Association of Scrub Typhus in

Children with Acute Encephalitis

Syndrome and Meningoencephalitis,
Southern India
Tina Damodar, Bhagteshwar Singh, Namratha Prabhu,1 Srilatha Marate,1 Vykuntaraju K. Gowda,
A.V. Lalitha, Fulton Sebastian Dsouza, Sushma Veeranna Sajjan, Mallesh Kariyappa, Uddhava V. Kinhal,
P.V. Prathyusha, Anita Desai, Kandavel Thennarasu, Tom Solomon, Vasanthapuram Ravi, Ravi Yadav

Scrub typhus is an established cause of acute encepha-

South America (1). A recent systematic review from
litis syndrome (AES) in northern states of India. We sys- hospital-based studies in India reported 25% of acute
tematically investigated 376 children with AES in south- undifferentiated febrile illness was caused by scrub
ern India, using a stepwise diagnostic strategy for the typhus. Most studies included were from southern
causative agent of scrub typhus, Orientia tsutsugamushi, India, but only 20% of included patients were <15
including IgM and PCR testing of blood and cerebrospi- years of age (2). Although scrub typhus illness is typi-
nal fluid (CSF) to grade its association with AES. We cally self-limiting, neurologic complications are seen
diagnosed scrub typhus in 87 (23%) children; of those, in 20%–25% of patients admitted to the hospital and
association with AES was confirmed in 16 (18%) cases, are associated with high mortality rates (3,4). Scrub
probable in 55 (63%), and possible in 16 (18%). IgM de- typhus can result in myriad neurologic manifesta-
tection in CSF had a sensitivity of 93% and specificity
tions, including meningitis, meningoencephalitis,
of 82% compared with PCR. Our findings suggest scrub
typhus as an emerging common treatable cause of AES
encephalopathy, seizures, stroke, neuropathy, optic
in children in southern India and highlight the importance neuritis, myositis, myelitis, involuntary movements,
of routine testing for scrub typhus in diagnostic algo- and Guillain-Barré syndrome, all of which are well
rithms. Our results also suggest the potential promise of recognized in adults (3,4).
IgM screening of CSF for diagnosis of AES resulting from Recent studies in India have identified O. tsutsuga-
scrub typhus. mushi as a major cause of acute encephalitis syndrome
(AES) outbreaks, especially in northern states of the

S crub typhus is an acute febrile illness caused by

an obligate intracellular gram-negative bacterium,
Orientia tsutsugamushi. It is transmitted through chig-
country, such as Uttar Pradesh, Bihar, West Bengal,
and Assam (5–7). Outbreaks of AES pose a major pub-
lic health problem in India, predominantly affecting
ger mites and is considered endemic to the tsutsuga- children (8). The definition of AES used for syndromic
mushi triangle (covering Asia, northern Australia, and surveillance is broad and includes all patients experi-
islands in the Indian and Pacific Oceans), although encing acute onset of fever and altered mental state
scrub typhus caused by other Orientia species has also (9,10). The clinical manifestation might be caused
been reported in Africa, France, the Middle East, and by encephalitis or meningitis (direct invasion of the

Author affiliations: National Institute of Mental Health and and Hospital, Bangalore (A.V. Lalitha, F.S. Dsouza); Vani Vilas
Neurosciences, Bangalore, India (T. Damodar, N. Prabhu, Women and Children’s Hospital, Bangalore Medical College and
S. Marate, P.V. Prathyusha, A. Desai, K. Thennarasu, V. Ravi, Research Institute, Bangalore (S.V. Sajjan, M. Kariyappa); The
R. Yadav); Christian Medical College, Vellore, India (B. Singh); Walton Centre NHS Foundation Trust, Liverpool (T. Solomon);
University of Liverpool, Liverpool, UK (B. Singh, T. Solomon); The Pandemic Institute, Liverpool (T. Solomon)
Liverpool University Hospitals NHS Foundation Trust, Liverpool
DOI: https://doi.org/10.3201/eid2904.221157
(B. Singh, T. Solomon); Indira Gandhi Institute of Child Health,
Bangalore (V.K. Gowda, U.V. Kinhal); St. John’s Medical College 1
These authors contributed equally to this article.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023 711
SYNOPSIS

central nervous system [CNS] by the pathogen) or National Vector Borne Disease Control Programme
encephalopathy without CNS invasion, such as in the (NVBDCP) and World Health Organization case
case of severe systemic infection, metabolic derange- definition of AES (8) (Appendix Table 1, https://
ment, or other neurologic complications after the in- wwwnc.cdc.gov/EID/article/29/4/22-1157-App1.
fection (10,11). Identifying the pathogenesis could in- pdf) and with illness duration of <30 days at the
form management and prognosis (10,12). time of hospital admission. Patients were those
Early diagnosis is key to initiating prompt specific treated at 3 tertiary-care hospitals in Bangalore,
treatment, which can reduce complications and fatal- Karnataka state, India (Indira Gandhi Institute of
ity rates of scrub typhus (2,13). Clinical diagnosis can Child Health, St. John’s Medical College and Hos-
be challenging because of the overlap of symptoms pital, and Vani Vilas Hospital), during March 2019–
with other tropical infections endemic to the area that March 2022.
can also cause AES (5), such as dengue, chikungunya,
malaria, and leptospirosis (14). Current microbiologi- Ethics Statement
cal diagnostics for scrub typhus, which are usually The study was approved by the institutional ethics
based on detecting IgM in serum samples or nucleic and review boards of the hospitals and the coordinat-
acid by PCR, have limitations. IgM appears in serum ing center, National Institute of Mental Health and
5–6 days after onset of illness, can persist long after Neurosciences. Full informed consent was taken by
acute illness, and might cross-react with IgM of other the study team, who were trained specifically in tak-
cocirculating pathogens (14,15). Therefore, in AES ing consent from caregivers, and assent from older
patients with simultaneous microbiological evidence children, using procedures and forms approved by
for another potential pathogen and O. tsutsugamushi, the institutional ethics committees.
confirming O. tsutsugamushi as the cause is difficult.
Detection of IgM in cerebrospinal fluid (CSF) is yet to Clinical Assessment and Data Collection
be used widely in patients with suspected neurologic Clinical coinvestigators (V.K.G., L.A.V., F.S.D., S.S.,
scrub typhus. Immunofluorescence assay has long M.K.) from the 3 centers performed clinical and
been considered the reference standard serologic test, neurologic examination of patients. After obtaining
but its use is limited by expense and challenges in consent, we entered detailed clinical history and ex-
interpretation. PCR might help overcome shortcom- amination findings on an electronic clinical proforma.
ings of serologic tests with respect to cross-reacting Results of routine laboratory tests and patient demo-
and persisting antibodies, but a positive result is only graphics were collected and entered online by N.P.,
likely during the bacteremia phase of infection (16). S.M., or T.D. We determined the normal range of rou-
Moreover, the recommended samples for O. tsutsuga- tine laboratory tests according to the age of the pa-
mushi PCR are blood or eschar material, whereas the tient (18) and defined single-organ dysfunction and
sensitivity of PCR on CSF remains unclear (7,16,17). multiorgan dysfunction syndrome according to es-
Therefore, a diagnostic approach using accessible tablished criteria (19).
tests to determine the association of scrub typhus
with AES is urgently needed. Microbiological Testing
We present preliminary findings of an ongoing Blood and CSF specimens of enrolled patients
multicenter prospective cohort study suggesting scrub were tested at the Department of Neurovirology,
typhus as a cause of AES in children in southern In- National Institute of Mental Health and Neurosci-
dia. We used a diagnostic strategy to investigate the ences, by using a laboratory algorithm designed
association of scrub typhus with AES. We describe the by Ravi et al. (5) with some modifications (Figure
clinical spectrum, epidemiology, and laboratory find- 1). First-line tests included serum IgM ELISA for
ings of children with scrub typhus manifesting as AES. various pathogens. CSF samples of patients with
We then identify patients demonstrating evidence of IgM-positive ELISA serum samples were diluted in
meningoencephalitis or encephalitis and explore the 1:10 proportion for detection of IgM. We performed
value of performing IgM ELISA on CSF samples. confirmatory tests on IgM-positive patients, includ-
ing real-time PCR for O. tsutsugamushi on CSF and
Methods blood samples. For PCR, we extracted DNA from
samples by using the QIAamp DNA mini kit (QIA-
Patients and Study Sites GEN, https://www.qiagen.com) and performed
We prospectively enrolled pediatric patients from real-time PCR targeting the 47kDa protein gene us-
1 month to 18 years of age who fulfilled the Indian ing the protocol described by Jiang et al. (20). In

712 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023w
 Scrub Typhus in Children, Southern India

Figure 1. Laboratory algorithm used for

serologic and molecular testing of samples
from children with acute encephalitis syndrome,
southern India. In case of clinical suspicion of a
second-line pathogen, irrespective of the first line
test results, second-line tests were performed.
Similarly, in the case of clinical suspicion of
a third-line pathogen, third-line tests were
performed. AES, acute encephalitis syndrome;
CSF cerebrospinal fluid.

addition, we also performed real-time PCR and typhus ME as those demonstrating clinical signs of
IgM ELISA for O. tsutsugamushi on stored CSF sam- either encephalitis or meningoencephalitis (Table 2).
ples of patients with a negative result after third-
line tests. We used the Scrub Typhus Detect IgM Statistical Analysis
ELISA kit (InBios International, http://inbios.com) We performed statistical analysis by using R version
and considered an optical density (OD) cutoff of 0.8 3.6.3 (The R Project for Statistical Computing, https://
in serum (15) and 0.5 in CSF (21) samples to be posi- www.r-project.org). We presented descriptive data for
tive. Scrub typhus was diagnosed in patients with categorical variables as frequencies, percentages, or both
IgM-positive real-time PCR or ELISA. and described continuous variables using mean +SD or
The level of certainty of association of scrub ty- median and interquartile range (IQR). To describe the
phus with AES in cases positive for >1 microbiological diagnostic accuracy of CSF IgM, we compared results
test(s) for O. tsutsugamushi was determined by using against CSF PCR to calculate the sensitivity, specificity,
criteria determined by Granerod et al. (11) with mod- positive predictive value (PPV), and negative predictive
ifications (Tables 1, 2). We identified patients with value (NPV) of CSF IgM with 95% CI. We also calcu-
meningoencephalitis/encephalitis (ME) and scrub lated those values for patients with scrub typhus ME.
Table 1. Diagnostic criteria for certainty in the association of AES with scrub typhus in children, southern India*
Association of AES with scrub Simultaneous evidence
typhus Real-time PCR Serum IgM ELISA CSF IgM ELISA of another pathogen(s)
Confirmed + +/− +/− +/−
Probable, single† – + +/− –
Probable, co-positive‡ – + + +
Possible – + – +
*AES, acute encephalitis syndrome; CSF, cerebrospinal fluid.
†Without evidence of another potentially causative pathogen.
‡With evidence of another potentially causative pathogen.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023 713
SYNOPSIS

Table 2. Definitions used for diagnostic association of AES with scrub typhus, ME, and scrub typhus ME in study of association of AES
with scrub typhus in children, southern India*
Condition Definition
Diagnostic association of AES with scrub typhus Confirmed: Detection of Orientia tsutsugamushi DNA by PCR in
CSF or blood
Probable (single): Positive serum IgM ELISA with or without
positive CSF IgM ELISA for Orientia tsutsugamushi and no other
explanatory pathogen or cause
Probable (co-positive): Positive serum IgM ELISA and positive
CSF IgM ELISA for Orientia tsutsugamushi with evidence of
another pathogen(s)
Possible: Positive serum IgM ELISA and negative CSF IgM ELISA
for Orientia tsutsugamushi with evidence of another pathogen(s)
Meningoencephalitis (22) Presence of >1 of the following findings: CSF pleocytosis,
meningeal enhancement or parenchymal inflammation on contrast
enhanced CT or MRI of brain, positive real time PCR in CSF
Scrub typhus ME Patients with meningoencephalitis AND positive real-time PCR or
serum IgM ELISA for Orientia tsutsugamushi (and no other
explanatory pathogen or cause) (i.e, patients with confirmed or
probable [single] diagnostic association of AES with scrub typhus)
*AES, acute encephalitis syndrome; CSF, cerebrospinal fluid; CT, computed tomography; ME, meningoencephalitis; MRI, magnetic resonance imaging.

Results Diagnostic Association of Scrub Typhus with AES

We included a total of 376 children with AES in the On the basis of serum IgM results, the association
study (Appendix Figure 1). Of those, scrub typhus of scrub typhus with AES was probable in 47/87
was diagnosed in 87 patients by using the laboratory (54%) patients and possible in 39/87 (45%) patients.
algorithm described. Further, on performing IgM ELISA on CSF samples,
the association was probable (single-positive) in 47
Microbiological Testing (58.8%) persons, probable (copositive) in 23 (26.4%)
We collected samples for microbiological testing a persons, and possible in 16 (18%) persons. Finally,
median of 11 (IQR 8–14) days from onset of symptoms on the basis of real-time PCR results, the associa-
and median of 4 (IQR 2–6) days after hospitalization. tion was confirmed in 16 (18%) patients, probable
Serum samples were positive for O. tsutsugamushi (single-positive) in 38 (43.7%) patients, probable (co-
IgM in 86/376 (22.8%) patients. Of those 86 patients, positive) in 17 (19.5%) patients, and possible in 16
39 (45.4%) had a positive microbiological test result (18.4%) patients (Figure 2).
for another pathogen (referred to as copositive) (Ap-
pendix Table 2); 47 (54.6%) were positive for O. tsu- ME and Scrub Typhus ME
tsugamushi IgM alone (referred to as single-positive). Of the 87 patients, 65 (74.7%) had findings suggestive
CSF samples were available for 82/86 patients of ME (Appendix Tables 3, 4). The diagnostic associa-
with O. tsutsugamushi IgM–positive serum samples tion of ME with scrub typhus was confirmed or prob-
and all 184 patients who had no etiologic diagnosis able (single-positive) in 54 (62%) patients (Figure 2),
after use of the laboratory algorithm. CSF samples and of those patients, 43 had ME. Therefore, among
were IgM-positive in 58/82 (71%) patients (23/36 of all 87 patients, 49.4% had scrub typhus ME (Figure 3).
copositive patients and 35/45 of single-positive pa-
tients). All 184 serum IgM-seronegative patients were Diagnostic Accuracy of CSF IgM Testing
negative for CSF IgM by ELISA. We performed IgM ELISA and real-time PCR on
Real-time PCR results were positive in 15/86 CSF samples of 266 patients (i.e., 82/86 patients with
(17%) patients with IgM-positive serum (real-time IgM-positive serum samples and 184/184 patients
PCR of both CSF and blood was positive in 2 patients; with no etiology after tests were performed per the
11 were positive by CSF PCR only and 2 by blood laboratory algorithm). We created a 2×2 table to
PCR only). Of the 184 CSF samples of patients with compare the performance of CSF IgM with CSF PCR.
no etiologic diagnosis after first-line and second-line The sensitivity of CSF IgM ELISA was 92.9% (95%
tests, 1 was positive by real-time PCR for O. tsutsuga- CI 66.1%–99.8%), specificity 82.1% (95% CI 76.8%–
mushi. In total, 16 patients were positive for O. tsutsu- 86.6%), PPV 22.4% (12.5%–35.2%), and NPV 99.5%
gamushi by PCR. Therefore, of 376 patients with AES, (97.3%–100%) (Table 3).
87 (23%) had a positive microbiological test for scrub CSF samples were available for 53/54 patients with
typhus (AES–scrub typhus) (Figure 2). confirmed or probable (single-positive) scrub typhus.

714 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023w
 Scrub Typhus in Children, Southern India

CSF IgM was positive in 36/42 (85.7%) patients with Demographic and Clinical Profile
ME and 5/11 (45.5%) patients without ME. Sensitiv- The male:female ratio of children with scrub typhus
ity of CSF IgM in patients with ME was 85.7% (95% CI was 1.5:1. Ages ranged from 2 months to 17 years; the
71.4–94.5%) and specificity was 54.5% (95% CI 23.3%– mean age was 8.5 (SD +4) years (Table 4). Proportions
83.2%); the corresponding PPV was 87.8% (78.8%– of AES-scrub typhus cases were highest in the months
93.3%) and NPV was 50.0% (28.6%–71.4%) (Figure 3). of August and September. In addition, the number of

Figure 2. Results of microbiological tests for scrub typhus (A) and

diagnostic association of scrub typhus with acute encephalitis
syndrome (B) in children, southern India. AES, acute encephalitis
syndrome; CSF, cerebrospinal fluid; OT, Orientia tsutsugamushi.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023 715
SYNOPSIS

Figure 3. CSF IgM ELISA results of children with scrub typhus ME, southern India. CSF samples were available in 42/43 children
with ME of which CSF IgM was positive in 85.7% children. AES, acute encephalitis syndrome; CSF, cerebrospinal fluid; ME,
meningoencephalitis.

AES-scrub typhus patients and their proportion of to- decreased power (19%), and abnormal plantar reflex-
tal AES patients followed the same pattern as the to- es (24%) (Table 5). Approximately 39% of the patients
tal number of AES cases (Appendix Figures 2, 3). The met criteria for multiorgan dysfunction syndrome
largest percentage of children (37%) were from An- (Appendix Table 5).
antapur district in Andhra Pradesh state, followed by
17% from Tumkur district in Karnataka state (Figure Laboratory Findings
4). Nearly 48% of patients were referred from another Anemia, leukocytosis, thrombocytopenia, transami-
hospital, and 34% received anti-infective medications nitis, hypoalbuminemia, and uremia were each pres-
before being admitted to the study hospital. The me- ent in >50% of patients (Table 6). CSF results revealed
dian duration of illness before admission to the study lymphocytic pleocytosis and elevated protein concen-
hospital was 6 (IQR 4–9.5) days. tration in most patients (Appendix Table 6).
All 87 children experienced fever and change in
mental state; fever was the first symptom in 95% of Treatment
cases. Around 62% of children had seizures; gener- Of the patients with scrub typhus, 44 (51%) required
alized tonic-clonic seizures were the most common care in the intensive care unit during their hospi-
type (74%), and some patients also had focal, tonic, talization, and 26 of those required ventilatory sup-
or absence seizures. Upon examination at the time port. All patients except 1 were prescribed doxycy-
of hospital admission, 55 (64%) patients had altered cline (100 mg 2×/d for 10 days). One patient died
mental state. The Glasgow Coma Scale at admission during hospitalization.
ranged from 3 to 15; the median was 13 (IQR 10–15)
(Table 5). Signs of meningeal irritation were detected Discussion
in 48% of patients, cerebellar signs in 21%, and papill- Our findings suggest that scrub typhus is a major
edema in 20%. Other neurologic findings were cranial cause of AES in children in southern India. Of 193
nerve abnormalities (6%), involuntary movements (51%) patients with a known etiology, a microbiologi-
(9%) and photophobia (9%), abnormal tone (50%), cal test for O. tsutsugamushi was positive in 87 (45%)

Table 3. Performance of cerebrospinal fluid IgM ELISA compared with cerebrospinal fluid real-time PCR for scrub typhus in children
with acute encephalitis syndrome and meningoencephalitis, southern India
Cerebrospinal fluid PCR
Cerebrospinal fluid IgM No. (%) positive No. (%) negative Total
Positive 13 (92.8) 45 (17.8) 58
Negative 1 (7.1) 207 (82.1) 208
Total 14 252 266

716 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023w
 Scrub Typhus in Children, Southern India

patients, making it the most common etiology ob- Table 4. Demographic details of children with scrub typhus
tained in the study. An increasing number of studies manifesting as acute encephalitis syndrome, southern India
Variable No. (%) patients
in Asia have reported the contribution of O. tsutsuga-
Age, y, n = 87
mushi to the burden of acute febrile illness in the con- <2 2 (2.3)
tinent, including South Korea, Japan, China, Taiwan, 2–9 50 (57.5)
Thailand, and Bhutan, countries where scrub typhus 10–18 y 35 (40.2)
Sex, n = 87
is a notifiable disease (24). Studies including screening M 52 (59.8)
for O. tsutsugamushi as part of systematic surveillance F 35 (40.2)
of childhood CNS infections in Cambodia, Vietnam, State, n = 81
Laos, Myanmar, and Thailand report its presence in Karnataka 44 (54.3)
Andhra Pradesh 36 (44.4)
1%–4.7% of children (17,25–28). Although studies in Tamil Nadu 1 (1.2)
India have documented meningoencephalitis as a Setting, n = 82
manifestation of scrub typhus in children (2,29,30), Rural 64 (78)
Urban 18 (22)
our study highlights the importance of systematic Risk factors, n = 78*
screening for scrub typhus in children with AES in Contact with shrubs, vegetation, or 49 (62.8)
southern India. Scrub typhus is a well-recognized agricultural farms
cause of acute febrile illness in the major southern In- Contact with animals, birds, or pets 47 (60.3)
Proximity to forest 14 (17.9)
dian states of Andhra Pradesh and Karnataka (31–33), *Based on response to a structured questionnaire in the form of Yes or No.
but we report scrub typhus is also a common cause of
AES in children from these states. typhus cases into 16 cases with confirmed asso-
Given the challenges in clinical diagnosis ciation, 55 with probable association, and 16 with
(10,14,15) and complexity of defining the causal possible association. Real-time PCR, which is con-
relationship of scrub typhus with AES on the ba- firmatory for scrub typhus, was positive in 6/39
sis of serum IgM ELISA, the most widely used test (15%) cases with microbiological evidence of an-
for scrub typhus (15), we used a causality strat- other pathogen and increased the diagnostic asso-
egy. This diagnostic strategy helped in differenti- ciation from possible to confirmed. We were able
ating the certainty of association of 87 AES–scrub to diagnose scrub typhus in 1 extra case in which

Figure 4. District-wise distribution

of children with scrub typhus
manifesting as acute encephalitis
syndrome, southern India.
Number of children from each
district with scrub typhus
manifesting as acute encephalitis
syndrome is indicated. The 3
recruiting hospitals and the
coordinating center are located
in Bangalore urban. Inset shows
location of study area in India.

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023 717
SYNOPSIS

IgM ELISA for O. tsutsugamushi and tests for other 9 (IQR 5.75–12.25) days before clinical specimen
pathogens were negative. Despite systematic test- sampling versus 11 (IQR 8.5–14.5) days for patients
ing, the prevalence of positive real-time PCR in with a negative PCR result.
children with AES caused by scrub typhus was Because IgM does not ordinarily cross the blood–
low in our study (16 [18%] children), although still CSF barrier, presence of those antibodies in CSF im-
higher than in other studies (7,34). PCR positivity plies their production within the CNS (35) and higher
might be maximized by collecting clinical samples certainty of association with the infection compared
sooner after illness onset and using whole blood or to serum IgM. Using CSF IgM ELISA increased the
buffy coat instead of serum to capture intracellu- certainty of association from possible to probable in
lar bacteria (14,16). In this study, patients with a 23 patients who had simultaneous evidence of an-
positive PCR had a median duration of illness of other pathogen. Although the kit is recommended for

Table 5. Clinical findings of children with scrub typhus manifesting as acute encephalitis syndrome, southern India
Clinical features, n = 86* No. (%) patients
Duration of illness, d
<5 38 (44)
>5 48 (56)
Clinical signs and symptoms
Fever 87 (100)
Change in mental status† 87 (100)
Seizure 53 (61.6)
Vomiting 46 (53.5)
Headache 32 (37.2)
New abnormal speech (e.g., slurred) including the inability to speak 24 (27.9)
Change in personality or behavior 18 (20.9)
Limb weakness 11 (12.8)
Arthralgia or myalgia 7 (8.1)
Respiratory symptoms‡ 8 (9.3)
Gastrointestinal symptoms§ 29 (33.7)
Urinary symptoms: decreased urine output, burning micturition 3 (3.5)
General and systemic examination findings
Pallor 23 (26.7)
Icterus 6 (7)
Lymphadenopathy: cervical, inguinal, axillary, mesenteric 16 (18.6)
Edema: periorbital, facial, lower limbs, upper limbs 17 (19.8)
Conjunctivitis/subconjunctival hemorrhage 17 (19.8)
Skin rash 12 (14)
Eschar: axilla, groin, dorsal aspect of penis 4 (4.7)
Abnormal bleeding: nasal, anal, gums 3 (3.5)
Respiratory system findings¶ 21 (24.4)
Gastrointestinal system findings# 50 (58.1)
Cardiac system abnormalities: abnormal heart sounds, abnormal pulse 4 (4.7)
Neurologic findings
Cranial nerve abnormality: 6th and 7th 5 (5.7)**
Sign of meningeal irritation: nuchal rigidity, Kernig’s sign, Brudzinski sign, bulging of anterior fontanelle 41 (47.7)
in infants
Photophobia 8 (9.3)
Papilledema 17 (19.8)
Abnormal tone 43 (50)
Paresis/paralysis: decreased power in >1 limbs 16 (18.6)
Exaggerated reflexes 4 (4.7)
Abnormal Plantar reflex 21 (24.4)
Involuntary movements†† 8 (9.3)
Cerebellar sign(s)‡‡ 18 (20.9)
*All 87 children had fever and change in mental status, but detailed clinical findings of just 86 children were recorded.
†Change in mental status was defined as >1 of the following: change in cognition (such as confusion or disorientation), drowsiness, coma, lethargy,
irritability, reduced activity, poor feeding, irrelevant/abnormal talk.
‡Includes cough and/or difficulty breathing. Both were present in 5 patients each.
§Includes >1 of the following symptoms: abdominal pain, abdominal distension, and diarrhea. Individually, abdominal pain was a symptom in 19 (22%),
abdominal distention in 12 (14%), and diarrhea in 3 (3.5%) patients.
¶Signs of respiratory distress occurred in 16 (19%) patients; reduced air entry or abnormal respiratory sounds occurred in 5 (5%) patients.
#Hepatomegaly was present in 47 (54.7%) patients, splenomegaly was present in 16 (18.6%) patients, and ascites was present in 4 (4.7%) patients.
**Four persons had abnormalities in 6th cranial nerve, and 1 in 7th cranial nerve.
††Opsoclonus and myoclonus, choreoathetoid movements and hemiballismus, abnormal perioral movements, lip smacking, teeth grinding, and rapid eye
blinking occurred in 1 patient each; tremors occurred in 2 patients.
‡‡Includes >1 of the following: truncal ataxia, gait abnormality, finger-nose incoordination, nystagmus, dysdiadochokinesis, and dysarthria.

718 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023w
 Scrub Typhus in Children, Southern India

detecting IgM in serum samples only, Murhekar et Table 6. Laboratory results of children with scrub typhus
al. (6) observed good correlation between OD values manifesting as acute encephalitis syndrome, southern India
Sample type and variables No. (%) patients
for O. tsutsugamushi IgM in serum and CSF. They de-
Peripheral blood, n = 87 unless stated otherwise
termined a cutoff OD value of 0.22 after testing CSF Anemia 79 (90.8)
samples from 374 children <14 years of age with AES Leukocytosis 45 (51.7)
in Gorakhpur, Uttar Pradesh state, India (35). A cutoff Leukopenia 4 (4.6)
Relative neutrophilia 31 (35.6)
OD value for IgM in CSF has not been determined Relative neutropenia 40 (46)
in the southern states in India, so we used a higher Relative lymphocytosis 43 (49.4)
cutoff (0.5), as used by Behera et al. (21) for CSF of Relative lymphopenia 26 (29.9)
Thrombocytopenia 45 (51.7)
children with scrub typhus ME in eastern India. Hyperbilirubinemia, n = 75 21 (28)
Our results demonstrate that, compared with Elevated transaminases, n = 85* 72 (84.7)
PCR, IgM ELISA of CSF had a sensitivity of 92.9%, but Hypoalbuminemia, n = 80 66 (82.5)
Elevated urea, n = 80 56 (70)
with a wide 95% CI, suggesting the estimate is less pre-
Elevated creatinine, n = 86 6 (7)
cise. Although the comparison is indirect, that sensitiv- Cerebrospinal fluid, n = 85 unless stated otherwise
ity is similar to that of serum IgM by the same ELISA Pleocytosis† 59 (69.4)
kit (92.4%) used for patients with acute febrile illness Lymphocytic pleocytosis‡ 54 (63.5)
Neutrophilic pleocytosis§ 5 (5.8)
caused by scrub typhus in southern India (14). The Elevated protein, n = 83 51 (61.4)
specificity of CSF IgM ELISA was moderate compared *Includes elevated levels of aspartate transaminase or alanine
transaminase.
to PCR at 82%. That finding might be because PCR †Cerebrospinal fluid pleocytosis was recorded if white blood cell counts
positivity was less common in our study, which could were >10 cells/μL in infants (1 mo–12 mo of age) and >4 cells/μL in older
be explained by delayed sampling during the course children (22).
‡Cerebrospinal fluid lymphocytic pleocytosis was defined as >50%
of illness, resulting in a higher likelihood of detection mononuclear cells in cerebrospinal fluid of patients with pleocytosis (23).
of IgM than DNA. In addition, the use of a single refer- §Cerebrospinal fluid neutrophilic pleocytosis was defined as a neutrophil
count >50% of total leukocytes in patients with cerebrospinal fluid
ence standard (PCR) in our study could result in a low pleocytosis (23).
PPV of IgM ELISA of CSF. The sensitivity of CSF IgM
in patients with scrub typhus ME was 85.7%. Because 2 such cases of scrub typhus associated with pediat-
only 11 patients did not have features suggestive of ric opsoclonus-myoclonus-ataxia syndrome have been
ME, ascertaining the true specificity is difficult. reported from India (42,43). Cerebellar signs, which
Almost three quarters of the patients with are uncommon in children with scrub typhus (3,13),
AES-scrub typhus had meningoencephalitis. Dis- were noted in almost one fifth of the children in our
tinguishing patients with scrub typhus ME from study. As reported by Vishwanath et al. (30), the sixth
patients with encephalopathy with other causes cranial nerve was the most affected cranial nerve. Pap-
is crucial. Therapeutic failure of doxycycline, the illedema was detected in 20% of children in our study.
drug of choice for scrub typhus, has been reported Few studies have reported direct retinal involvement
in patients with scrub typhus ME (36). This fail- and isolated optic disc edema in the absence of raised
ure could be caused by inadequate concentration intracranial pressure in scrub typhus (29,44,45); how-
of doxycycline in CSF at conventional doses and ever, findings in this area remain inconclusive in our
might indicate the need for increased dosages, in- study. Presence of eschar typically occurs in 4%–46%
travenous administration, or administration of oth- of patients with scrub typhus; therefore, while specific,
er antimicrobial agents such as rifampin that have eschar is not a sensitive marker (30), and it was found
good penetration to the CNS. However, the efficacy in only 5% of patients in this study.
of this treatment is yet to be proven (37,38). The first limitation of our study is that, whereas
The neurologic manifestations in children with serum IgM ELISA is the most widely used specific
scrub typhus that meet the broader epidemiologic defi- test for O. tsutsugamushi, we used a single-positive
nition of AES are rarely reported (13,25,39,40), and no IgM result as a criterion for diagnosis of scrub ty-
data from southern India have been published. Of all phus. Obtaining serial blood samples and perform-
children with scrub typhus in our study, 8 (9%) had ing immunofluorescence or similar assays to dem-
involuntary hyperkinetic movements that are rare onstrate a 4-fold rise in antibody titers would have
neurologic manifestations of scrub typhus more often enabled more certainty in the diagnosis, especially
reported in adults than children (41). Opsoclonus-my- in cases in which antibodies to another pathogen
oclonus, best recognized as part of opsoclonus-myoc- were detected. However, we defined those patients
lonus-ataxia syndrome associated with neuroblastoma as having possible scrub typhus to allow for this un-
in children, is rarely caused by infections (13,41). Only certainty, and they comprised only 18% of the scrub

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 29, No. 4, April 2023 719
SYNOPSIS

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etymologia revisited
Tularemia
[t-lə-rē-mē-ə]

A n infectious, plaguelike, zoonotic disease caused by the

bacillus Francisella tularensis. The agent was named af-
ter Tulare County, California, where the agent was first iso-
lated in 1910, and Edward Francis, an Officer of the US Public
Health Service, who investigated the disease. Dr. Francis first
contracted deer fly fever from a patient he visited in Utah in
the early 1900s. He kept a careful record of his 3-month il ness
and later discovered that a single attack confers permanent
immunity. He was exposed to the bacterium for 16 years and
even deliberately reinfected himself 4 times.
Tularemia occurs throughout North America, many parts
of Europe, the former Soviet Union, the Peoples Republic of
China, and Japan, primarily in rabbits, rodents, and humans.
The disease is transmitted by the bites of deerflies, fleas, and
ticks; by contact with contaminated animals; and by ingestion of
contaminated food or water.
Clinical manifestations vary depending on the route of
Originally published introduction and the virulence of the agent. Most often, an
in November 2007 ulcer is exhibited at the site of introduction, together with
swelling of the regional lymph nodes and abrupt onset of
fever, chills, weakness, headache, backache, and malaise.

Source:
1. Dorland’s illustrated medical dictionary, 31st edition. Philadelphia:
Saunders; 2007; Benenson AS, editor. Control of communicable diseases
manual. Washington: American Public Health Association; 1995; www.
whonamedit.com

https://wwwnc.cdc.gov/eid/article/13/11/e1-1311_article

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