Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study

Authors: SHRIVASTAVA, AAKASH - National Centre For Disease Control; KUMAR, ANIL - National Centre For Disease Control; THOMAS, JERRY - Centers For Disease Control And Prevention (CDC) - United States; BHUSHAN, GYAN - State Health Society, Bihar; ISENBERG, SAMANTHA - Centers For Disease Control And Prevention (CDC) - United States; CARTER, MELISSA - Centers For Disease Control And Prevention (CDC) - United States; CHHABRA, MALA - National Centre For Disease Control; MITTAL, VEENA - National Centre For Disease Control; KHARE, SHASHI - National Centre For Disease Control; SEJVAR, JAMES - Centers For Disease Control And Prevention (CDC) - United States; DWIVEDI, MAYANK - Centers For Disease Control And Prevention (CDC) - United States; JOHNSON, RUDOLF - Centers For Disease Control And Prevention (CDC) - United States; PIRKLE, JAMES - Centers For Disease Control And Prevention (CDC) - United States; YADAV, RAJESH - National Centre For Disease Control; VELAYUDHAN, ANOOP - National Centre For Disease Control; PAPPANNA, MOHAN - National Centre For Disease Control; SINGH, PANKAJ - National Centre For Disease Control; SOMASHEKAR, D - National Centre For Disease Control; PRADHAN, ARGHYA - National Centre For Disease Control; GOEL, KAPIL - National Centre For Disease Control; PANDEY, RAJESH - National Centre For Disease Control; KUMAR, MOHAN - National Centre For Disease Control; KUMAR, SINGH - National Centre For Disease Control; SHARER, DANIEL - Emory University; HALL, PATRICIA - Emory University; GRAHAM, LEIGH ANN - Centers For Disease Control And Prevention (CDC) - United States; MATTHEWS, THOMAS - Centers For Disease Control And Prevention (CDC) - United States; JOHNSON, DARRYL - Centers For Disease Control And Prevention (CDC) - United States; SCHIER, JOSHUA - Centers For Disease Control And Prevention (CDC) - United States; CHAKRABARTI, AMIT - National Institute Of Occupational Health; PERUMAL, SHIVA - National Institute Of Occupational Health; KUMAR, RAMESH - National Institute Of Occupational Health; VALENTIN, LIZ - Centers For Disease Control And Prevention (CDC) - United States; CALDWELL, KATHY - Centers For Disease Control And Prevention (CDC) - United States; JARRETT, JEFF - Centers For Disease Control And Prevention (CDC) - United States; Harden, Leslie - Les; Takeoka, Gary; TONG, SUXIANG - Centers For Disease Control And Prevention (CDC) - United States; SINGH, RAM - National Centre For Disease Control; SING, RAVI SHANKAR - National Centre For Disease Control; EARHART, KEN - Centers For Disease Control And Prevention (CDC) - United States; DHARIWAL, A.C. - National Vector Borne Disease Control Programme; CHAUHAN, L.S. - National Centre For Disease Control; LASERSON, KAYLA - Centers For Disease Control And Prevention (CDC) - United States; VENKATESH, S. - National Centre For Disease Control; SRIKANTIAH, PADMINI - National Centre For Disease Control

Submitted to: The Lancet Global Health
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/17/2016
Publication Date: 1/30/2017
Citation: Shrivastava, A., Kumar, A., Thomas, J., Bhushan, G., Isenberg, S.L., Carter, M., Chhabra, M., Mittal, V., Khare, S., Sejvar, J., Dwivedi, M., Johnson, R., Pirkle, J.L., Yadav, R., Velayudhan, A., Pappanna, M., Singh, P., Somashekar, D., Pradhan, A., Goel, K., Pandey, R., Kumar, M., Kumar, S., Sharer, D., Hall, P., Graham, L., Matthews, T.P., Johnson, D., Schier, J., Chakrabarti, A., Perumal, S., Kumar, R., Valentin, L., Caldwell, K., Jarrett, J., Harden, L.A., Takeoka, G.R., Tong, S., Singh, R., Sing, R., Earhart, K., Dhariwal, A., Chauhan, L., Laserson, K., Venkatesh, S., Srikantiah, P. 2017. Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study. The Lancet Global Health. 5(4):e458-e466. http://dx.doi.org/10.1016/S2214-109X(17)30035-9.
DOI: https://doi.org/10.1016/S2214-109X(17)30035-9

Interpretive Summary: Seasonal outbreaks of acute neurological illness with high mortality among young children occur annually in Bihar, the largest litchi growing region in India. The recurring outbreaks were thought to be caused by exposure to pesticides or heavy metals, infectious encephalitis, and/or litchi consumption. The Indian National Centre for Disease Control and the U.S. Centers for Disease Control and Prevention partnered to characterize the illness and determine the cause. They contacted ARS to develop a method to detect and quantify the main known toxin present in litchi seeds, methylenecyclopropylglycine (MCPG). They asked that ARS test for MCPG in the pericarp, arils and seeds of fruit of varying ripeness. USDA scientists discovered a second toxin in litchi, hypoglycin A. They also developed O-18 isotopic labeling method to quantify hypoglycin A in litchi. Both toxins were found in litchi arils independent of ripeness. As a result of this collaborative research effort, litchi consumption and associated hypoglycin A/MCPG toxicity was confirmed as the cause of these outbreaks. Recommendations have been made to minimize litchi consumption among young children, ensure children have an evening meal throughout the outbreak season and implement rapid glucose correction for children with suspected illness. Hundreds of children’s lives will be saved annual due to this collaborative research effort.

Technical Abstract: Background: Seasonal outbreaks of an acute neurologic illness with high mortality among young children occur annually in Muzaffarpur, Bihar, the largest litchi (lychee) fruit cultivation region in India. A wide range of infectious and non-infectious etiologies, including an association with litchi consumption, have been postulated for this illness, though none has been confirmed. In 2014, we investigated this outbreak to determine etiology and risk factors. Methods: We conducted hospital-based surveillance and a 1:2 age-matched case control study. A case was defined as a child <15 years of age from Muzaffarpur district admitted with new-onset seizures or altered sensorium in the last seven days. Clinical and environmental samples were tested for infectious and non-infectious etiologies, including the presence of hypoglycin A and/or methylenecyclopropylglycine (MCPG), naturally-occurring fruit-based toxins which cause hypoglycemia. Results: Among 390 cases identified 29 May-17 July, 2014, median age was four years; 121 (31%) died. On admission, 219 (61%) of 357 patients were afebrile (<99.5°F) and 204 (63%) of 327 had blood glucose =70 mg/dL; 257 (66%) experienced illness onset between 3am—8am. Cerebrospinal fluid revealed <5 WBC/mm3 in 52 (84%) of 62 patients. Exposures significantly associated with illness in matched bivariate analysis included consumption of litchis (matched odds ratio (mOR) 2.1, 95% confidence interval (CI) 1.2 – 3.5) and eating the last meal prior to 6pm (mOR 2.0, 95% CI 1.2 – 3.2) in the 24 hours prior to illness onset. Higher socioeconomic status (OR 0.4 (95% CI 0.2 – 0.9) and routinely washing vegetables and fruits (mOR 0.3, 95% CI 0.2 – 0.6) were protective. A stratified multivariable model revealed that the association of eating litchis with illness was strongly exacerbated in the absence of an evening meal (OR 9.8, 95% CI 0.6 – 159.6). Laboratory testing for infectious agents and pesticides were negative. Metabolites of hypoglycin A and/or MCPG were detected in 67% of 72 urine specimens from case-patients and none of 35 controls. Hypoglycin A and MCPG were also detected in seed and fruit (aril) of all 19 unripe and ripe litchis tested from Muzaffarpur. Conclusions: This is the first confirmation that this recurring outbreak of acute hypoglycemic encephalopathy is associated with hypoglycin A/MCPG toxicity and litchi consumption. In order to prevent illness and save lives in Muzaffarpur, we recommend minimizing litchi consumption among young children, ensuring children in the area receive an evening meal throughout the outbreak season, and implementing rapid glucose correction for children with suspected illness.