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



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).



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.



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.



US Centers for Disease Control and Prevention.
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Aakash
A
Shrivastava
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Anil
A
Kumar
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Jerry D
JD
Thomas
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India; Center for Global Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Kayla F
KF
Laserson
Muzaffarpur District Health Department, Government of Bihar, Sadar Hospital, Muzaffarpur, Bihar, India.
Gyan
G
Bhushan
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Melissa D
MD
Carter
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Mala
M
Chhabra
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Veena
V
Mittal
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Shashi
S
Khare
National Center for Emerging and Zoonotic Infectious Diseases, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
James J
JJ
Sejvar
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India.
Mayank
M
Dwivedi
Battelle at the Centers for Disease Control and Prevention, Atlanta, GA, USA.
Samantha L
SL
Isenberg
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Rudolph
R
Johnson
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
James L
JL
Pirkle
Department of Human Genetics, Emory University, Decatur, GA, USA.
Jon D
JD
Sharer
Department of Human Genetics, Emory University, Decatur, GA, USA.
Patricia L
PL
Hall
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India; India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Rajesh
R
Yadav
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India; India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Anoop
A
Velayudhan
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India; India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Mohan
M
Papanna
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Pankaj
P
Singh
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
D
D
Somashekar
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Arghya
A
Pradhan
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Kapil
K
Goel
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Rajesh
R
Pandey
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Mohan
M
Kumar
India Epidemic Intelligence Service, National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Satish
S
Kumar
National Institute of Occupational Health, Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, Meghani Nagar, Ahmedabad, Gujarat, India.
Amit
A
Chakrabarti
National Institute of Occupational Health, Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, Meghani Nagar, Ahmedabad, Gujarat, India.
P
P
Sivaperumal
National Institute of Occupational Health, Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, Meghani Nagar, Ahmedabad, Gujarat, India.
A Ramesh
AR
Kumar
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Joshua G
JG
Schier
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Arthur
A
Chang
Battelle at the Centers for Disease Control and Prevention, Atlanta, GA, USA.
Leigh Ann
LA
Graham
Battelle at the Centers for Disease Control and Prevention, Atlanta, GA, USA.
Thomas P
TP
Mathews
Oak Ridge Institute for Science and Education Fellow at the Centers for Disease Control and Prevention, Atlanta, GA, USA.
Darryl
D
Johnson
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Liza
L
Valentin
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Kathleen L
KL
Caldwell
National Center for Environmental Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Jeffery M
JM
Jarrett
Western Regional Research Center, US Department of Agriculture, Albany, CA, USA.
Leslie A
LA
Harden
Western Regional Research Center, US Department of Agriculture, Albany, CA, USA.
Gary R
GR
Takeoka
National Center for Immunizations and Respiratory Diseases, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Suxiang
S
Tong
National Center for Immunizations and Respiratory Diseases, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Krista
K
Queen
National Center for Immunizations and Respiratory Diseases, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Clinton
C
Paden
National Center for Immunizations and Respiratory Diseases, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Anne
A
Whitney
National Center for Emerging and Zoonotic Infectious Diseases, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Dana L
DL
Haberling
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Ram
R
Singh
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
Ravi Shankar
RS
Singh
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India; Center for Global Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Kenneth C
KC
Earhart
National Vector Borne Disease Control Programme, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Nirman Bhavan, New Delhi, India.
A C
AC
Dhariwal
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
L S
LS
Chauhan
National Centre for Disease Control, India, Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India, Delhi, India.
S
S
Venkatesh
Global Disease Detection Program, India, US Centers for Disease Control and Prevention, Embassy of the United States, Shanti Path, Chanakyapuri, New Delhi, India; Center for Global Health, US Centers for Disease Control and Prevention, Atlanta, GA, USA. Electronic address: pks6@cdc.gov.
Padmini
P
Srikantiah
D000071072:Acute Febrile Encephalopathy / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology; D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D003521:Cyclopropanes / Q000032:analysis; D004196:Disease Outbreaks / Q000706:statistics & numerical data*; D005260:Female; D005638:Fruit / Q000633:toxicity*; D005998:Glycine / Q000031:analogs & derivatives / Q000032:analysis; D006801:Humans; D007005:Hypoglycins / Q000032:analysis; D007194:India; D032125:Litchi / Q000633:toxicity*; D008297:Male; D020258:Neurotoxicity Syndromes / Q000175:diagnosis* / Q000453:epidemiology / Q000209:etiology; D016017:Odds Ratio
D003521:Cyclopropanes; D007005:Hypoglycins; C041757:hypoglycin; C059830:methylenecyclopropylglycine; D005998:Glycine