A recent study from Bangladesh has reported high case fatality in children with Shigella encephalopathy [6] We have also noticed an increase in mortality due to Shigella encephalopathy in our center which prompted us to analyze the hospital records which showed that there was only one death between 2013 and 2015 (unpublished data). Lethal toxic encephalopathy or Ekiri syndrome (a severe form of encephalopathy resulting in rapid prog-ression to coma and death) is reported in children with shigellosis from abroad but not from India [7]. The present study aimed to describe the clinical charac-teristics of Shigella encephalopathy in children and to identify factors associated with mortality.

The study was conducted in the Pediatric Intensive Care Unit (PICU) of the Government Medical College, Kozhi-kode, a tertiary referral centre. Children between 1 month and 12 years of age admitted from 1 June, 2016 to 31 May, 2019 with a diagnosis of Shigella encephalopathy were included in the study. The data collection was done prospectively from January, 2018 to May, 2019 with retrospective data from June, 2016 to December, 2017. The study was approved by the institutional ethics committee.

Shigella encephalopathy was suspected based on the temporal association of diarrhea with altered sensorium, seizures or both in children. Stool microscopy and culture were done in all cases, apart from other investigations including complete blood count, blood culture, cerebrospinal fluid analysis and culture, blood sugar, serum electrolytes, renal and liver function tests. The diagnosis was confirmed if Shigella spp. was isolated from a stool sample or rectal swab, or if polymerase chain reaction (PCR) from a stool sample was positive. Children with a negative stool culture or PCR, history of seizures poorly controlled with anti-epileptics, and those whose sensorium improved after correction of shock were excluded from the study.

The clinical characteristics were recorded and the factors associated with mortality were studied. The following definitions were chosen: Delayed presentation: Presentation to the hospital 48 hours after the onset of symptoms; Undernutrition: weight for age or weight for height below –2 z-scores on the WHO child growth standards; Fluid refractory shock: persistent shock despite administration of 60 mL/kg of fluid in first hour or development of fluid overload features like hepato-megaly or lung crepitations; Multi organ dysfunction: dysfunction of 2 or more organ systems other than the CNS; Prolonged seizure: seizures lasting for more than 30 minutes without the child regaining consciousness in between; Prolonged altered sensorium: altered sensorium lasting more than 12 hours; Hyponatremia: serum sodium concentration less than 135 mmol/L; Hypocalcemia: serum ionized calcium less than 1.1 mmol/L; Lymphocyto-penia: Lymphocyte count below the normative value for the corresponding age.

All children were treated with ceftriaxone and other supportive measures, which included management of seizures and raised intracranial tension. Indications for mechanical ventilation included worsening respiratory failure, refractory shock and a score on the Glasgow coma scale of <8. Seizures were managed in accordance with the unit protocol which included a benzodiazepine, followed by fosphenytoin and levetiracetam or sodium valproate, depending on the response. Hypertonic saline (3%) was used as therapy for raised intracranial tension. Shock was managed as per standard protocol, including fluid boluses and inotropic support in fluid refractory shock. Appropriate intravenous fluids were used for rehydration and replacement of ongoing losses.

Statistical analysis: Qualitative variables were summarised as frequency and percentages and associa-tion of mortality with risk factors were tested using chi square test. A P value of <0.05 was considered to be statistically significant. Strength of association of risk factors with mortality was estimated in terms of relative risk (RR) and its 95% confidence interval (95% CI). A multivariate logistic regression was done to find out adjusted odds ratio of the variables. Those variables which were found to be significant on univariate analysis were selected for modeling using binary logistic regre-ssion to obtain an adjusted OR and its 95% CI. Statistical analysis was performed using SPSS V.16 (SPSS, Chicago, Illinois, USA).

Out of 158 probable cases, Shigella encephalopathy was confirmed in 60 children (Fig. 1). Among them, 2 children had epilepsy with poorly controlled seizures and were not included for the analysis. The final sample consisted of 58 children with confirmed shigella encephalopathy. The prospective and retrospective data included 40 and 18 children, respectively (27 girls, age range 38 days-12 years). Stool culture was positive for shigella in 23 (40%) children while the rest had stool PCR positive for Shigella spp.

Fig.1 Study flow chart.

Nearly half (48%) of the diarrheal episodes occurred during the months of May and June. All except 5 children (53; 91%) were admitted to the PICU within 48 hours, and 45 (78%) of them on the first day of illness itself. The initial symptom was fever in 54 (93%) children and seizures, loose stools, vomiting and abdominal pain in one child each. Seizures and altered sensorium were the predominant neurological symptoms. Altered sensorium or seizures preceded loose stools in 16 (28%) children, while the majority (42, 72%) developed features of encephalopathy after the onset of loose stools (Table I). S. sonnei was the commonest organism identified in stool culture (33%) followed by S.boydii (3%) and S. flexneri (2%). Blood culture was sterile in all cases.

We studied the clinical characteristics and mortality in 58 children with Shigella encephalopathy during a period of three years. More than a quarter of the children died, possibly due to the occurrence of lethal toxic encephalo-pathy. Lethal toxic encephalopathy or Ekiri syndrome, first reported from Japan is a rapidly progressing fulminant encephalopathy associated with shigellosis in children [7-8]. In the present sample, children who died had a similar progress of encephalopathy with death occurring within 48 hours of the onset of the disease in 47% of cases.

The cause of death in lethal toxic encephalopathy is not yet well understood, although severe cerebral edema has been described and it is suggested that prevention will help to improve the outcome [7,9]. Entry of inflammatory cytokines into the brain in susceptible children, might be the reason for severe encephalopathy [10]. Our findings are also suggestive of the role of cerebral oedema.

In a large series from Israel, a disproportionate number of cases had developmental delay and intellectual disability, suggesting a possible increased susceptibility [9], though, we could not confirm the association. Although hypocalcemia and hyponatremia have been reported in children who died due to encephalopathy, they were not significantly associated with mortality in our series [7,9].

S sonnei was the commonest serogroup isolated in our series, although S flexneri has been reported as the most common serogroup in India [11-13]. Recent studies have reported increasing incidence of S sonnei infections in this region [14]. A shift towards S sonnei has been observed in other countries as socioeconomic conditions improve [15]. A significant association of S sonnei with encephalopathy has been reported earlier, suggesting increased virulence and might partly explain the increased mortality [6].

Delayed presentation and prolonged altered senso-rium were found to be independently associated with mortality, suggesting that timely initiation of antibiotics shortens the duration of illness and results in bacterio-logical clearance, as reported in literature [16]. One limitation of the present study is that the exact cause of rapidly progressing encephalopathy leading to death could not be identified in all children since we could not carry out brain imaging studies in all children and autopsy could be done in one child only.

The increased mortality in shigella encephalopathy in the present sample underscores the need for further studies on the changing virulence of Shigella organisms, as well as host-specific risk factors and optimal treatment.

Ethics Clearance: Institutional ethics committee of the Government Medical College, Kozhikode; No. GMCKKD/RP2018/IEC/15, dated 11 January, 2018.

Contributors: MPJ: designed study, collected the data and wrote the initial draft of the paper; MGG, PK: helped in writing the manuscript and interpretation of the data; VKG: patient management and helped in collection of the data; BG: expert in statistics who did the statistical analysis; PP, GA, PMA: conducted microbiological analysis.

Funding: None; Competing interest: None stated.

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