Empty stom­ach, deadly con­se­quence

Solv­ing a deadly col­li­sion be­tween mal­nour­ished chil­dren and the con­sump­tion of an ev­ery­day fruit

The Hamilton Spectator - - FOCUS - ELLEN BARRY

DR. RA­JESH YADAV

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 high­pitch cry in the early morning, many par­ents said.

Then the youths be­gan hav­ing seizures and slip­ping into co­mas. In about 40 per cent 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.

But there were few sign­posts for in­ves­ti­ga­tors.

In­stead of oc­cur­ring in clus­ters, 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 Cen­ters for Dis­ease Control and Pre­ven­tion in At­lanta, pub­lished in the Bri­tish med­i­cal jour­nal The 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 (some­times spelled litchi). In two sea­sons, the num­ber of re­ported cases per year dropped to less than 50 from hun­dreds.

“It was an un­ex­plained ill­ness for so many years,” said Pad­mini Srikan­tiah, a se­nior epi­demi­ol­o­gist with the CDC and the se­nior author of the pa­per. “This is kind of em­blem­atic of why we col­lab­o­rate, to build this kind of sys­tem­atic ap­proach.”

The Lancet ar­ti­cle walks through a two-year med­i­cal de­tec­tive story, as epi­demi­ol­o­gists like Yadav closely ex­am­ined the lives of hun­dreds of af­flicted chil­dren, try­ing to un­der­stand ev­ery­thing they had eaten, drunk and breathed.

“It was a very in­tense sit­u­a­tion, be­cause we wit­nessed chil­dren dy­ing in front of our eyes ev­ery day, as soon as they ar­rived at the hos­pi­tal,” said Yadav, who now works with the CDC in At­lanta. Es­pe­cially dif­fi­cult were the de­tailed in­ter­views of par­ents, many of whom had car­ried a con­vuls­ing or co­matose child for hours to get to the hos­pi­tal.

“They were in a kind of panic,” he said. “Their chil­dren were dy­ing, and it was an un­known thing.”

The first clue

There was no ev­i­dence the chil­dren had in­fec­tions.

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 — the im­me­di­ate as­sump­tion in many out­breaks here.

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.

The sec­ond clue

Most of the vic­tims had very low blood sugar lev­els.

Hav­ing col­lected bi­o­log­i­cal sam­ples from more than 300 chil­dren, the re­searchers were able to scan a large num­ber of mark­ers — in­clud­ing some they hadn’t sus­pected.

Glu­cose had never been a par­tic­u­lar con­cern for in­ves­ti­ga­tors. But some of the af­fected chil­dren had strik­ingly low lev­els, and those with low blood glu­cose were twice as likely to die, Srikan­tiah said.

“It seemed to be a lit­tle sig­nal,” she con­tin­ued. “One of the things we heard mul­ti­ple times from the chil­dren’s moth­ers was that they didn’t re­ally eat dinner prop­erly.”

The third clue

Out­breaks had been as­so­ci­ated with the ac­kee fruit.

It was in the fall of 2013, dur­ing a con­fer­ence call with col­leagues in At­lanta, 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 that in­hibits the body’s abil­ity to syn­the­size glu­cose, lead­ing to acute hy­po­glycemia, or low blood glu­cose lev­els.

“It had been go­ing on for a decade, if not a cen­tury, be­fore peo­ple re­ally fig­ured out what it was,” Srikan­tiah said. “Now, the grand­moth­ers and the moth­ers teach their kids, ‘Don’t eat the un­ripe ac­kee fruit.’”

By late 2014, lab­o­ra­tory tests con­firmed that ly­chees also con­tain high lev­els of hy­po­glycin, as well as a sim­i­lar toxin known as methylenecy­clo­propyl glycine, or MCPG.

This was an an­swer hid­ing in plain sight. The Muzaf­farpur area, in In­dia’s east, pro­duces about 70 per cent of In­dia’s ly­chee har­vest, and around the af­fected vil­lages, “you re­ally couldn’t go 100 me­tres with­out bump­ing into a ly­chee or­chard,” Srikan­tiah said.

Though or­chards were typ­i­cally guarded by care­tak­ers, chil­dren of­ten ate ly­chees that were un­ripe or that had fallen to the ground. But 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.

The fourth clue

Af­fected chil­dren had huge meta­bolic im­bal­ances.

By early 2015, CDC lab­o­ra­to­ries had de­vel­oped a test to mea­sure hy­po­glycin in urine. They found ex­tra­or­di­nary ab­nor­mal­i­ties in the af­fected chil­dren. “The folks in the ge­netic labs said ‘We haven’t seen any­thing like this,’” Srikan­tiah said. “This was clearly ab­nor­mal.”

With that es­tab­lished, 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.

“It was a very in­tense sit­u­a­tion, be­cause we wit­nessed chil­dren dy­ing in front of our eyes ev­ery day, as soon as they ar­rived at the hos­pi­tal.”

PHO­TOS BY KUNI TAKAHASHI, NEW YORK TIMES

Dr. Mohan Ku­mar, right, checks on Sul­man Khan, 8, as his mother, Nasee­ban Begam, cen­tre, looks on at Sri Kr­ishna Med­i­cal Col­lege Hos­pi­tal in Muzaf­farpur, In­dia, in 2013.

Am­ren­dar Ku­mar com­forts his daugh­ter Sanam Ku­mari, 2, at the Sri Kr­ishna Med­i­cal Col­lege Hos­pi­tal. A med­i­cal in­ves­ti­ga­tion into a some­times deadly ill­ness that for decades has been af­flict­ing hun­dreds of chil­dren each sum­mer in a re­gion of In­dia has solved the mys­tery.

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