Litchi: Controversy erupts over Muzaffarpur mystery disease study

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The Lancet Global Health paper published on January 30, 2017.

The scientist who investigated the mystery disease that proved fatal for many 15-year old children in Muzaffarpur, Bihar at the instance of the State government has raised ethics issues about the way the research has been published by the journal Lancet Global Health on January 30.

“Not giving due credit for work done by others is not acceptable in science,” Dr. T. Jacob John, a virologist who was earlier attached to the Christian Medical College, (CMC) Vellore says.

“They quote our study but don’t honestly say what we have found. If they did that then they can’t claim originality. They have done a large case-control study but borrowed all important information connected with the illness from us,” he argues.

Dr. John published in Current Science in May 2014 evidence of a link between a fruit in Jamaica, the ackee, from the same family as litchi, and a disease called acute encephalopathy in Jamaicans. He showed the close clinical similarity between ackee poisioning and the Muzaffarpur illness, where litchi consumption and skipping the evening meal could result in very low blood glucose and acute encephalopathy, leading to seizures and coma, and death in many cases.

Lancet author refutes claim

The Lancet authors, however, refute this. “We have acknowledged and cited all three of Dr. John and his colleagues’ papers in Current Science,” Dr. Padmini Srikantiah at CDC Atlanta and the corresponding author said in an email. “There are a few key findings in our study that have not been, to our knowledge, reported previously. First: the evidence of the metabolites of hypoglycin A and methylenecyclopropylglycine (MCPG) in the specimens of affected children, and the demonstrated metabolic abnormalities that resulted due to the effects of these toxins. And, second, a statistically significant epidemiological association between illness and litchi consumption, as well as the modifying effect of the absence of an evening meal.”

Dr. John’s pioneering work 

Dr. John’s team had in the May 2014 paper pointed out that the illness was due to non-infectious encephalopathy and not viral encephalitis as was widely suspected. The absence of inflammatory cell response in cerebrospinal fluid, hypoglycaemia and inconsistent presence of fever were the basis on which he called it as encephalopathy. That it was a form of encephalopathy associated with low blood sugar was again emphasised in an August 2014 paper in Current Science.

litchi1“While in 2013 people from Delhi’s National Centre for Disease Control, India (NCDC) were still searching for more viruses [as the cause], I went to the villages and talked to parents, neighbours and doctors and came up with the hypothesis that it is a biochemical disease and not an infectious disease,” he says.

The May 2014 paper points out a link between the disease and litchi harvest season, the sudden presentation with serious illness, the symptoms of the disease and under nourishment in the affected children.

MCPG and disease link

Besides describing the origin of the disease, the paper mentions MCPG present in litchi, which is similar in action to hypoglycin A found in ackee. “Our hypothesis is that the Muzaffarpur illness is caused by MCPG in litchi,” says the paper. It also mentions about MCPG causing derangement of fatty acid metabolism.

A December 2015 Current Science paper reported presence of MCPG in litchi (both unripe and ripe fruits) based on chemical analysis. It is true that Dr. John did not report MCPG or hypoglycin A in samples of children but the study strongly suggested the role of MCPG.

A May 2016 paper in  Indian Pediatrics again emphasis the link between MCPG toxin found in litchi and the disease and its effect in animals. It says: “Since the part of the fruit consumed by humans contains MCPG, and experimentally it has been shown to cause hypoglycemia in starved animals, the biological plausibility of causality by MCPG is thus confirmed.”

While Dr. John had first raised the suscipion of hypoglycin A in ackee and its similarity to Muzaffarpur disease even in the 2014 paper and followed up on that in the 2015 and 2016 papers, Dr. Srikantiah told me that her team was alerted about the link and its effect on rats by her colleagues at CDC Atlanta.  Dr. Srikantiah’s team makes only a passing mention of Dr. John’s work on the association of litchi and the disease in the Lancet Global Health paper, and clubs its along with other suspected causes such as exposure to pesticides and infectious encephalitis.

Contrary to Dr. Srikantiah’s claim that the modifying effect of the absenc of evening meal in disease causation was their team’s contribution, Dr. John had pointed this out earlier. “Our finding provides the much needed evidence for biological plausibility that litchi consumption by undernourished children, especially after prolonged fasting, triggers the hypoglycaemic encephalopathy early in the morning (4-8 am),” the December 2015 paper says.

The August 2014 paper says: “The hypoglycaemia points to an inhibited gluconeogenesis.” It mentions how well-nourished children are not affected due to glycogen reserve in the body and presumably because a specific metabolic pathway for glucose generation (gluconeogenesis) is not triggered.

Disease prevention and recommendations

During a June 2014 outbreak, Dr. John and another doctor tested blood sugar level immediately after hospitalisation and infused 10% dextrose within four hours of illness onset. This helped save 74% children; six children who died did not receive dextrose infusion on time.

“In view of our observations and conclusions, the Government of Bihar has already introduced some interventions” such as asking parents to restrict litchi consumption by children, making sure no child goes to bed without eating a meal, measuring blood glucose level and infusing 10% dextrose immediately on admission.

Published in The Hindu on February 3, 2017

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