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

• Type of Material: Article
• Authors: Aakash Shrivastava, National Centre for Disease Control; Anil Kumar, National Centre for Disease Control; Jerry D Thomas, Emory University; Kayla F. Laserson, Centers for Disease Control and Preventions; Gyan Bhushan, Sadar Hospital; Melissa D. Carter, Centers for Disease Control and Preventions; Mala Chhabra, National Centre for Disease Control; Veena Mittal, Centers for Disease Control and Preventions; Shashi Khare, National Centre for Disease Control; James J Sejvar, Centers for Disease Control and Preventions; Mayank Dwivedi, Centers for Disease Control and Preventions; Samantha L. Isenberg, Centers for Disease Control and Preventions; Rudolph Johnson, Centers for Disease Control and Preventions; James L. Pirkle, Centers for Disease Control and Preventions; Jon D. Sharer, Emory University; Patricia Hall, Emory University; Rajesh Yadav, Centers for Disease Control and Preventions; Anoop Velayudhan, Centers for Disease Control and Preventions; Mohan Papanna, Centers for Disease Control and Preventions; Pankaj Singh, India Epidemic Intelligence Service; D Somashekar, India Epidemic Intelligence Service; Arghya Pradhan, India Epidemic Intelligence Service; Kapil Goel, India Epidemic Intelligence Service; Rajesh Pandey, India Epidemic Intelligence Service; Mohan Kumar, India Epidemic Intelligence Service; Satish Kumar, India Epidemic Intelligence Service; Amit Chakrabarti, National Institute of Occupational Health; P. Sivaperumal, National Institute of Occupational Health; A. Ramesh Kumar, National Institute of Occupational Health; Joshua Schier, Emory University; Arthur Chang, Centers for Disease Control and Preventions; Leigh Ann Graham, Centers for Disease Control and Preventions; Thomas P. Mathews, Centers for Disease Control and Preventions; Darryl Johnson, Centers for Disease Control and Preventions; Liza Valentin, Centers for Disease Control and Preventions; Kathleen L. Caldwell, Centers for Disease Control and Preventions; Jeffery M. Jarrett, Centers for Disease Control and Preventions; Leslie A. Harden, Western Regional Research Center; Gary R. Takeoka, Western Regional Research Center; Suxiang Tong, Centers for Disease Control and Preventions; Krista Queen, Centers for Disease Control and Preventions; Clinton Paden, Centers for Disease Control and Preventions; Anne Whitney, Centers for Disease Control and Preventions; Dana L. Haberling, Centers for Disease Control and Preventions; Ram Singh, National Centre for Disease Control; Ravi Shankar Singh, National Centre for Disease Control; Kenneth C. Earhart, Centers for Disease Control and Preventions; A. C. Dhariwal, National Vector Borne Disease Control Programme; L. S. Chauhan, National Centre for Disease Control; S. Venkatesh, National Centre for Disease Control; Padmini Srikantiah, Centers for Disease Control and Preventions
• Language: English
• Date: 2017-01-30
• Publisher: Elsevier: Creative Commons
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/S2214-109X(17)30035-9
• Title of Journal or Parent Work: Lancet Global Health
• ISSN: 2214-109X
• Volume: 5
• Issue: 4
• Start Page: e458
• End Page: e466
• Grant/Funding Information: This study was supported by a CDC Research Project Cooperative Agreement Grant numbers GH-10-002 U2G GH000066-01-05.; US Centers for Disease Control and Preventions
• Keywords: neurology; pediatrics; encephalopathy; global health
• Research Categories: Health Sciences, Public Health

Abstract

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 μg/g to 152·0 μg/g and MCPG ranged from 44·9 μg/g to 220·0 μg/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.