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Indian Pediatr 2014;51: 651-653 |
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Clinical Profile of Scrub Typhus in Children
and its Association with Hemophagocytic Lymphohistiocytosis
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Naveen Sankhyan, LG Saptharishi, Kandasamy Sasidaran,
*Anil Kanga and Sunit C Singhi
From the Department of Pediatrics, PGIMER, Chandigarh;
and *Department of Microbiology, Indira Gandhi Medical College, Shimla,
India.
Correspondence to: Prof. Sunit C Singhi, Professor and
Head, Department of Pediatrics, Advanced Pediatric Centre, Post Graduate
Institute of Medical Education and Research, Chandigarh 160 012, India.
Email: [email protected]
Received: February 24, 2014;
Initial review: February 25, 2014;
Accepted: June 21, 2014.
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Objective: To study the clinical profile of children with scrub
typhus and its association with hemophagocytic lymphohistiocytosis.
Methods: Children presenting with unexplained fever and
multi-systemic involvement between May to December 2011 were tested
for scrub typhus using IgM ELISA kits. Occurrence of Hemophagocytic
lymphohistiocytosis in IgM positive cases of scrub typhus was
studied. Results: Of the 35 children with unexplained fever
and multi-systemic involvement, 15 children (9 boys) tested positive
for scrub typhus. Thrombocytopenia, hypoalbuminemia and raised
hepatic transaminases were observed in all children. Out of seven
children evaluated for hemophagocytic lymphohistiocytosis. 3 met the
criteria for hemophagocytosis. Two children (one with hemophagocytic
lymphohistiocytosis) died. Conclusions: Scrub typhus is a
common cause of unexplained fever in children in northern India.
Hemophagocytic lymphohistiocytosis can occasionally complicate scrub
typhus in children.
Keywords: Infectious vasculitis,
Rickettsial disease, Hemophagocytosis.
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Scrub typhus is an acute febrile illness caused by
infection with Orientia tsutsugamushi. It is characterized by
focal or disseminated vasculitis and perivasculitis, involving the
lungs, heart, liver, spleen, and central nervous system. It is reported
from many countries in the world [1], and recent reports from many parts
of India highlight its endemicity in India [2].
Hemophagocytic lymphohistiocytosis syndrome (HLH) is
a rare but potentially fatal clinical syndrome resulting from
dysregulated activation and proliferation of lymphocytes. Infections are
important triggers for hemophagocytosis [3]. There are few case reports
of scrub typhus associated HLH in children [4,5]. We report our
experience with pediatric scrub typhus at a hospital in Northern India,
and highlight its association with HLH.
Methods
This study was done from May 2011 to December 2011 at
a tertiary care pediatric hospital in northern India. Children admitted
with unexplained fever and evidence of multi-systemic involvement were
prospectively enrolled and followed-up till discharge from hospital.
Clearance was obtained from the Institutional Ethics Committee. A total
of 35 children were tested for scrub typhus using the IgM ELISA (In Bios
International, Inc.) assay. Additionally, blood culture, urine culture,
malaria rapid diagnostic test, malarial smears, leptospira serology, and
WIDAL tests were done in all children.
The diagnosis of hemophagocytosis was established
using the criteria proposed by Henter, et al. [6]. For this
study, we could use only six among the eight characteristics because of
the unavailability of natural-killer (NK) cell activity assessment and
sCD25 quantification. Supportive evidence for HLH included cerebral
symptoms with moderate pleocytosis and/or elevated protein and elevated
transaminases, bilirubin and LDH [7].
Categorical variables were reported as frequencies, and
continuous as mean± SD (parametric) or median and ranges
(non-parametric).
Results
Based on clinical suspicion, a total of 35 admitted
children were tested for scrub typhus. Samples of fifteen children (9
boys) tested positive for scrub typhus. The children reported from the
states of Himachal Pradesh, Haryana, Punjab and Uttar Pradesh, besides
Union Teritory of Chandigarh. All these children (median age 78 months,
range 24-140 months) presented during the months of July to October. The
median (range) duration of fever was 7 (3-22) days. The other presenting
features were: sensorial changes (11), vomiting (10), seizures (9),
rapid breathing (8), edema (7), cough (5), rash (5), bleeds (2) and
jaundice in two children. On examination, hepatosplenomegaly was found
in nearly all the children. The characteristic ‘eschar’ was found
in only 2 children (Table I). Thrombocytopenia,
hypoalbuminemia and elevated tranaminases were observed in all children.
Half the children had hyponatremia. Eleven children underwent CSF
examination; eight had raised CSF proteins and five had pleocytosis
(lymphocytic in 3, neutrophilic in 2).
TABLE I Findings on Examination and Investigations in Children with Scrub Typhus
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Clinical features |
No. (%) |
Investigations |
No. (%) |
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Hepatomegaly |
14 (93) |
TLC >15 ×109/L |
7 (47) |
|
Splenomegaly |
13 (87) |
Platelets < 150 ×109/L |
15 (100) |
|
Rash |
10 (67) |
Platelets < 50 ×109/L |
7 (47) |
|
Edema |
9 (60) |
Serum albumin < 25 g/L |
15 (100) |
|
Petechiae |
7 (47) |
Serum Na <135 mmol/L |
8 (53) |
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Raised intracranial pressure |
5 (33) |
Serum creatinine (>1 mg/dL) |
3 (20) |
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Wheeze/crepts |
7 (47) |
Hb* (gm/L) |
91 ± 21 |
|
Lymphadenopathy |
6 (40) |
AST** (IU/L) |
145 (108-1479) |
|
Eschar |
2 (13) |
ALT** (IU/L) |
96 (60-1131) |
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Meningeal signs |
5 (33) |
CSF cells** (No./mm3) |
40 (20-60) |
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*Data as mean±SD, **data as median
(range), TLC- total leukocyte count, Hb- Hemoglobin, AST-Aspartate
aminotransferase (IU/L), ALT-Alanine aminotransferase (IU/L). |
Doxycycline was the drug used in 10 children and
azithromycin in the rest. The median (range) time to defervescence was 6
(3-9) days. Two children with proven scrub typhus died. The mean (range)
hospital stay of the survivors was 11 days.
Seven children were evaluated for HLH; five of these
underwent bone marrow examination. Three children met the criteria for
HLH (Table II). All children with HLH had prominent
hepatosplenomegaly. One of these 3 children died and the diagnosis was
established only post mortem. No clinical or laboratory feature could
reliably distinguish these children from those who did not develop
hemophagocytosis.
TABLE II Profile of Three Children with Scrub Typhus-induced Hemophagocytic Lymphohistiocytosis
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Age(y)/ |
Fever |
Clinical features and Examination
findings |
AST/ALT |
TG |
Albumin |
Ferritin
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sex |
duration(d) |
|
(IU/L) |
(mg/dL) |
(g/L) |
(ng/mL) |
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7/M |
7 |
Tachypnea, pallor, edema, hypotension,
wheeze on auscultation |
136/60 |
286 |
22 |
2640 |
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9/F |
10 |
Skin bleeds, altered sensorium, seizures,
jaundice,
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lymphadenopathy, edema, hypotension,
wheeze on auscultation |
439/74 |
846 |
17 |
19706 |
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6.5/F |
8 |
seizures, altered sensorium, rash, rapid
breathing, jaundice,
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edema, hypotension |
112/51 |
286 |
17 |
644 |
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AST-Aspartate aminotransferase
(IU/L), ALT-Alanine aminotransferase (IU/L), TG-
Triglycerides(mg/dL). |
Discussion
In our series hepatosplenomegaly was seen in nearly
all children with scrub typhus, two-thirds had evidence of rash and
fluid leak, clinical pulmonary manifestation were seen in half, and CNS
manifestation occurred in one-third of the children. Being a tertiary
care referral center, our patient series may not be a true reflection of
the disease spectrum in the community. However, scrub typhus was
diagnosed in children hailing from five North Indian states. This data
extends the previous observations [8], and suggests that scrub typhus is
possibly endemic in Northern India.
In a study of thirty children with scrub typhus from
Thailand, most children presented during the rainy season and
lymphadenopathy (93%), hepatomegaly (73%), eschar (68%), conjunctival
hyperemia (33%), maculopapular rash (30%), and splenomegaly (23%) were
the commonest signs. Eleven patients had interstitial pneumonitis and
one patient had meningitis [9].
Most children in our series did not have the
characteristic eschar. Eschars have been reported to be rare in previous
studies from this region [10]. The variation in cutaneous immunity and
possible previous exposure to the pathogen in indigenous populations
have been cited as a possible explanations for the absence of an eschar
in scrub typhus [10]. In a
study from Korea, among 208 adults with scrub typhus, factors
independently associated with the severe complications were; the absence
of eschar, WBC counts >10, 000/mm3,
and albumin ≥3.0
g/dL [11]. Response to appropriate treatment is often described as
‘dramatic’ with early defervescence [9]. However, in our series, the
median time to defervescence was 6 days, possibly reflecting the
severity of involvement in our patients.
Despite the recognition of HLH in rickettsial
infection, till now only few case reports of acquired HLH in scrub
typhus are available in children [4,5,12].
We diagnosed HLH in 3 of our 7 children with scrub typhus
evaluated for HLH. This suggests that HLH may not be uncommon in
children with severe scrub typhus. Understanding this would drive us to
evaluate the children earlier for acquired HLH, treating which could
change the outcome of severe scrub typhus. For patients with reactive
HLH associated with pathogens other than EBV, supportive care and
treatment of the underlying infection is associated with recovery in
60%-70% [13]. Two of the three children in our series recovered with the
control of infection. One child with scrub typhus and HLH died before
the diagnosis could be suspected or established.
The current study is limited because of its single-center
origin and small sample size. Another drawback is the lack of
confirmation of the diagnosis using the gold standard micro-immunoflurosence
assay. Larger multi-centric studies are thus required to elaborate on
the endemicity of scrub typhus in India and its spectrum of
manifestations. To optimize outcomes of children with severe scrub
typhus, co-existing HLH needs to be suspected early and investigated
promptly. Treatment protocols for ricketssia-induced HLH in children
need evaluation in future studies.
Contributors: SN: conceptualized the
study, organized the data, analyzed, interpreted the data, and prepared
the first draft; SLG: data acquisition, data analysis and
interpretation, manuscripts revision SK: helped in data collection and
analysis; KA: coordinated the laboratory testing and analysis of
results; SS: conceptualized the study, revised drafts for important
intellectual content and approved the final manuscript. All authors
contributed to the final version of manuscript.
Funding: None; Competing interests: None
stated.
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What This Study Adds?
• The atypical clinical
manifestations with increased propensity for secondary
hemophagocytosis in children with scrub typhus is highlighted in
this series from Northern India.
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