Strange Fruit: Toxins in lychees suspected of being deadly for children

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Something happened to a three year old girl from the Eastern Indian state of Bihar while she was sleeping. The night before, Khushi had gone to sleep exhausted after a long, taxing day playing in the courtyard of her village, Raja Pakkar, and among the vast groves of lychee trees that dominated the region’s fields. There was nothing out of the ordinary, nothing that gave cause to suspect she’d be fighting for her life only hours later.

Khushi woke up in the morning feeling unwell. She shook uncontrollably. Her mental state deteriorated quickly and her body seemed destined to follow the downward trajectory. Her father scrambled to find enough money to find transportation that would take her to the hospital. It took hours and by the time the family set out on the long trip, it was already almost noon.

By the time the three year-old arrived at the Shree Krishna Medical College and Hospital (SKMCH) in Muzaffarpur, her condition was critical. Yet, her case was far from an isolated incident. The hospital overflowed with children suffering from a similar illness, taxing the institution’s modest resources. Kids lay three to a bed and on the floor and on tables. Something was killing Bihar’s children.

Kuchi died from her condition. She wasn’t alone there either.

As the situation spiralled out of control, politicians faced increased pressure to act. When politicians like Bihar State’s Chief Minister Nitish Kumar arrived at the hospital they faced protests outside of the hospital. He had gone to “take stock of the situation” following the death of over 100 children due to suspected Acute Encephalitis Syndrome (AES). Relatives of the children and fearful villagers shouted “Nitish Kumar wapas jao” (Nitish Kumar go back) while waving black flags. If it hadn’t been for the wall of police protecting him, there’s no telling where the situation would have gone. The morning of his arrival, the Health Department announced that seven more children had died, increasing the tally to 107 fatalities.

The hospital overflowed with children suffering from a similar illness, taxing the institution’s modest resources. Kids lay three to a bed and on the floor and on tables. Something was killing Bihar’s children.

Tone-deaf, as career politicians tend to be, Kumar announced an ex-gratia of ₹4 lakh to the families of those who died. As if the paltry sum, stood as a measurement for the families’ incalculable loss.

Parents of children who had succumbed to the illness struggled to contain their rage. Meanwhile, doubt and fear plagued those whose sons and daughters remained healthy, unsure whether their family would be next. Public health officials initiated Japanese Encephalitis vaccination drives, even though it ran against the steady trail of evidence that had accrued over the years. And politicians did what they did best. They visited the hospitals and made believe feigned concern and usefulness. The social fabric in the Bihar beginning to show signs of tearing. Many suspected that they knew the cause.

It started with a lychee tree.

***

Proliferation of lychee consumption outside of East Asia has been steadily rising since the 1990s. A quick search for lychee recipes on the Food Network site yields nearly 90 recipes (including drinks) while a similar search on Yummly provides almost 400 recipes. Clearly, the fruit has permeated Western kitchens and cupboards.

With Foodie culture hitting the mainstream, home cooks are more adventurous and increasingly turn their noses to canned goods. Fresh, fresh, fresh is the buzzword. It’s just as well since global supply lines have made it possible to have exotic products once available only in canned or frozen form. The lychee exemplifies this perfectly. And that opens up an opportunity for unripened lychees to sneak into the kitchen. Inquisitive kids may fall for the same thing.

Once the purview of East Asian countries, lychee production has become a global endeavor. Farmers from the Indian subcontinent, South Africa, Brazil, the Caribbean, Australia, Israel, and the United States now grow the fruit. China remains the top producer, followed closely by Taiwan.

Letchi-Réunion-1
Unripe lychees.

This has happened despite the potential dangers that accompanies lychee over-consumption and despite documented cases of illness associated with the fruit.

Since 1995, outbreaks of an unexplained acute encephalopathy (swelling of the brain) has stricken young children in Muzaffarpur. The outbreaks are associated with high rates of fatalities and tend to peak in June. Monsoon rains are normally accompanied by a drop in case incidence. Possible explanations for the outbreaks included heat stroke, pesticide residues, viral encephalitis, and heavy metal contamination.

Because of Muzaffarpur’s extensive lychee fruit producing industry that was expanding in the region, some health experts postulated that the fruit played a role in the outbreaks. The illness afflicted children younger than fifteen years old exclusively. Nearly every case featured the acute onset of seizures and/or altered mental status. The mysterious outbreaks became an annual occurrence.

“There has been an increase in reports of outbreak of encephalopathy in children from the eastern part of India, where it is characterized by a syndrome of sudden onset of fever of high grade and associated with altered sensorium. The reporting of such incidences increases in and around the peak of Indian summer months confined to the geographical regions that flourish in litchi plantation for the past couple of decades.”

In 2013 and 2014, the National Centre for Disease Control (NCDC) in India and the U.S. Center for Disease Control (CDC) collaborated to investigate the possible causes of the neurological illness. They focused on the two main referral hospitals in Muzaffarpur.

The 2013 investigation involved 133 patients, 71% of whom were between 1-5 years of age. The fatality rate during the outbreak was 44%. The investigators set out to test for signs of the various pathologies proposed during previous years. Cerebrospinal fluid was examined for 56 patients. 31 children (55%) had normal white blood cell counts indicating that viral encephalitis could be reasonably ruled out. 48 of 59 (81%) had normal CSF proteins. 75% of the patients had normal CSF glucose levels. However, the investigators noted that at the time of admission, 21% of the children suffered from hypoglycemia.

Even though a significant portion of the children had normal WBC counts, the investigators conducted more tests for infectious pathogens known to cause encephalitis in the region. Multiple tests for Japanese encephalitis virus were done. All were negative. Tests were also performed for flaviviruses, especially for West Nile virus. Again, the results were negative.

Having ruled out infection, the investigators returned to the children suffering from hypoglycemia at the time of admission. An analysis of risk factors for death was a revelation. It indicated that among those who died, low blood glucose levels were the common denominator.

According to a paper published in the CDC’s Morbidity and Mortality Weekly Report,

“A case-control study enrolled 101 case-patients and 202 age-matched controls, 101 from the hospital and 101 from the community. Ill children had spent a greater amount of time in agricultural fields or orchards than controls.”

As a result, the investigation suggested to public health experts that the illness plaguing the children of Muzaffarpur was most likely a noninflammatory encephalopathy than an infectious encephalitis, raising the concern that the patients suffered from a toxin-mediated illness.

It wasn’t until the 2014 outbreak that investigators began to narrow down and speculate on a possible cause. After establishing that the outbreak followed similar patterns as the previous year’s, members of the NCDC and CDC stressed that the ultimate cause had yet to be established. However, the investigators made a cautious attempt at determining the origin of the encephalopathy.

“The consistent finding of hypoglycemia among affected children underscores the importance of examining the possible role of compounds that might acutely result in low blood sugar, seizures, and encephalopathy, including the possible role of MCPG (methylenecyclopropylglycine) in litchis.”

The final conclusion came in a letter submitted to The Lancet by T. Jacob John and Mukul Das. Pulling on the accumulated data, they concluded that leechy consumption by young children after skipping led to the onset of severe hypoglycemia during the early morning hours. The condition eventually caused convulsions and mental deterioration among the children.

***

After published reports pinpointed methylenecyclopropyl glycine (hypoglycin) as the most likely culprit for the outbreaks of hypoglycemic encephalopathy, public health officials and politicians in Bihar pushed back against the notion that lychees played any part. The Muzaffarpur-based National Center for Litchis sponsored subsequent studies that claimed to completely refute the NCDC and CDC data as well as Jacob and Das’ theory that lychee consumption played any part in the children’s illness.

Vijay Yewale, the National President of the Indian Academy of Pediatrics, published an editorial in Indian Pediatrics that asserted that the most likely cause for the cases of acute encephalopathy was through a pathogen like the Japanese Encephalitis virus. His recommendation was to increased vaccinations against JE. Yewale failed to cite any evidence for his claim and refused to even mention the fact that the analysis of blood and cerebrospinal fluid clearly indicated that pathogens known to cause encephalitis were not present.

Unfortunately, in his defense of the lychee industry, Vishal Nath cherry-picked facts to suit his argument.

In 2016, Vipin Vashishtha, a pediatrician at Mangla Hospital and Research Center in Uttar Pradesh, argued against John and Das’ conclusion. He questioned whether it would be possible for small children to consume enough lychees to accumulate sufficient toxins in their bodies to bring about hypoglycemia and whether the hypoglycin found in semi-ripe and ripe lychees was potent enough. He went on to bemoan the paucity of data regarding hypoglycin levels in sick children, claiming,

“No attempt was made to confirm exposure to MCPG by assessing specific metabolites of the putative toxin in the body fluids of the cases.”

In Viashishtha’s analysis, the available data did not add up. Ultimately, he questioned that if lychee consumption by children was the cause, why didn’t similar outbreaks occurred in other places known to have significant lychee production industries?

The only problem with that particular argument was that outbreaks just like Muzaffarpur’s had occurred well outside India’s borders. Between 2004-2009, Bac Giang Province in Vietnam experienced annual surges in acute encephalitis syndrome during the summer that also coincided with the short harvest period for Vietnamese lychees.

What’s more, documentation of “lychee sickness” in Chinese scientific journals stretches back at least as far as 1976. According Li Jie Zhang and Robert E. Fontaine, “Lychees are widely cultivated and well renowned in China. Cautionary messages about the dangers of binging on lychees abound from ancient folklore to the modern electronic media, but these accounts are vague about the disease it causes.”

***

With fresh lychees increasingly available in markets around the world, the question inevitably arises: are children being put at risk? According to Peter Spencer, senior scientist at Oregon Health & Science University, there shouldn’t be cause for alarm.

“Lychee toxicity will affect anyone who lacks stores of glycogen in their liver,” he says. “The risk of illness will also increase with (a) the maturity of the lychee fruit (immature fruit has higher levels of hypoglycin in the pulp, and the concentration decreases as the pulp matures), (b) the amount of lychee fruit eaten at any one time, (c) other food has not been eaten during the day.

“These conditions prevail in several low-income countries in South/SE Asia; the scenario is unlikely in high-income countries such as the U.S. However, occasional children with mild post-lychee nausea and headache would not be unexpected.”

1280px-Litchi_chinensis_fruits
Ripe lychees.
1267px-Litchi_chinensis_Luc_Viatour
Over-ripened lychees.

Eating canned lychees is even less cause for concern since they probably have lower levels of hypoglycin. It’s the fruit’s cousin, the Jamaican ackee, that is the real cause for concern since it contains more hypoglycin. Even with the U.S. government regulating the acceptable levels of the toxin in cans, Spencer urges vigilance.

“Caution is warranted because every can cannot be tested,” he says, while adding “The public view of the natural origin of plants, which inevitably makes them healthy to eat (in any amount), is a falsehood.”

***

After the 2019 outbreak that claimed nearly 150 children’s lives, critics of the lychee theory in India remain defiant, as you’d expect from individuals with financial ties to the agricultural sector. In response to the recent spate of deaths in Muzaffarpur, the Director of the National Research Centre on Litchi, Dr. Vishal Nath defended the fruit (and by extension the growers and his job) during a series of print and TV interviews.

According to Nath, “Litchis have nothing to do with encephalitis. There are no toxins in the edible part of the litchi… In 11 years of my experience at the Muzaffarpur-based research centre, I did not come across any side effects of the fruit.”

Unfortunately, in his defense of the lychee industry, Vishal Nath cherry-picked facts to suit his argument. For example, he argued that had lychee consumption was responsible for the fatal hypoglycemia rich Indian children should have been showing up in droves at the hospital. Conveniently, he ignored the fact that rich children were less likely to have gone to bed on empty stomachs, a key factor in hypoglycemic encephalopathy outbreaks. The scientific literature clearly states that undernourishment contributes to the onset of the illness.

Going further, Nath claimed that lychee consumption could not cause hypoglycemia since the fruit contains sugars. Assertions like that either demonstrate his blatant intellectual dishonesty or an equally disturbing grasp of basic biochemistry.

Outside of the India lychee industry, public health experts are far less sanguine as data and studies continue to indicate that MCPG in lychees are the most likely culprit. However, unlike scientists tied to the lychee industry, they are refraining from making sweeping generalizations about the cause of hypoglycemic encephalopathy.

None of the scientific back and forth matters to the people of Bihar in the long run. While politicians and special interest groups guard their lychee trees, parents all over the state will live in fear of the next harvest season. Will their child be the next victim?

REFERENCES:

John, TJ. Das, Mukul, and Vashishtha, Vipin. “Point-Counterpoint: Outbreaks of hypoglycemic encephalopathy in Muzaffarpur, India: Are these caused by toxins in Litchi fruit?” Indian Pediatrics, 53 (2016):399-401

Pandey, Tunashree. “Litchi has nothing to do with encephalitis: Expert,” India Today. https://www.indiatoday.in/india/story/litchi-encephalitis-director-research-centre-1555505-2019-06-25. Accessed on November 5, 2019.

Pathak, VK, Yadav K, Majhi J. “Decoding mystery disease: Litchi as idiopathic triggering cause of hypoglycemia-induced encephalitic syndrome,” Indian Journal of Community Family Medicine 2019 5 16-18.

Phan, Nga Thi et al. “Hypoglycemic Toxins and Enteroviruses as Causes of Outbreaks of Acute Encephalitis-like Syndrome in Children, Bac Giang Province, Northern Vietnam,” Emerging Infectious Diseases 24 no8 (2018): 1435-1442.

Sharma, Betwa. “Ferrying The Dead: A Bihar Ambulance Driver On The Other Side Of The Encephalitis Crisis,” The Huffington Post. https://www.huffingtonpost.in/entry/bihar-ambulance-driver-on-other-side-of-encephalitis-crisis_in_5d0a26b5e4b06ad4d2593100?ncid=other_huffpostre_pqylmel2bk8&utm_campaign=related_articles. Accessed on November 5, 2019.

Sengupta, Chiranjib. “India: Is Khushi, 3, a victim of poverty or encephalitis?” Gulf News. https://gulfnews.com/world/asia/india/india-is-khushi-3-a-victim-of-poverty-or-encephalitis-1.64726296. Accessed on November 5, 2019.

Shrivastava, Aakash, et al.”Association of acute toxic encephalopathy with litchi consumption in an outbreak in Muzaffarpur, India, 2014: a case-control study,” The Lancet, 5 (2017): e458-e466.

Shrivastava, Aakash, et al. “Outbreaks of Unexplained Neurological Illness – Muzaffarpur, India, 2013-2014,” Morbidity and Mortality Weekly Report, 64 no3 (2015): 49-53

Spencer, Peter, Palmer, Valerie. “The enigma of litchi toxicity: an emerging health concern in southern Asia,” The Lancet, 5 (2017): e383-384

Spencer, Peter, Palmer, Valerie, Mazumder, Rajarshi. “Probably Toxic Cause for Suspected Lychee-Linked Viral Encephalitis,” Emerging Infectious Diseases, 21 no5 (2015): 904-905

Zhang, Li Jie, Fontaine, Robert. “Lychee-associated encephalopathy in China and its reduction since 2000,” The Lancet, 5 (2017): e865

WORDS: Marc Landas @marclandas

IMAGE CREDIT: Creative Commons

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