Acute encephalopathy syndrome (AES) is characterized by sudden onset of seizures and altered sensorium of infectious or non-infectious origin. Seasonal outbreaks of fatal hypoglycaemic AES in children, associated with eating fruit from the Sapindaceae family (e.g., ackee, litchi), have been reported globally [1,2]. Since 1995, AES outbreaks have been reported during the litchi-harvesting season from May–July in Muzaffarpur, the largest commercial litchi-producing district of Bihar, India [3]. An AES outbreak investigation in Muzaffarpur in 2014 linked known toxins hypoglycin A and α-methylene cyclopropyl glycine (MCPG) in litchi fruit to hypoglycaemic AES in children [3]. Following the 2014 outbreak, the Government of Bihar implemented community-based interventions to prevent hypoglycemia in children. They also strengthened the clinical management of hypoglycaemic seizures in public health facilities [4]. The number of AES cases and deaths declined from 2015–18, suggesting that the interventions were effective. However, in May–June 2019, AES cases increased. We conducted a descriptive epidemiological analysis of the AES cases. | | Methods | | We identified AES cases from established hospital-based surveillance in the two tertiary referral hospitals in Muzaffarpur. We defined a suspected AES case as seizures or altered sensorium in a child aged ≤15 years admitted from 1 May to 2nd July 2019. We excluded patients aged six months to 6 years who were admitted for fever and a single generalized convulsion of <15 minutes in duration and recovered consciousness within 60 minutes of seizure. We conducted a review of medical records and abstracted data using a structured tool for socio-demographics, clinical history, duration of hospitalization, treatment, and laboratory profile. We also assembled a prospective cohort of probable cases admitted to the hospital during the investigation. We defined a probable AES case as new-onset seizures or altered sensorium of <7 days duration in a child aged ≤15 years admitted t from 1 May to 2 July 2019. For the cohort of probable cases, we interviewed the caregivers using a structured clinical-epidemiological questionnaire for socio-demographics, anthropometry, illness characteristics, treatment-seeking behavior, meal assessment, exposure to litchi fruit, and exposure to health messages. For anthropometry, we calculated Z-scores using the World Health Organization 2006 standardized growth tables [5]. | | Results | | Of the 655 suspected and probable AES cases identified, the case fatality rate (CFR) was 21% (139 deaths). The median age was four years (interquartile range: 3 months–14 years), and 58% (378) were females. The first case was reported on 5 May 2019, cases peaked on 15 June, and the last case on 2 July (Figure 1). Among cases with available data, 75% (389/518) had blood glucose levels of <70 mg/dL upon hospital admission, and 75% (476/638) were residents of Muzaffarpur district. We identified cases from 15 (94%) of 16 blocks in the Muzaffarpur district and calculated a district incidence of 22 per 100,000 children ≤15 years old. | | The prospective cohort comprised 94 probable AES cases; CFR was 26%. Among probable cases, 63% (49/78) of caregivers were wage workers, and 34% (31/91) were of low socioeconomic status. Symptoms were reported in the early morning (3 am to 8 am) for 67% (62/93) of cases, and 97% (90/93) presented with seizures. Among probable cases with anthropometry data, 62% (43/69) were underweight (i.e., weight-for-age Z score <-2), 44% (25/57) stunted (i.e., height-for-age Z score <-2), and 43% (10/23) wasted (i.e., weight-for-height Z score <-2). Primary health facilities referred 46% (43/93) of probable cases to the two tertiary hospitals for admission. Among cases referred, only 30% (13/43) received hypoglycemia and seizure management at the primary health facility. | | Eating litchis in the 24 hours and seven days before illness onset was reported by 57% (54/94) and 87% (59/68) of caregivers, respectively. Skipping any meal and skipping the evening meal in the 24 hours before illness onset was reported by 55% (48/88) and 44% (28/63) of caregivers, respectively. Among probable cases, 45% (27/60) of caregivers reported Government Supplementary Nutrition (GSN) programme enrollment. Sixty percent (50/83) of caregivers said a visit by health workers in the week before illness. Still, only 8% (7/83) reported receiving messages on AES prevention and early treatment by health workers in the past month. | | Conclusions | | The 2019 AES outbreak in Muzaffarpur district, Bihar, occurred among young children with hypoglycemia upon hospital admission and had high associated mortality. Although the Government of Bihar implemented community and clinical measures to prevent AES cases after the 2014 outbreak, a large proportion of the AES cases did not benefit from the prevention measures based on our investigation [4]. New state and district health leadership, turnover of community and facility-level healthcare workers, lack of ongoing training and focused community outreach, and competing health priorities might have been factors responsible for the resurgence. To prevent future AES cases, we recommended prompt emergency management of hypoglycemia and seizures at primary health facilities before referral. We recommend enrollment of all eligible children to GSN and enhanced community health communications to reinforce the importance of an evening meal for children and limiting the eating of litchi fruit during the harvesting season from May to July

We initiated an epidemiological investigation following the death of a previously healthy 17 year-old boy with neuro-melioidosis. A case was defined as a culture-confirmed melioidosis patient from Udupi district admitted to hospital A from January 2013-July 2018. For the case control study, we enrolled a subset of cases admitted to hospital A from January 2017- July 2018. A control was resident of Udupi district admitted to hospital A in July 2018 with a non-infectious condition. Using a matched case-control design, we compared each case to 3 controls using age and sex groups. We assessed for risk factors related to water storage, activities of daily living, injuries and environmental exposures (three months prior to hospitalization), using conditional regression analysis. We identified 50 cases with case fatality rate 16%. Uncontrolled diabetes mellitus was present in 84% cases and 66% of cases occurred between May and October (rainy season). Percutaneous inoculation through exposure to stagnant water and injury leading to breakage in the skin were identified as an important mode of transmission. We used these findings to develop a surveillance case definition and initiated training of the district laboratory for melioidosis diagnosis.

BACKGROUND: Muzaffarpur district in Bihar State of India recorded a resurgence of acute encephalopathy syndrome (AES) cases in the summer of 2019 after no reported outbreak in 3 y. Earlier studies generated evidence that litchi consumption and missing the previous evening's meal were associated with AES. We investigated the recent outbreak to understand the risk factors associated with AES. METHODS: We conducted a matched case-control study by comparing AES cases with healthy controls from case-households and the neighborhood community for risk factors like missing evening meal and litchi consumption before onset of AES. RESULTS: We recruited 61 cases and 239 controls. Compared with the community controls, case-patients were five times more likely to have reported eating litchi in the 7 d preceding the onset of illness (adjusted OR [AOR]=5.1; 95% CI 1.3 to 19) and skipping the previous evening's meal (AOR=5.2; 95% CI 1.4 to 20). Compared with household controls, case-patients were five times more likely to be children aged <5 y (AOR=5.3; 95% CI 1.3 to 22) and seven times more likely to have skipped the previous evening's meal (AOR=7.4; 95% CI 1.7 to 34). CONCLUSIONS: Skipping the previous evening's meal and litchi consumption were significantly associated with AES among children in Muzaffarpur and adjoining districts of Bihar.

BACKGROUND: Outbreaks of unexplained illness frequently remain under-investigated. In India, outbreaks of an acute neurological illness with high mortality among children occur annually in Muzaffarpur, the country's largest litchi cultivation region. In 2014, we aimed to investigate the cause and risk factors for this illness. METHODS: In this hospital-based surveillance and nested age-matched case-control study, we did laboratory investigations to assess potential infectious and non-infectious causes of this acute neurological illness. Cases were children aged 15 years or younger who were admitted to two hospitals in Muzaffarpur with new-onset seizures or altered sensorium. Age-matched controls were residents of Muzaffarpur who were admitted to the same two hospitals for a non-neurologic illness within seven days of the date of admission of the case. Clinical specimens (blood, cerebrospinal fluid, and urine) and environmental specimens (litchis) were tested for evidence of infectious pathogens, pesticides, toxic metals, and other non-infectious causes, including presence of hypoglycin A or methylenecyclopropylglycine (MCPG), naturally-occurring fruit-based toxins that cause hypoglycaemia and metabolic derangement. Matched and unmatched (controlling for age) bivariate analyses were done and risk factors for illness were expressed as matched odds ratios and odds ratios (unmatched analyses). FINDINGS: Between May 26, and July 17, 2014, 390 patients meeting the case definition were admitted to the two referral hospitals in Muzaffarpur, of whom 122 (31%) died. On admission, 204 (62%) of 327 had blood glucose concentration of 70 mg/dL or less. 104 cases were compared with 104 age-matched hospital controls. Litchi consumption (matched odds ratio [mOR] 9.6 [95% CI 3.6 - 24]) and absence of an evening meal (2.2 [1.2-4.3]) in the 24 h preceding illness onset were associated with illness. The absence of an evening meal significantly modified the effect of eating litchis on illness (odds ratio [OR] 7.8 [95% CI 3.3-18.8], without evening meal; OR 3.6 [1.1-11.1] with an evening meal). Tests for infectious agents and pesticides were negative. Metabolites of hypoglycin A, MCPG, or both were detected in 48 [66%] of 73 urine specimens from case-patients and none from 15 controls; 72 (90%) of 80 case-patient specimens had abnormal plasma acylcarnitine profiles, consistent with severe disruption of fatty acid metabolism. In 36 litchi arils tested from Muzaffarpur, hypoglycin A concentrations ranged from 12.4 mug/g to 152.0 mug/g and MCPG ranged from 44.9 mug/g to 220.0 mug/g. INTERPRETATION: Our investigation suggests an outbreak of acute encephalopathy in Muzaffarpur associated with both hypoglycin A and MCPG toxicity. To prevent illness and reduce mortality in the region, we recommended minimising litchi consumption, ensuring receipt of an evening meal and implementing rapid glucose correction for suspected illness. A comprehensive investigative approach in Muzaffarpur led to timely public health recommendations, underscoring the importance of using systematic methods in other unexplained illness outbreaks. FUNDING: US Centers for Disease Control and Prevention.