A retrospective analysis of scrub typhus meningitis in children

Introduction: Scrub typhus is a re-emerging threat worldwide and meningitis due to it is being increasingly recognised. There are few studies on paediatric patients with scrub typhus meningitis. Objective: To describe the epidemiological, clinical and laboratory profile of children admitted with scrub typhus meningitis to a hospital in eastern India along with treatment outcome. Method: This is a retrospective analysis of the hospital records from September 2015 to January 2017 of all children between 1 month to 12 years of age admitted to the Institute of Child Health, Kolkata, India, with fever, neck rigidity and evidence of both meningitis and scrub typhus. The epidemiological features, clinical signs and symptoms, laboratory findings and treatment outcomes of the children were noted. Chi‐square test was used for comparing categorical variables and the student’s unpaired t‐test for comparing the continuous variables. A p-value of less than 0.05 was considered statistically significant. Results: There were five children with scrub typhus, with a CSF picture of meningitis during the study period. Mean duration of fever before presentation was 11.6 ± 1.8 days. The male: female ratio was 4:1 and the urban: rural ratio 1:4. The mean age was 78 ± 37.5 months. Vomiting, headache, altered sensorium and seizures were the common symptoms. Signs of meningeal irritation, pallor and lymphadenopathy were the common findings on physical examination. Conclusion: Meningitis is an uncommon complication of scrub typhus in children, only 5 cases being recorded from September 2015 to January 2017 at the Institute of Child Health, Kolkata, India. _________________________________________ Institute of Child Health, Kolkata, India *Correspondence: dr.roy85@gmail.com (Received on 24 March 2017: Accepted after revision on 19 May 2017) The authors declare that there are no conflicts of interest Personal funding was used for the project. Open Access Article published under the Creative Commons Attribution CC-BY License DOI: http://dx.doi.org/10.4038/sljch.v47i1.8422 (


Introduction
Scrub typhus is caused by Orientia tsutsugamushi and is a serious re-emerging threat as untreated cases may have a 30-35% mortality 1 . Among its various neurological complications, meningitis is the most common 2 . The intracellular rickettsia apparently enter the central nervous system (CNS) via infected monocytes during meningeal inflammation or through the endothelium of the luminal membrane 3. Although numerous studies have reported occurrence of meningitis in scrub typhus in children, we have found only one paediatric study that has investigated the features of this meningitis 4 .

Objective
To describe the epidemiological, clinical and laboratory profile of children admitted with scrub typhus meningitis to a hospital in eastern India along with treatment outcome.

Method
We did a retrospective study of the hospital records of all children admitted to the Institute of Child Health, Kolkata, India, with fever and neck rigidity between September 2015 and January 2017. Children 1 month to 12 years of age with both evidence of meningitis and scrub typhus without any other obvious co-infection were included in the study. Meningitis was defined by the presence of more than 5 cells in the cerebrospinal fluid (CSF). Scrub typhus was defined by both Weil-Felix test (WFT) and IgM ELISA (for scrub typhus) positivity. The epidemiological features, clinical signs and symptoms, laboratory findings and treatment outcomes were noted. The CSF pictures of three children who suffered from tuberculous meningitis (TBM) (proven by clinical features of tuberculosis, positive geneXpert/cartridge based nucleic acid amplification test and positive response to anti-tubercular drugs) were also collected from the hospital records, so as to compare with the CSF picture of scrub typhus meningitis.
WFT and IgM ELISA (for scrub typhus) are routinely done on all children admitted to our hospital with clinical suspicion of scrub typhus. WFT is considered positive at titres ≥1:80 5 and IgM ELISA (In Bios International Inc., Seattle) is considered positive at optical density >0.5 6 . Wherever necessary, tests for malaria, dengue, enteric fever, blood culture and urine culture are also done.
Lumbar puncture (LP) for cerebrospinal fluid (CSF) study (provided no contra-indication exists), is done on any child admitted with fever and any one of the following: (a) neck rigidity, (b) repeated convulsions and/or prolonged convulsions in a child with no other obvious cause of seizure, (c) convulsions in a child less than 6 months or more than 5 years of age with no other obvious cause of seizure, (d) definite evidence of raised intracranial pressure of magnetic resonance imaging (MRI) of brain/ ophthalmoscopy, (e) headache and vomiting with clinical suspicion of meningitis. CSF is routinely tested for cytology, glucose, protein, gram stain, ZN Stain, geneXpert/CB-NAAT and bacterial culture but whenever suspected, Indian ink stain, PCR for Herpes and other tests are also done.
Statistical analysis was performed using GraphPad QuickCalcs and 'Math is Fun', two online software available freely on the internet 7,8 . Descriptive data were expressed as mean ± standard deviation. Chi-square test was used for comparing categorical variables and student's unpaired t-test test was used for comparing the continuous variables. A p-value of less than 0.05 was considered statistically significant.

Results
We found five children with scrub typhus, with a CSF picture of meningitis during the study period. The epidemiological, clinical and laboratory parameters documented in the records are illustrated in Tables 1-3.   In Table 4, the CSF findings in our study are compared with the CSF findings in a few paediatric and adult studies in the literature.

Table 4: Comparison of literature on CSF parameters of scrub typhus meningitis with that of present study
Our study Meena et al. 4 Lurshay et al. 14 Abhilash et al. 3 Varghese et al. 15  Three children were treated with intravenous (IV) doxycycline, one child with IV azithromycin and one child with oral azithromycin. Fever subsided within 24-48 hours in 2 children (the child treated with oral azithromycin and 1 child treated with IV doxycycline) and within 48-72 hours in the remaining 3 children. There were no complications or mortality.

Discussion
Although scrub typhus is a re-emerging disease, there are already numerous studies in the medical literature regarding its overall presentation in both adult and paediatric age groups. However, the incidence of meningitis due to scrub typhus varies greatly in different studies 4,[9][10][11][12][13][14]  To the best of our knowledge, there has been only one systematic study on scrub typhus meningitis in the paediatric age group, from Jaipur, India published in 2015 on only seven children 4 . Extensive search revealed few incomplete descriptions of one or two cases of meningitis described as part of an article on the overall presentations of paediatric scrub typhus 9,16,17 .
In the present study males were more affected, particularly those more than 5 years of age, probably due to their higher outdoor sports activity. The higher incidence in rural background may be due to more rodent and mite vectors in this environment. Headache (60%), vomiting (80%), altered sensorium (60%) and seizure (60%) were present in most of the patients with meningitis. Similar findings have been observed by Meena et al in paediatric patients of scrub typhus meningitis 4 and Abhilash et al in adults 3 . However, a literature review revealed that the incidence of these neurological findings (headache etc.) are not as high when a general sample of patients with scrub typhus (both with and without meningitis) was studied 4,[9][10][11][12][13] . For example, in a study by Kumar et al on thirty-five children diagnosed with scrub typhus (which included two children with meningitis), the occurrence of headache (11%), vomiting (49%), altered sensorium (17%) and seizure (11%) were much lower than that observed in our study population of exclusively meningitis patients 10 .
Thus, the presence of these symptoms should raise the suspicion of meningitis in scrub typhus.
The CSF findings in our study are compared with other studies in Table 4. It appears that our observations correlate well with the other studies. The mean cell count is lower in children than in adults. Children showed more lymphocytic predominance in CSF cytology. Protein is only mildly raised and glucose is almost normal in the CSF, mimicking the picture of aseptic meningitis. Confusion with TBM can often be resolved by the presence of a higher amount of protein and lower amount of glucose in the CSF of patients with TBM, as seen in our cases and the CT/MRI picture of the brain may be characteristic in TBM and serve to differentiate between the two. The clinical picture in scrub typhus meningitis may also be confused with partially treated pyogenic meningitis but Varghese et al in a study on adult patients observed that the mean duration of fever in pyogenic meningitis was 3.3 days versus a mean duration of fever of 8.4 days in scrub typhus meningitis 15 . In our study the mean duration of fever was 11.6±1.8 days in scrub typhus meningitis. The remaining clinical and laboratory parameters are similar to those observed in studies done on the general presentation of children with scrub typhus 4,[9][10][11][12][13] . Thus, although signs like rash, eschar and hepatomegaly as well as markers like anaemia, thrombocytopenia and raised liver transaminases can help in suspecting scrub typhus in febrile children, they probably have no role in predicting or diagnosing meningitis.
Both doxycycline and azithromycin are equally efficacious as treatment for scrub typhus meningitis as described in our study. Phimda  This study will serve to enrich the scant literature on scrub typhus meningitis in the paediatric age group. In the developing countries, where scrub typhus meningitis, tuberculous meningitis and partially treated pyogenic meningitis are very common, confusion is very likely to arise, unless the paediatrician is well-informed about the detailed clinical and laboratory features of scrub typhus meningitis in children.

Conclusion
Meningitis is an uncommon complication of scrub typhus in children, only 5 cases being recorded from September 2015 to January 2017 at the Institute of Child Health, Kolkata, India.