Endemic rise in cases of acute kidney injury in children in Indonesia and Gambia: what is the likely culprit and why?

A sudden rise in the cases of acute kidney injury (AKI) has been reported in Indonesia and Gambia that has been linked to the consumption of tainted syrup medications for cough, colds, pain, and fever. Preliminary investigations revealed multiple lapses in quality control during manufacturing including substitution of diethylene glycol (DEG) and ethylene glycol (EG) for the more expensive but non-toxic solvent glycerol. In this editorial report, we shed light upon the current situation and urge the investigating authorities to make those responsible accountable to regain public trust. A sudden rise in the cases of acute kidney injury (AKI) has been reported in Indonesia and Gambia that has been linked to the consumption of tainted syrup medications for cough, colds, pain, and fever. Preliminary investigations revealed multiple lapses in quality control during manufacturing including substitution of diethylene glycol (DEG) and ethylene glycol (EG) for the more expensive but non-toxic solvent glycerol. In this editorial report, we shed light upon the current situation and urge the investigating authorities to make those responsible accountable to regain public trust. There has recently been a sudden increase in the hospitalizations and deaths of children who developed acute kidney injury following the consumption of cough and antipyretic syrups in Indonesia and Gambia. This situation has not only panicked the affected societies but has implications beyond their borders. The World Health Organization (WHO) is concerned about the possibility of illegal redistribution of these contaminated syrups in other international markets.1World Health OrganizationMedical Product Alert N°6/2022: substandard (contaminated) paediatric medicines.https://www.who.int/news/item/05-10-2022-medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicinesDate accessed: October 20, 2022Google Scholar In Gambia, as of November 1, 2022, 70 deaths of children, mostly aged <5 years, have been reported. These deaths were associated with the ingestion of adulterated anti-histamine and cough-and-cold syrups, manufactured in a single batch in 2021 by an Indian pharmaceutical company. The incident prompted the WHO to issue a global medical product alert against the 4 contaminated products (Table 1),1World Health OrganizationMedical Product Alert N°6/2022: substandard (contaminated) paediatric medicines.https://www.who.int/news/item/05-10-2022-medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicinesDate accessed: October 20, 2022Google Scholar followed by an inspection and shutdown of the production facility by the Indian authorities. Gambian authorities have so far been able to recall about 83% of the tainted syrup bottles. However, the WHO and the Gambian National Regulator (Medicines Control Agency) have advised caution because direct causation has not yet been established.Table 1Characteristics of the suspected cough-and-cold medications that have been since removed from distributionVariableGambiaIndonesiaProduct namePromethazine Oral SolutionKofexmalin Baby Cough SyrupMakoff Baby Cough SyrupMagrip N Cold SyrupTermorex SyrupFlurin DMP SyrupUnibebi Cough SyrupUnibebi Fever SyrupUnibebi Fever DropsParacetamol DropsParacetamol Syrup, PeppermintVipcol SyrupReported active ingredientsPromethazinePheniramine maleate, ammonium chloride, and mentholCTM, phenylephrine HCl, and dextromethorphan HBrParacetamol, phenylephrine HCl, and CTMParacetamolParacetamol, CTM, pseudoephedrine HCl, and dextromethorphan HBrParacetamol, guaifenesin, and CTMParacetamolParacetamolParacetamolParacetamolParacetamol, guaifenesin, menthol, and CTMIndication for useNausea and vomiting, and antiallergic agentCoughCoughCough and fluFeverCough and fluCough and fluFeverFeverFeverFeverCough and fluPackaging, ml1001251001006060606015156060ManufacturerMaiden Pharmaceuticals LimitedMaiden Pharmaceuticals LimitedMaiden Pharmaceuticals LimitedMaiden Pharmaceuticals LimitedKonimexYarindo FarmatamaUniversal Pharmaceutical IndustriesUniversal Pharmaceutical IndustriesUniversal Pharmaceutical IndustriesAfi Farma Pharmaceutical IndustriesAfi Farma Pharmaceutical IndustriesAfi Farma Pharmaceutical IndustriesManufacturing countryIndiaIndiaIndiaIndiaIndonesiaIndonesiaIndonesiaIndonesiaIndonesiaIndonesiaIndonesiaIndonesiaDistribution permit number/lot numberaLot number is used for Gambian medications, whereas distribution permit number is used for Indonesian medications.ML21-202ML21-199ML21-203ML21-198DBL7813003537A1 (batch: AUG22A06)DTL0332708637A1DTL7226303037A1DBL8726301237A1DBL1926303336A1GBL1801707636A1GBL0101704237A1DTL7801706637A1Manufacture dateDecember 2021December 2021December 2021December 2021August 2022N/AN/AN/AN/AN/AN/AN/AExpiration dateNovember 2024November 2024November 2024November 2024August 2025N/AN/AN/AN/AN/AN/AN/APackaging languageEnglishEnglishEnglishEnglishIndonesianIndonesianIndonesianIndonesianIndonesianIndonesianIndonesianIndonesianCTM, Chlorphenamine maleate; N/A, data not available.The data have been collected from World Health Organization advisories: Medical Product Alert N°6/2022: substandard (contaminated) pediatric medicines (dated October 5, 2022)1World Health OrganizationMedical Product Alert N°6/2022: substandard (contaminated) paediatric medicines.https://www.who.int/news/item/05-10-2022-medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicinesDate accessed: October 20, 2022Google Scholar; and Medical Product Alert N°7/2022: substandard (contaminated) pediatric liquid dosage medicines (dated November 2, 2022).a Lot number is used for Gambian medications, whereas distribution permit number is used for Indonesian medications. Open table in a new tab CTM, Chlorphenamine maleate; N/A, data not available. The data have been collected from World Health Organization advisories: Medical Product Alert N°6/2022: substandard (contaminated) pediatric medicines (dated October 5, 2022)1World Health OrganizationMedical Product Alert N°6/2022: substandard (contaminated) paediatric medicines.https://www.who.int/news/item/05-10-2022-medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicinesDate accessed: October 20, 2022Google Scholar; and Medical Product Alert N°7/2022: substandard (contaminated) pediatric liquid dosage medicines (dated November 2, 2022). Indonesia, on the other hand, has had a more difficult time dealing with the soaring number of cases of acute kidney injury–affected children. As of November 15, 2022, the country has reported >324 cases along with 199 deaths (Figure 1), which have been linked to the consumption of at least 8 locally produced syrups. Toxicologic testing detected traces of diethylene glycol (DEG) or ethylene glycol (EG) in 7 of the 11 tested children, and a kidney biopsy resulted positive for calcium oxalate, an alcohol dehydrogenase metabolite of DEG/EG.2Bona M.F. Paat Y. Menkes Pastikan Gangguan Ginjal Akut pada Anak Disebabkan Zat Kimia [Ministry of Health confirms pediatric acute kidney injury caused by chemical substance].https://www.beritasatu.com/news/995769/menkes-pastikan-gangguan-ginjal-akut-pada-anak-disebabkan-zat-kimiaDate accessed: November 2, 2022Google Scholar Indonesian authorities have since implemented a blanket ban on the sale of all syrup medications, and have advised the use of powder, tablet, or capsule forms of such drugs for an indefinite period.3Office of Assistant to Deputy Cabinet Secretary for State Documents and TranslationHealth Ministry urges parents to remain vigilant of acute kidney failure in children.https://setkab.go.id/en/health-ministry-urges-parents-to-remain-vigilant-of-acute-kidney-failure-in-children/Date accessed: October 20, 2022Google Scholar Gambian authorities have estimated an associated mortality rate of about 90%, whereas Indonesian figures put the mortality rate around 61.4%. These levels of mortality are significantly higher than those previously reported for pediatric patients with acute kidney injury, even in critical care wards (6.4%–32.3%).4Uber A.M. Sutherland S.M. Acute kidney injury in hospitalized children: consequences and outcomes.Pediatr Nephrol. 2020; 35: 213-220Crossref PubMed Scopus (38) Google Scholar Both countries have identified excessive DEG/EG contamination in syrup medications as the probable common cause behind these cases, particularly paracetamol-containing preparations (used for fever, cough, cold, and pain).1World Health OrganizationMedical Product Alert N°6/2022: substandard (contaminated) paediatric medicines.https://www.who.int/news/item/05-10-2022-medical-product-alert-n-6-2022-substandard-(contaminated)-paediatric-medicinesDate accessed: October 20, 2022Google Scholar Both DEG and EG are odorless, water-miscible organic compounds with a sweetish taste, commonly used as industrial solvents and in the manufacturing of antifreeze, dyes, and brake fluids.5Jha V. Chugh K.S. Nephropathy associated with animal, plant, and chemical toxins in the tropics.Semin Nephrol. 2003; 23: 49-65Abstract Full Text PDF PubMed Scopus (0) Google Scholar Active pharmaceutical compounds, like paracetamol, are non–water soluble and require nontoxic solvents, like glycerol and propylene glycol, to provide a liquid base. In addition, these solvents act as preservatives, thickeners, and sweetening agents, and confer antimicrobial properties.5Jha V. Chugh K.S. Nephropathy associated with animal, plant, and chemical toxins in the tropics.Semin Nephrol. 2003; 23: 49-65Abstract Full Text PDF PubMed Scopus (0) Google Scholar,6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar Manufacturers illegally replace glycerol and propylene glycol with toxic DEG/EG or cheaper grades of the nontoxic solvents, which are tainted with DEG/EG, thereby leading to poisoning. The minimum lethal dose for DEG is yet to be determined but is estimated to range from 0.014 to 0.35 mg/kg.6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar The toxicity of DEG/EG is primarily determined by their metabolite glycolaldehyde, which can hinder numerous aspects of cellular metabolism while also exacerbating cellular damage. The formation of oxalic acid and calcium oxalate monohydrate crystals, which can cause cerebral edema and kidney failure, related to tubular system blockade and injury, can be seen within 8 to 24 hours of consumption of a lethal dose. If untreated, death from multiorgan failure typically occurs within 24 to 36 hours of glycol ingestion.5Jha V. Chugh K.S. Nephropathy associated with animal, plant, and chemical toxins in the tropics.Semin Nephrol. 2003; 23: 49-65Abstract Full Text PDF PubMed Scopus (0) Google Scholar,6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar For pediatric patients presenting with DEG-associated acute kidney injury, treatment involves concurrent hemodialysis with fomepizole (alcohol dehydrogenase inhibitor) administered over 4 hours. In resource-limited settings, peritoneal dialysis with oral ethanol (0.8–1.0 ml/kg loading dose, followed by 0.15 ml/kg per hour of 95% ethanol diluted in orange juice) is suggested.6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar However, caution must be observed while administering ethanol, given its toxic effects. Regrettably, the present incidents are not the first time that spurious DEG/EG-containing syrups have been identified as a cause of pediatric morbidity and mortality. More than 300 child deaths have been reported in the past due to the consumption of tainted syrups.6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar Just 2 years ago, India reported 12 deaths due to the consumption of locally produced tainted cough syrups, the fourth such incident in the country after 1998 (33 deaths), 1986 (14 deaths), and 1973 (14 deaths). Other countries, like the United States, Panama, Haiti, South Africa, and Bangladesh, have also reported deaths due to cough syrup–related DEG/EG poisonings.5Jha V. Chugh K.S. Nephropathy associated with animal, plant, and chemical toxins in the tropics.Semin Nephrol. 2003; 23: 49-65Abstract Full Text PDF PubMed Scopus (0) Google Scholar,6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar Clearly, such incidents highlight lapses in regulatory oversight, implementation, and cross-country checks of the pharmaceutical industry. These incidents negatively shape public trust and opinion toward the medical and pharmaceutical sectors. Indian authorities found multiple lapses in the production process of these medicinal syrups, including bypassing quality checks of raw products, mislabeling product shelf life, and missing records and logbooks, among others. According to the All-India Organization of Chemists and Distributors, none of the products produced by the implicated pharmaceutical company is available for sale in India. Although Indian authorities pointed out that final approval and sale of the drugs is the onus of the importing country, Gambian authorities noted their limited resource capacity, which can only prioritize quality checks on antimalarial drugs, antibiotics, and pain killers, rather than cough syrups. Indonesia, on other hand, has now promised stricter scrutiny of the pharmaceutical sector while increasing imports of antidotes (fomepizole injections) from Singapore and Australia. A pilot study from 2014 highlighted that most of the drugs made in India and sold in Africa are of poorer quality than those sold in India or other countries, exposing an exporting bias based on cutting costs and maintaining company reputation.7Bate R. Jin G.Z. Mathur A. Attaran A. Poor-quality drugs and global trade: a pilot study.Am J Heal Econ. 2016; 2: 373-398Crossref Google Scholar Developing countries have always struggled with drug regulation and control because of a lack of resources.8Fernandez F.M. Hostetler D. Powell K. et al.Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries.Analyst. 2011; 136: 3073-3082Crossref PubMed Google Scholar This is becoming increasingly difficult, particularly in the light of the current coronavirus disease 2019 (COVID-19) situation, which necessitates providing funds for other purposes, such as medical care and social assistance. Relatively lenient rules for punishment are another cause promoting adulteration and the sale of counterfeit drugs. In addition, India’s non-inclusion in WHO standards for national bodies that regulate medication standards globally is a serious concern, given India’s reputation as the “Pharmacy of the World.” Understandably, parents of young children are now unsure of the medications that they have recently purchased, and the possible consequences of administering DEG- and EG-contaminated drugs to their children before definitive findings are released by the authorities. In such perilous times, it is necessary that the companies and individuals responsible be made accountable and the investigation findings be made public. National regulators should make sure that companies adhere to the WHO Good Manufacturing Practice Guidelines and follow the international certification scheme for medications meant for export.6Alkahtani S. Sammons H. Choonara I. Epidemics of acute renal failure in children (diethylene glycol toxicity).Arch Dis Child. 2010; 95: 1062-1064Crossref PubMed Scopus (23) Google Scholar Such measures will help not only to regain public trust but also prevent the spread of misinformation and hesitancy. All the authors declared no competing interests. TPU and NJ conceptualized the present study and were responsible for data collection, synthesis, and writing the initial draft of the article. NJ was responsible for visualizations, while project administration was done by TPU. Supervision was done by HA. All authors were involved in preparing the final draft of the article. The authors have read and agreed on the final version for publication.

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