et al. Seroprevalence & seroincidence of Orientia
tsutsugamushi infection in Gorakhpur, Uttar Pradesh, India:
A community-based serosurvey during lean (April-May) &
epidemic (October-November) periods for acute encephalitis
syndrome. Indian J Med Res 2020; 151 : 350-60.
18. Sadanandane C, Jambulingam P, Paily KP, Kumar NP, Elango A,
Mary KA, et al. Occurrence of Orientia tsutsugamushi, the
etiological agent of scrub typhus in animal hosts and mite
vectors in areas reporting human cases of acute encephalitis
syndrome in the Gorakhpur Region of Uttar Pradesh, India.
Vector Borne Zoonotic Dis 2018; 18 : 539-47.
19. Thangaraj JWV, Vasanthapuram R, Machado L, Arunkumar G,
Sodha SV, Zaman K, et al. Risk factors for acquiring scrub
typhus among children in Deoria and Gorakhpur Districts,
Uttar Pradesh, India, 2017. Emerg Infect Dis 2018; 24 : 2364-7.
20. Govt of Uttar Pradesh. AES/JE control strategy. Treatment with
Doxycycline/Azithromycin. 21/F/S.NO/AES/JE/2016/2044-
49. 2016.
21. Thangaraj JWV, Zaman K, Shete V, Pandey AK, Velusamy S,
Deoshatwar A, et al. Eectiveness of Presumptive Treatment
of Acute febrile illness with doxycycline or azithromycin in
preventing acute encephalitis syndrome in Gorakhpur, India:
A cohort study. Indian Pediatr 2020; 57 : 619-24.
22. Prakash Gangwar S, Thangaraj JWV, Zaman K, Vairamani V,
Mittal M, Murhekar M. Sequelae following acute encephalitis
syndrome caused by Orientia tsutsugamushi. Pediatr Infect
Dis J 2020; 39 : e52-4.
23. Aneja S and Joshi J. Presumptive Treatment of acute febrile
illness for preventing acute encephalitis syndrome: Does it
work? Indian Pediatr 2020; 57 : 607-8.
For correspondence: Dr Manoj V. Murhekar, ICMR- National Institute of Epidemiology, Chennai 600 077, Tamil Nadu, India
e-mail: mmurhekar@nieicmr.org.in
[Downloaded free from http://www.ijmr.org.in on Wednesday, May 5, 2021, IP: 103.210.200.142]