Association of the past epidemic of Mycobacterium tuberculosis with mortality and incidence of COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a remarkable and varying impact in every country, inciting calls for broad attention. Recently, the Bacillus Calmette-Guérin (BCG) vaccination has been regarded as a potential candidate to explain this difference. Herein, we hypothesised that the past epidemic of Mycobacterium tuberculosis (M. tuberculosis) may act as a latent explanatory factor for the worldwide differences seen in COVID-19 impact on mortality and incidence. We compared two indicators of past epidemic of M. tuberculosis, specifically, incidence (90 countries in 1990) and mortality (28 countries in 1950), with the mortality and incidence of COVID-19. We determined that an inverse relationship existed between the past epidemic indicators of M. tuberculosis and current COVID-19 impact. The rate ratio of the cumulative COVID-19 mortality per 1 million was 2.70 (95% confidence interval [CI]: 1.09-6.68) per 1 unit decrease in the incidence rate of tuberculosis (per 100,000 people). The rate ratio of the cumulative COVID-19 incidence per 1 million was 2.07 (95% CI: 1.30-3.30). This association existed even after adjusting for potential confounders (rate of people aged 65 over, diabetes prevalence, the mortality rate from cardiovascular disease, and gross domestic product per capita), leading to an adjusted rate ratio of COVID-19 mortality of 2.44, (95% CI: 1.32-4.52) and a COVID-19 incidence of 1.31 (95% CI: 0.97-1.78). After latent infection, Mycobacterium survives in the human body and may continue to stimulate trained immunity. This study suggests a possible mechanism underlying the region-based variation in the COVID-19 impact.

Fig 1. The hypothesis of trained immunity in latent tuberculosis infection.

Fig 2. (a) Tuberculosis (TB) incidence rate of 90 countries in 1990 and (b) TB mortality rate of 28 countries in 1950, according to the BCG vaccination status in 2015.

The dark grey diamond represents the mean value of the corresponding Y-axis values. The bottom and top of the box represent the 25th and 75th percentiles, respectively, and the band near the middle of the box is the 50th percentile (median). ‘Whiskers’ represent the maximum and minimum that extend 1.5 times the interquartile range from the box edges. The vertical dash line represents the mean of Y values across all participants in 1990 and 1950. * Information was obtained from Global Note [12]. ** Information was obtained from References [–16]. The mortality rate of tuberculosis in China was substituted by that of Taiwan. Data of South Korea were estimated based on data collected in 1954. † Information was obtained from the BCG World Atlas [18]. Norway was moved from groups A to B [19]. The P-values shown above the bar were calculated using Bonferroni adjusted t-test. TB, tuberculosis.

Fig 3. Scatterplot of the incidence rate of tuberculosis (TB) in 1990 versus (a) the cumulative mortality rate of COVID-19 and (b) the cumulative incidence rate of COVID-19 on 5 April 2020 according to BCG vaccination status among 90 countries.

*Information was obtained from “Global Note” [12]. **On 5 April 2020. Information was obtained from “Our World in Data” [1]. † Information was obtained from the “BCG World Atlas” [18]. A: The country currently has a universal BCG vaccination programme. B: The country used to recommend BCG vaccination for everyone, but currently, it does not. C: The country never had universal BCG vaccination programmes. Norway was moved from groups A to B [19]. TB, tuberculosis.

Fig 4. Scatterplot of the mortality rate of tuberculosis (TB) in 1950 versus (a) cumulative mortality rate of COVID-19 and (b) the cumulative incidence rate of COVID-19 on 5 April 2020, according to BCG vaccination status among 28 countries.

* Information was obtained from References [–16]. The mortality rate of tuberculosis in China was substituted by that of Taiwan. Data of South Korea were estimated based on data collected in 1954 [17]. ** On 5 April 2020. Information was obtained from “Our World in Data” [1]. † Information was obtained from “the BCG World Atlas” [18]. A: The country currently has a universal BCG vaccination programme. B: The country used to recommend BCG vaccination for everyone, but currently, it does not. C: The country never had universal BCG vaccination programmes. Norway was moved from groups A to B [19]. TB, tuberculosis.