New Delhi: Another report from Gambia has concluded that 70 children died in the country last year due to acute kidney injury, after they had consumed paediatric formulations contaminated with toxins, manufactured by an Indian drug maker.
These toxins were diethylene glycol (DEG) and ethylene glycol (EG). The report, which did a causality assessment of the deaths, is the fourth in the series to make such a conclusion.
All these four reports contradict the stand taken by the Indian government, which said that it found no contamination in its assessment of the products.
The former head of the Central Drugs Standard Control Organisation, V.G. Somani, had written a damning letter to the World Health Organisation (WHO) on December 13, 2022, saying the UN agency warning against the four products had no scientific basis.
There is no direct causal relationship between cough syrup consumption and deaths of children in Gambia. @WHO‘s premature conclusion was unfortunately amplified by global media for building a wrong narrative against India’s pharmaceutical products.
DCGI to @WHO @MoHFW_INDIA pic.twitter.com/SXxiUiYGqx
— DD News (@DDNewslive) December 16, 2022
“It may be emphasised here that Gambia has informed, as per media reports, that there has been no direct causal relation established yet between the cough syrup consumption, and the deaths, and that certain children who had died had not consumed the syrup in question,” he had said.
The causality assessment report, which has been prepared by international experts, says, “Based on the detailed review of 56 cases of AKI [acute kidney injury] in children in the Gambia DEG/EG poisoning could be confirmed as a cause of AKI and death in 22 children. For the remaining 34, DEG/EG poisoning also needs to be considered as likely cause in at least 30 [children] despite absence of confirmed exposure given the epidemiologic context, the absence of other identified causes, the notorious difficulty to assess medicine exposure in detail and the fact that two children in this group had autopsy findings suggestive of DEG/EG poisoning.”
In summary, “the causality assessment committee certified that the outbreak of acute kidney injury in children in Gambia is attributable to the medicines contaminated with DEG/EG.”
The Wire has seen a copy of the report. The Wire has sought responses from the current CDSCO head, Rajeev Raghuvanshi, who is the Drug Controller General of India.
The Wire did not receive any responses till the time of going to press. The story will be updated if and when he responds. The government’s response will also be added if and when it comes.
The report has added the results of the three labs where the Maiden Pharmaceuticals products were sent for testing by the WHO.
The Wire had reported that according to the results of tests conducted by one of these labs, DEG was present in extremely high concentrations. The summary of the reports of the other two labs in France and Ghana, where one product that had the highest concentration was sent, also confirmed the presence of DEG and EG.
Summary of lab results. Source: Screengrab of Causality Assessment Report
Thirty-eight products, or medicines made by manufacturers of other countries, were sent for testing. The report says except for four medicines made by Maiden Pharmaceuticals, none of the 34 were found to be contaminated.
All 34 products that were found to not have EG and DEG were released for marketing on November 11, 2022, the report adds.
Besides these lab reports, a report from US-CDC and a parliamentary report from the Gambia have also concluded that the deaths of these children were linked to the products of Maiden Pharmaceuticals, The Wire reported.
Causality assessment
For doing the causality analysis, the researchers followed what is known as the French Imputability Method of Causality Assessment. It takes two factors into account – ‘chronological’ and ‘seismological’ scores – which determine the imputability score.
The ‘chronological score’ is determined by the time of occurrence of the event, evolution of the event after stopping treatment with the drugs in question, influence of possible re-exposure of the drug. The seismological score takes into account the signs and symptoms of patients and causes not related to drugs and lab investigations.
The committee planned to assess 69 cases. However, three of the cases did not meet the standard definition of acute kidney injury and 10 had insufficient data. Then, an in-depth assessment was carried out for 56 cases.
The most common clinical findings showed fever in 54 out of 56 cases, vomiting in 52, and insufficient production of urine or oliguria/anuria in 51 cases.
The median value of urea was found to be 28.5 mmo1/L – about five times more than ideal levels. The creatinine was 702.3 umol/L – about 100 times higher than the limits. High levels of urea and creatinine were clear indicators of acute kidney disease.
The overall mortality was found to be 100% in all the 56 cases assessed.
Out of the 56 cases, 22 were assessed as likely to have been exposed to DEG and EG from the analysed oral liquid formulations. The other 34 were assessed to have suspected poisoning but of an uncertain or unknown exposure. Two of the patients in this particular group had an autopsy that confirmed renal and hepatic pathological findings consistent with features of DEG/EG poisoning.
Earlier, a Gambian epidemiologist had told The Wire that conducting an autopsy in all cases was difficult because either the parents had buried the dead bodies, or they were not ready for investigation.
The remaining four cases had possible alternative/contributing diagnosis and incomplete evidence for the ingestion of a medicinal product containing the poison (DEG & EG), the report said.
A flow chart of causality carried out by the causality assessment committee. Source: Screengrab of Causality Assessment Report
The report also said after the Gambian government withdrew the syrups from the market, even from the houses, children stopped dying – a finding that is consistent with other reports related to the incident. This fact can be interpreted as a “dechallenge at the population level”, which means withdrawal of the drugs that led to cessation of the outbreak, says the causality assessment report.
And, this fact is “highly suggestive” [of the fact] that the 30 children also died due to severe DEG/EG poisoning just like in the [other] 22 cases. As of December 9, 2022, no further cases of acute kidney injury have been detected,” the report adds.
These findings took the ‘chronological’ and ‘seismological’ scores into account, which finally led to the calculation of ‘imputability’.
In the French method, the only modification was that the researchers had to do away with the “rechallenge” step, i.e., to see if the disease returned in those children if the said formulations were reintroduced. “Re-challenge (return of symptoms when treatment is reintroduced) could not be used as the children had all died,” says the report.
The extrinsic imputability was assessed by using the current literature available on this subject.
The expert committee on causality assessment was led by professor Abdou Niang, a specialist in internal medicine at Senegal’s Cheikh Anta Diop University.
The other members included an expert in toxicology from Senegal Toxicology Control Center, two in paediatrics and clinical pharmacology from Finland’s Clinical Toxicology Helsinki University Hospital and UK’s All Wales Toxicology Centre University Hospital, two in infectious diseases and epidemiology from the WHO, one each in neurosurgery, internal medicine, microbiology and pathology from Gambia’s Edward Francis Small Teaching Hospital, and one in cardiology from Gambia’s Bafrow Medical Center.
Earlier, the WHO had also refused to accept the findings of the Indian expert committee that claimed no toxins were found in the Maiden Pharmaceuticals products sent to Gambia and that there was no proof of link between the deaths and the medicines.