Discussion
This is a descriptive study which aimed to investigate the characteristics of subjects with severe and mild COVID-19 pneumonia. According to the study results, BCG vaccination status is not related to clinical condition in COVID-19 pneumonia, whereas, increasing age and low-income are the factors associated with severe COVID-19 pneumonia.
BCG vaccine, a live attenuated bacterial vaccine derived from Mycobacterium bovis, is recommended in countries with a high incidence of tuberculosis.6 Beyond immunisation against tuberculosis, BCG vaccine provides improved immune response against some viral pathogens including respiratory syncytial virus, influenza A virus and herpes simplex virus type 2. These nonspecific immune effects, known as trained immunity, occur via epigenetic reprogramming of monocytes and production of IL-1β, TNF and IL-6 during subsequent viral infection.7 Observational studies on clinical reflection of the immunopathogenesis of BCG vaccine report that BCG vaccination and presence of a BCG scar among infants reduce the risk of respiratory tract infections.8,9
Countries’ vaccination policies gained importance during the COVID-19 pandemic. Analyses of the relationship between countries’ BCG vaccination databases and their COVID-19 statistics suggest that BCG vaccination significantly reduces COVID-19 mortality rates, and that the earlier a country establishes a BCG vaccination policy, the lower COVID-19 deaths per million inhabitants. National BCG vaccination policies are also thought to be related to flattened COVID-19 growth curves.4,10 Another report which analyzed data of 210 countries and territories have shown that BCG-vaccination policy was associated with lower COVID-19 morbidity and mortality rates, but not with case-fatality rate. High median age, low per capita gross domestic production adjusted to purchasing power and high per capita health expenditure were found to be related to higher morbidity and mortality rates in COVID-19.11 In Turkey, national BCG-immunisation programme has been implemented since 1953 for control of tuberculosis. BCG vaccination rates reached 94.4% in 2013.12,13
The study population consisted of BCG-vaccinated and -unvaccinated COVID-19 pneumonia cases in order to compare the severity of the disease in the two groups. BCG-vaccinated and -unvaccinated groups were similar in terms of body-mass index, gender distribution, smoking status and presence of diabetes and hypertension. However they were significantly different in terms of age and income; such as, BCG-unvaccinated group was significantly older compared to BCG-vaccinated group and nearly all subjects in BCG-unvaccinated group were low-income. A possible explanation for low income of people without BCG vaccination is people migrating from rural to urban areas in search of employment and earn living. As the major outcome of the study, in severe COVID-19 pneumonia patients, the rate of cases not vaccinated with BCG was significantly higher than in patients with mild COVID-19 pneumonia. However, the most important confounding factor in the study was the uneven distribution of income between the unvaccinated group and the vaccinated group. Accordingly, logistic analysis revealed that increasing age and low income level were predictive of severe disease, whereas BCG vaccination status is not related to the severity of COVID-19 pneumonia.
This is the first study to evaluate severity of clinical condition with BCG-vaccination status in COVID-19 pneumonia patients. Previous reports are based on analysis of COVID-19 statistics and countries’ national BCG vaccination policies. However, international comparisons of COVID-19 epidemiology are difficult because the ways in which countries record COVID-19 cases and deaths are different depending on the polymerase chain reaction results or clinical decision. Population characteristics of countries such as population density, median age, and urban population and mainly SARS-CoV-2 test rates are major confounders that may lead to misjudgement of BCG vaccination policy is beneficial.14 According to a report published very recently, there was no statistically significant difference in the SARS-CoV-2 positive test results between the BCG-vaccinated group and the non-vaccinated group.15 Also in Brazil, which has been carrying out the BCG vaccination program since 1920, the morbidity and mortality rates of COVID-19 disease have reached today’s distressing levels, also questions any protective role of BCG vaccination in the COVID-19 outbreak.
Second most important finding of the present study is that increasing age and low-income are the predictors of severe disease in COVID-19 pneumonia. Age is reported as main risk factor for disease severity and mortality in COVID-19 since the beginning of the outbreak.16-23 The relationship between low-income and serious COVID-19 emerged mainly after news that low-income minority residents were most affected, from the USA, especially New York City. According to various reports from different states non-Hispanic black patients were disproportionately hospitalized with diagnosis of COVID-19. However, the absence of any difference in intensive care unit admission and mortality rates in black patients suggests that the distinction in SARS-CoV-2 infection rates is due to socioeconomic inequalities rather than racial and ethnic differences.24,25 In line with previous reports on the importance of socioeconomic inequalities in COVID-19, in the present study, low income was an independent predictor of severe disease.
Most prevalent comorbidities reported in serious or critically ill subjects with COVID-19 are diabetes mellitus, chronic lung disease and cardiovascular disease.16-18,20,21 The percentage of COVID-19 cases with at least one underlying health condition was higher among those hospitalized compared to non-hospitalized.17 Yet, data from countries may vary for different reasons, like health policies implemented in the countries, proportion of elderly population, prevalance of concomitant diseases and whether or not comorbidities are under control. Prompt measures taken by Turkish Government early in the epidemic may be the reason why comorbid disease rates were not an independent predictor of severe COVID-19 pneumonia in the present study. Because immediately after the first COVID-19 case was detected in Turkey, people with chronic illness were considered on leave in public and private sector.
The major strength of the present study is that severity of COVID-19 pneumonia is assessed in BCG vaccinated and unvaccinated inhabitants of the same country, which implements national BCG vaccination policy. Another strength of the study is that all patients are evaluated in a single center, providing homogeneity in clinical evaluation of patients. Main limitation of the study is the relatively low number of subjects. However, since BCG vaccine is administered regularly in the country, the number of individuals who have not been vaccinated is limited in the country.
Acknowledgements: KA and TN had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. KA constructed hypothesis for research, KA, TN, and PÖ contributed substantially to the study design, TN, and PÖ contributed substantially to data collection, KA, and TN performed data analysis and interpretation. KA, TN, and PÖ substantially contributed to the writing of the manuscript. KA, TN, and PÖ approved final manuscript. No funding was received for the study.