Three years ago, Dr Rajesh Yadav, an investigator with the India Epidemic Intelligence Service, moved to the city of Muzaffarpur, the site of one of the country’s most mysterious outbreaks — and he waited.
Every year in mid-May, as temperatures reached scorching heights, parents took children who had been healthy the night before to the hospital.
The children awakened with a high-pitch cry in the early morning, many parents said.
Then the children began having seizures and slipping into comas. In about 40 percent of cases, they died.
Every year in July, with the arrival of monsoon rains, the outbreak ended as suddenly as it began.
Beginning in 1995, investigations variously ascribed the phenomenon to heat stroke; to infections carried by rats, bats or sand flies; or to pesticides used in the region’s ubiquitous lychee orchards. However, there were few signposts for investigators.
The illness typically struck only one child in a village, often leaving even siblings unaffected.
A joint investigation by India’s National Center for Disease Control and the India office of the US’ Centers for Disease Control, published in the British medical journal Lancet Global Health on Tuesday, has identified a surprising culprit: the lychee fruit itself, when eaten on an empty stomach by malnourished children.
In 2015, as a result of the investigation, health officials began urging parents in the area to be sure to feed young children an evening meal and to limit their consumption of lychees. In two seasons, the number of reported cases per year dropped to less than 50 from hundreds.
For 20 years, clinicians were unable to determine if the disease, which led to acute brain swelling known as encephalopathy, was caused by an infection.
Investigators pored over records from the previous year’s outbreak and were struck by the fact that many of the sick children did not have a fever. Analysis of spinal fluid samples overwhelmingly showed that the affected children did not have elevated counts of white blood cells, a sign the body is fighting infection.
Having collected biological samples from more than 300 children, the researchers were able to scan a large number of markers — including some they had not suspected.
Glucose had never been a particular concern for investigators.
However, some of the affected children had strikingly low levels and those with low blood glucose were twice as likely to die.
It was in the fall of 2013, during a conference call with colleagues in the US, that someone mentioned “Jamaican vomiting sickness,” an outbreak in the West Indies that for many decades caused brain swelling, convulsions and altered mental states in children.
The outbreak turned out to be tied to hypoglycin, a toxin found in the ackee fruit — commonly found in Jamaica — that inhibits the body’s ability to synthesize glucose, leading to acute hypoglycemia, or low blood glucose levels.
By late 2014, laboratory tests confirmed that lychees also contain high levels of hypoglycin, as well as a similar toxin known as methylenecyclopropyl glycine.
The Muzaffarpur area, in India’s east, produces about 70 percent of India’s lychee harvest.
Although orchards were typically guarded by caretakers, children often ate lychees that were unripe or that had fallen to the ground. However, because everyone in the region eats them, it was difficult for many to believe that, in isolated cases, it could set off a catastrophic illness.
By early 2015, centers laboratories had developed a test to measure hypoglycin in urine. They found extraordinary abnormalities in the affected children.
The investigators asked participants if they would be comfortable issuing recommendations based on their findings: That young children in the affected areas be encouraged to always eat an evening meal and that consumption of lychees should be limited.
Everyone agreed, and it was done.
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