Sudden deaths among adults in India: Some observations

Sir,

We find great interest in the article titled ‘Factors associated with unexplained sudden deaths amongst adults aged 18-45 yr in India – A multicentric matched case–control study’ by Ponniah et al1, and we would like to highlight a few interesting observations.

The authors endeavoured to address the pressing question of the surge in unexplained sudden deaths among young adults through a retrospective study design. They concluded that COVID-19 vaccination was not linked to this increase, while family history and lifestyle behaviours were associated with a heightened risk of unexplained sudden deaths.

The outcomes of this case–control study, as indicated by the odds ratios and power analysis, provide compelling insights. However, a closer look reveals the following:

1. First, the motivation for the case–control methodology is unclear. The paper misses to mention the randomized controlled trials (RCTs) for the COVID-19 vaccines, which were started in 2020. RCT data with long-term follow up can tell with confidence whether the vaccines are causing unexplained sudden deaths

2. The median days between vaccination and death of cases were 257.8 days – the same metric is reported as 266.3 days for controls. However, the controls are alive, so it is unclear how the authors compute this metric

3. Acknowledging the accomplishments in COVID-19 vaccination in India, the 20 per cent single-dose vaccine rate among cases appears too high. Furthermore, the percentage of single-dose is significantly lower at 12.4 per cent for the controls. Therefore, whether the cases could have died before the second dose was scheduled or were denied a second dose by their physicians due to serious adverse events following vaccination or other reasons merits investigation

4. Interestingly, out of the 577 cases with any vaccination status (the first set of rows in Table I), records for only 288 (266+22 in the second set of rows) were present for the interval between vaccination and date of death. This appears inconsistent

5. Alcohol abuse has been attributed to higher odds of sudden deaths. This was significantly associated with the univariate analysis, particularly binge drinking before death or interview. The exclusion of this variable in the multivariable models should be explained by the authors

6. Furthermore, there were different types of vaccines used. Failure to differentiate between messenger RNA, vector-based and live-attenuated vaccines is a notable drawback, as potential differences in vaccine types are pertinent.

Literature shows that even after rigorous investigations for sudden cardiac deaths using forensic autopsy, pathology and next-generation sequencing, 25 per cent of cases remain unexplained in Hong Kong and 31 per cent in Denmark, which presents an unexplored area23. There is a notable grey area as COVID-19 vaccines are linked to an expedited onset of atherosclerosis and thrombosis, or at the very least, adverse events related to vascular complications. Consequently, dismissing vaccines as a potential risk factor based on models with overmatched subjects could have deleterious implications for future assessments. In this light, ruling out vaccine associations should be approached with caution considering level IIIB evidence of case-control studies45.

The proposed factors associated with unexplained sudden deaths align with existing risk factors; however, the study lacks a substantial contribution towards understanding the recent increase in such deaths. Ecological observations indicate an upward trend, and long-term randomized trials or prospective studies are crucial for a nuanced understanding, given that enormous quality-adjusted life years are at stake.

In conclusion, while the study provides results from samples across the country, methodological and reporting concerns necessitate careful interpretation. A multidisciplinary approach involving forensic experts, pathologists, geneticists and investigators, along with prospective cohort studies, would enhance the robustness of findings in studies of this nature. Until then, it would be wise to avoid exonerating the COVID-19 vaccines.