Uzbekistan Children Died from Unregulated Cough Syrup and Resulting Nephrotoxicity

The poisoning cascade

DEG poisoning tends to start with gastrointestinal symptoms, including nausea, vomiting, abdominal pain, and diarrhea. The most prominent clinical manifestation is nephrotoxicity, causing acute kidney injury (AKI) and anion gap metabolic acidosis, Perazella said. As in Uzbekistan, patients then experience neurological problems, which can include encephalopathy, multiple peripheral and cranial neuropathies, and muscle weakness in all limbs. Oxygen levels drop, and patients become comatose and may die. In the Uzbekistan children, 46 of the 50 were placed on ventilators.

Overall, the National Children's Medical Center, in which Murtalibova practices, treated approximately 73 patients. Only two of them died at the hospital, she said. She credits the lower mortality rate to clinicians who quickly collaborated and brainstormed on how to adequately care for these children who were acutely ill. “In my hospital, we involved all specialists for treatment of these patients, including neurologists, pulmonologists, and ENT [ear, nose, and throat] doctors, and we had the opportunity to [provide] MRIs [magnetic resonance imaging] for these patients,” she told Kidney News.

Many of the children became comatose, and the physicians did not know why. The MRIs revealed posterior reversible encephalopathy syndrome. A neurologist recommended that the children be treated with the osmotic diuretic mannitol, which can lower pressure and swelling in the brain, and with intravenous immune globulin (IVIG). “I think the main difference between the treatment from the two hospitals in Tashkent was the use of mannitol in every hemodialysis session and using IVIG,” Murtalibova said.

During the outbreak, the National Children's Medical Center received resources, including hemodialysis filters, through Murtalibova's involvement in the International Pediatric Nephrology Association (IPNA). She is a mentee through the IPNA Junior Empowerment and Mentorship Program and sought support from her mentors. After the children's urinary function was restored, Murtalibova said urine analyses showed that most of the children had calcium oxalate dihydrate crystals. These can be caused by ethylene glycol, another contaminant that may have been in the medication.

A call to action and awareness

Murtalibova wants her paper to raise awareness and spur a call to action regarding the lack of drug regulations, which can lead to severe illness and death, in resource-limited countries. “Last year was a very, very sad year for Uzbekistan,” she said. “We lost so many children because we just did not know why this was happening.” Once the cough syrup was identified as the cause of the severe illness, government officials warned people not to use it and directed pharmacists to remove it from shelves. (It is unknown whether the Indian manufacturer faced any consequences.)

Murtalibova said physicians in Uzbekistan know about safer, regulated drugs from regions, such as the United States and Western Europe, but their patients cannot afford these medications. “They’re very expensive, so we cannot prescribe them. Indian drugs are cheaper…[but] my goal is to increase the awareness that these kinds of things can happen when we use these kinds of drugs.”

Creating or improving the drug regulatory process in resource-limited countries is an uphill battle, Perazella said. “It's all about finances and income and poverty, and unfortunately, where this is happening is in countries that don't have a lot of money, so they can't have rigorous oversight like the US FDA [Food and Drug Administration] and the European Union,” he said. Because of this disparity among countries, Murtalibova said it is critical that the global nephrology community—not only those in resource-limited countries—becomes aware of these toxic effects so clinicians can act fast to save lives.

Pediatric nephrologist Howard Trachtman, MD, FASN, adjunct professor of pediatrics at the University of Michigan, was horrified to hear of these deaths. He wonders if the international nephrology community can implement standards of care or help countries push for national legislation. But, he acknowledged, “It's going to be very difficult because the only reason why laws don't get implemented is because countries like Nigeria or India won't dedicate the resources that are necessary to police” these drug manufacturers.

Perazella's editorial outlines several other similar cases, including 78 children in Gambia with AKI after DEG poisoning from cough syrup made in India; 84 children with AKI in Nigeria from teething syrup made in Lagos; and 219 pediatric deaths in Panama from a European cough syrup that contained DEG, which was substituted and sold as pharmaceutical-grade glycerin from a company in China.

As Perazella pointed out, because there have been at least 60,000 bottles of cough syrup and lotions contaminated with DEG in recent years, the 219 reported deaths likely reflect only a fraction of the total mortality. Improved surveillance systems are needed to detect these poisoning events quickly to enable prompt notification of physicians and patients, Trachtman added.

Perazella said he titled his editorial Hiding in Plain Sight because “we’ve known about this for a long time. We’ve seen it happen time and time again, yet nothing seems to happen. Here it is in [2024], and these [unfortunate] children in Uzbekistan and the surrounding areas are dying and suffering serious complications of contamination of products. It just shouldn't happen.”

In November 2023, after her paper was published online, Murtalibova attended the 15^th Asian Congress of Pediatric Nephrology in Dubai, United Arab Emirates. A pediatric nephrologist from Bangladesh pulled her aside to discuss her paper. He told her that he had experienced a similar outbreak in his country, in which children were also poisoned by cough syrup with DEG. That outbreak occurred in 1992—over 30 years earlier.