Lychee-associated acute hypoglycaemic encephalopathy outbreaks in Muzaffarpur, India – Author's reply
Authors: Akshay C Dhariwal, Srinivas Venkatesh, Lakhbir Singh Chauhan, Anil Kumar, Aakash Shrivastava, Gyan Bhushan, Amit Chakrabarti, Ram Singh, Ravi Shankar Singh, Jerry D Thomas, Kayla F Laserson, Padmini Srikantiah
Journal: The Lancet Global Health (2017)

As we acknowledged in our study,1Shrivastava A Kumar A Thomas JD et al.Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar research from T Jacob John and Mukul Das, and others2John TJ Das M Acute encephalitis syndrome in children in Muzaffarpur: hypothesis of toxic origin.Curr Sci. 2014; 106: 1184-1185Google Scholar, 3Shah A John TJ Recurrent outbreaks of hypoglycaemic encephalopathy in Muzaffarpur, Bihar.Curr Sci. 2014; 107: 570-571Google Scholar, 4Das M Asthana S Singh SP Dixit S Tripathi A John TJ Litchi fruit contains methylene cyclopropyl-glycine.Curr Sci. 2015; 109: 2195-2197Crossref Google Scholar have contributed essential points to the discussion of the acute toxic encephalopathy outbreaks in Muzaffarpur. At the outset, we would like to underscore the importance of empirical data to support public health recommendations. Systematic investigations, executed with methodological rigour, using representative data are essential to move from the realm of hypotheses to that of evidence-based conclusions and recommendations. This is particularly important when the cause of a recurring outbreak of unexplained illnesses is investigated, especially when the illness is due to toxicity associated with consumption of lychee (also spelled litchi)—a fruit that is an important source of agricultural income for the affected region. Additionally, our investigations systematically ruled out other hypotheses regarding this illness,1Shrivastava A Kumar A Thomas JD et al.Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar including the long-claimed possibilities of viral or pesticidal causes.5Biswas SK International Centre for Diarrhoeal Diseases ResearchOutbreak of illness and deaths among children living near lychee orchards in northern Bangladesh.Bangladesh ICDDRB Health Sci Bull. 2012; 10: 15-22Google Scholar, 6Samuel PP Muniaraj M Thenmozhi V Tyagi BK Entomo-virological study of a suspected Japanese encephalitis outbreak in Muzaffarpur district, Bihar, India.Indian J Med Res. 2013; 137: 991-992PubMed Google Scholar In the investigation of an unexplained illness, as in the case of Muzaffarpur, the exclusion of other possible causes should not be overlooked. The National Centre for Disease Control (NCDC) is the Indian Government's national public health service agency with a mandate to support state governments in outbreak investigations and management. As a federal agency, the NCDC initiates an investigation only after official consensus with state health authorities. In Muzaffarpur, we did our investigations with the approval of the state and district health authorities, and the participation of key paediatricians—to whom we are extremely grateful, and who have been acknowledged and thanked by name7Shrivastava A Srikantiah P Kumar A et al.Outbreaks of unexplained neurologic illness—Muzaffarpur, India, 2013–2014.MMWR Morb Mortal Wkly Rep. 2015; 64: 49-53PubMed Google Scholar and as a group.1Shrivastava A Kumar A Thomas JD et al.Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study.Lancet Glob Health. 2017; 5: e458-e466Summary Full Text Full Text PDF PubMed Scopus (61) Google Scholar We take this opportunity to again express our sincere appreciation to Dr Braj Mohan, Dr Arvind Kumar, Dr GS Sahni, Dr Rajiva Kumar, and the other dedicated clinicians in Muzaffarpur for their collaboration and support. Data from our 2013 investigation indicated that hypoglycaemia among affected children was associated with increased mortality.7Shrivastava A Srikantiah P Kumar A et al.Outbreaks of unexplained neurologic illness—Muzaffarpur, India, 2013–2014.MMWR Morb Mortal Wkly Rep. 2015; 64: 49-53PubMed Google Scholar, 8National Centre for Disease Control Investigation Team. Prospective hospital-based surveillance of acute neurologic syndrome cases in Muzaffarpur, Bihar, 2013. First India Epidemic Intelligence Service Conference; Delhi, India; Nov 20, 2013.Google Scholar Because of this, in 2013 and 20148National Centre for Disease Control Investigation Team. Prospective hospital-based surveillance of acute neurologic syndrome cases in Muzaffarpur, Bihar, 2013. First India Epidemic Intelligence Service Conference; Delhi, India; Nov 20, 2013.Google Scholar, 9Department of Health, Government of Bihar. Minutes of AES task force meeting for early preparedness for early AES control and management in Bihar, 2014; Patna, India; March 13, 2014.Google Scholar, 10Directorate General of Health Services, Ministry of Health and Family Welfare Government of India. D.O.1-4/2012/EPID/NCDC. New Delhi, India; April 9, 2014.Google Scholar the Director General of Health Services, Government of India, and the NCDC provided recommendations to the Government of Bihar on rapid screening for, and correction of, hypoglycaemia among affected children as a necessary intervention to reduce mortality. To our knowledge, when we initiated our investigation in 2013 and at the time of our field investigation in 2014, no focused remedial public health measures were in place in Muzaffarpur regarding parents and carers limiting children's lychee consumption and ensuring children eat an evening meal.11Department of Health Government of Bihar. Standard operating procedure for treatment of AES cases in Bihar. Patna, India; 2014.Google Scholar In the absence of any epidemiological data on lychee consumption and the lack of any human biological evidence to support hypoglycin A or methylene cyclopropyl glycine (MCPG) toxicity, recommendations to limit lychee consumption would have been premature at that time. In February, 2015, the laboratory results from our 2014 investigation indicated metabolites of hypoglycin A and MCPG were present in the urine of ill children, and both hypoglycin A and MCPG in the aril of lychees collected from Muzaffarpur. This, in addition to our epidemiological data, which showed a significant association between lychee consumption and illness, as well as the laboratory evidence of metabolic disruption due to hypoglycin A and MCPG toxicity in cases but not controls, provided the conclusive data to confirm the lychee–hypoglycin A–MCPG hypothesis. During prospective surveillance, we used a highly sensitive case definition to ensure that all potential cases were captured. This is not unusual in investigations of unexplained, severe illnesses, and also helped to ensure patients received appropriate and prompt clinical management.12Coggon D Martyn C Palmer KT Evanoff B Assessing case definitions in the absence of a diagnostic gold standard.Int J Epidemiol. 2005; 34: 949-952Crossref PubMed Scopus (69) Google Scholar If there had been misclassification between cases and controls, as Das and John suggest, the significant associations identified between lychee consumption, absence of evening meal, and illness would have, at worst, been biased toward the null. Both case-patients and controls were residents of villages in the Muzaffarpur district—ie, the same community. Controls were identified among children who were admitted to the same hospitals where case-patients were admitted. The presence of lychee orchards and agricultural fields, and the availability of lychees were ubiquitous in the Muzaffarpur villages where both case-patients and controls lived. It was with these data, and after a multisectoral meeting of stakeholders from district-level, state-level, and national-level agencies in February, 2015, that the Director General of Health Services, Government of India, issued official recommendations to the Government of Bihar to encourage parents and carers in the affected Muzaffarpur area to minimise children's lychee consumption and ensure they eat an evening meal, and to re-emphasise the need for clinicians to rapidly test for, and correct, hypoglycaemia among children with suspected illness.13Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. D.O. A.1-4/2012/EPID/NCDC, 2015. New Delhi, India; March 4, 2015.Google Scholar After this, the NCDC and, more broadly, the Ministry of Health and Family Welfare, and the Ministry of Women and Child Development have continued to support the Government of Bihar's response to the Muzaffarpur outbreaks in 2015 and 2016,14Ministry of Health and Family Welfare Government of India. D.O.NHSRC 11-12/CP/08/MOHFW/622: Involvement of ASHAs for prevention and control of acute encephalopathy syndrome to minimize morbidity and mortality in Muzaffarpur district. New Delhi, India; Oct 1, 2015.Google Scholar, 15Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. D.O. A. 1-4/2016/EPID/NCDC. 2016. New Delhi, India; Feb 10, 2016.Google Scholar, 16Ministry of Women and Child Development. F. No. 19-23/2013-CD-I (PART): support from ICDS for tackling acute encephalopathy syndrome in children in Muzaffarpur and Malda districts. 2015. New Delhi, India; May 14, 2015.Google Scholar and have advocated for effective clinical and public health management, preparation of health and nutrition messages and communication materials for local health workers, organisation of specialised training for clinicians, and the provision of surveillance support. This sustained advocacy effort from multiple agencies led to the Government of Bihar officially incorporating these recommendations into their revised operation guidelines for acute encephalitis management, in which special attention was paid to lychee-growing districts.17Department of Health Government of Bihar. Revised standard operating procedures for treatment of AES cases in Bihar. Patna, India; 2016.Google Scholar Critical public health planning and preventive activities are required to effectively address disease outbreaks, whether it is in Muzaffarpur or elsewhere in India. It will take the concerted efforts of many scientists and public health officials working respectfully together to successfully achieve these goals. The NCDC remains committed to the provision of public health support to state governments. We declare no competing interests. The findings and conclusions in this letter are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. LSC retired in September 2014. Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control studyOur 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. Full-Text PDF Open AccessLychee-associated acute hypoglycaemic encephalopathy outbreaks in Muzaffarpur, IndiaThe article by Aakash Shrivastava and colleagues in The Lancet Global Health (April, 2017)1 is timely, and presents an important finding: validation of lychee-associated hypoglycaemic encephalopathy. First described in India,2–4 the disease is caused by lychee (also spelled litchi) consumption after a prolonged fast by undernourished children due to the presence of a hypoglycaemic agent, methylene cyclopropyl glycine (MCPG). The President of the Indian Academy of Pediatrics expressed scepticism when cases of encephalopathy were first linked with lychee consumption in 2014. Full-Text PDF Open Access