Many BCG studies showing a significant relationship between BCG and a reduction in COVID-19 mortality and/or morbidity have been criticized for not considering confounding factors, and simply assessing the differences in the incidence/mortality of COVID-19 based on having or not having BCG vaccination policy, as well as sharing the same sources of information with questionable data accuracy. 25, 28, 29, 30 These studies were, therefore, considered to represent only weak evidence. On the other hand, other studies have found no statistical evidence for an association between BCG vaccination policy and either SARS-CoV-2 morbidity or mortality, as shown by Chimoyi L et al.30, Aksu et al.31, Fukui M et al.28, Clément et al.32, Hamiel U et al.33, Asahara M,34 and Hensel J.35 et al.. However, these studies also did not define the possible confounding effects of TB or malaria.
A confounding factor may mask an actual association or falsely demonstrate an apparent association between a study’s variables where no real association between them exists.36 This confounder may lead to the overestimation of the true association between an exposure and outcome.37 One of limitations of this study is that it did not address whether there is an overestimation of the BCG effect, since it focused on the relationship between TB prevalence and BCG status Furthermore, it is limited by not measuring BCG vaccination coverage rate, stage of epidemic, socio-economic differences, and differences in practicing of preventive measures to contain the disease, etc.
The efficacy and effectiveness of BCG vaccination against TB have been found to differ considerably between studies and populations.38
The BCG vaccine has a documented protective effect against TB meningitis and disseminated TB in children, but it prevents neither primary infection nor, more importantly, the reactivation of a latent pulmonary infection, which is the principal source of bacillary spread in the community. The impact of BCG vaccination on the transmission of Mycobacterium TB is, therefore, limited.39
Despite BCG being effective in 50% of the target population, much controversy surrounds its effect on mild forms of infection, as well as the duration of its effect. 25
According to the WHO’s recommendations, countries with low TB burdens may limit BCG vaccination to infants in high-risk groups (or TST-negative older children) and adults at high risk for occupational TB exposure and who are TST negative. 38 Most people with TB immunoreactivity do not develop active TB upon immunosuppression, suggesting that they have cleared their infections while retaining immunological memory to them.40
In most European Union (EU) and Western European countries, the tuberculosis (TB) notification rates are lower than 20 cases per 100,000 population. This rate is decreasing by around 4% yearly in the EU, overall. In 2003, it reached 13.8 per 100,000. 41,42
Table 1 shows a highly significant association between TB prevalence and certain BCG groups: countries not implementing BCG vaccinations had low TB prevalence, and vice versa (p value = 0.000). Table 2 and Figure 1 show the ROC analyses indicating that BCG group is significantly associated with corresponding TB prevalence. These results confirm an association between TB prevalence and BCG status.
The finding of this study that BCG status is highly associated with TB prevalence leads us to conclude that BCG studies can be easily confounded by LTB. The ranking of mortality rates within BCG group statuses shown in a stem–leaf plot (Figure 2) follows the rank of association between TB prevalence and BCG status. This gives the impression of high mortality within groups with no BCG vaccination and low mortalities within countries with BCG vaccination.
This could apply to all BCG studies not adjusting for LTB.
In countries that do not undertake vaccination, confounding occurs simply because of a possible low TB prevalence, giving a false impression that not administering BCG is the cause of high mortality. Another possible confounder is previous TB prevalence, since the immunity generated by TB lasts for a certain period of time. We tried to control for this by considering the highest available TB prevalence during 2011–2018.
For these reasons, BCG studies should be designed properly to avoid bias. Estimation using the TST could also confound the LTB studies since BCG results in a positive TST result. We took the TB prevalence among countries as a proxy reflecting LTB infection to avoid this bias. However, in clinical trials, both TST and IGRA testing seem to be important, since BCG vaccination can cause a positive result for nontuberculous mycobacteria, while IGRA testing does not.
The low COVID-19 mortality in some countries cannot be explained by either low TB prevalence or malaria-free status, such as in Cyprus, which has not implemented BCG vaccination, and Slovakia, which previously implemented a BCG program. These findings suggest that other factors play roles in decreasing COVID-19 mortality