A total of 225 countries were eligible to be included in the analysis. Tuberculosis and population-level data were available for 214 countries. COVID-19 and BCG coverage data were available for 180 and 175 countries, respectively.
Distribution of COVID-19 cases and deaths by income level of countries
The COVID-19 cases were significantly different between countries of different income levels (Kruskal-Wallis test, p<0.0001) (Figure 1). All differences except that between low and lower-middle-income countries were statistically significant (Mann-Whitney test, p<0.0005 for all). Similarly, COVID-19 deaths were significantly different between countries in different income levels (Kruskal-Wallis test, p<0.0001) (Figure 2). All differences except that between low and lower-middle-income countries were statistically significant (Mann-Whitney test, p<0.005 for all). There was no statistically significant difference in the case fatality rate and the level of income (Figure 3).
Relationship of COVID-19 cases and deaths with immunity from BCG at country level
The BCG coverage was inversely correlated with the incidence of TB (rs==-0.164, p=0.03). However, it showed no significant correlation with the cases or deaths per 100,000 from COVID-19 (p=0.43 and 0.247, respectively). Instead, as shown in Table 1, the countrywide TB incidence had a strong inverse correlation with the COVID-19 cases per 100,000 population (rs=-0.743, p=0.0001) and COVID-19 deaths per 100,000 population (rs=-0.611, p=0.0001). Similar correlations were observed for both pulmonary (both bacteriologically confirmed and clinically confirmed) and extra-pulmonary TB. The association between COVID-19 and TB was strongest when comparing the TB incidence in patients over 65-years, in which both COVID-19 cases per 100,000 population (rs=-0.785, p=0.0001) and COVID-19 deaths per 100,000 population (rs=-0.647, p=0.0001) showed significant inverse correlations. The correlation between the younger age group (15-64 years) was also significant, but less strong (Cases (rs=-0.742, p=0.0001) and deaths (rs=-0.621, p=0.0001)).
We further assessed the relationship between the incidence of TB and COVID-19 cases and deaths stratified by countries with BCG coverage <95% vs. ≥95% (Table 1). All correlations with COVID-19 deaths were higher in countries with BCG coverage <95% than ≥95%. Similar observations were observed for COVID-19 cases except for three parameters, which were marginally higher in countries with higher BCG coverage. The Case Fatality Rate (CFR) showed a weak inverse correlation with TB deaths in countries (rs=-0.208, p=0.006).
Table 1 The correlations of COVID-19 cases and death with BCG coverage and incidence of TB
|
COVID-19 cases per 100,000 population
|
COVID-19 deaths per 100,000 population
|
Cases
|
Total population
|
BCG coverage <95%
|
BCG coverage ≥95%
|
Total population
|
BCG coverage <95%
|
BCG coverage ≥95%
|
BCG coverage
|
0.136 (p=0.091)
|
0-.064 (p=0.588)
|
0.176 (p=0.111)
|
0.061 (p=0.447)
|
-0.057 (p=0.629)
|
0.227 (p=0.038)
|
Pulmonary TB – Bacteriologically confirmed
|
-0.687 (p<0.0005)
|
-0.556 (p<0.0005)
|
-0.591 (p<0.0005)
|
-0.570 (p<0.0005)
|
-0.574 (p<0.0005)
|
-0.333 (p=0.002)
|
Pulmonary TB – Clinically confirmed
|
-0.699 (p<0.0005)
|
-0.674 (p<0.0005)
|
-0.567 (p<0.0005)
|
-0.516 (p<0.0005)
|
-0.639 (p<0.0005)
|
-0.246 (p=0.0026)
|
Extra-pulmonary TB
|
-0.652 (p<0.0005)
|
-0.626 (p<0.0005)
|
-0.537 (p<0.0005)
|
-0.541 (p<0.0005)
|
-0.607 (p<0.0005)
|
-0.314 (p=0.004)
|
Overall TB incidence
|
-0.743 (p<0.0005)
|
-0.644 (p<0.0005)
|
-0.663 (p<0.0005)
|
-0.611 (p<0.0005)
|
-0.645 (p<0.0005)
|
-0.379 (p<0.0005)
|
TB incidence in 15-64-year group
|
-0.742 (p<0.0005)
|
-0.649 (p<0.0005)
|
-0.677 (p<0.0005)
|
-0.621 (p<0.0005)
|
-0.646 (p<0.0005)
|
-0.405 (p<0.0005)
|
TB incidence in >65-year group
|
-0.785 (p<0.0005)
|
-0.701 (p<0.0005)
|
-0.697 (p<0.0005)
|
-0.647 (p<0.0005)
|
-0.704 (p<0.0005)
|
-0.382 (p<0.0005)
|
BCG - Bacillus Calmette–Guérin vaccine
TB - Tuberculosis
When stratified according to income level, the BCG coverage showed a statistically significant moderate inverse correlation with both cases (rs=-0.545, p<0.0005) and deaths (rs= -0.564, p<0.0005) within the high-income group countries. No other income group showed a statistically significant correlation with BCG coverage. The correlation of COVID-19 cases and deaths with the incidence of TB in the population over 65-years progressively increased according to the income status of the country (Figures 4 & 5).
Multivariate analysis
Regarding the linear regression performed for COVID-19 cases per 100,000 population, the model was statistically significant (F (3,62) = 27.028, p<0.0005) and explained 54.6% of the variance observed. It identified a statistically significant effect on the caseload from the income status of a country; and a significant inverse effect from the presence of BCG vaccination policy. The WHO estimates of the BCG coverage of the population were not statistically significant (Table 2).
Table 2 Linear regression analysis for COVID-19 cases per 100,000 population
Covariate
|
Regression coefficient
|
Significance
|
(Constant)
|
68.647
|
0.001
|
WHO estimates of BCG coverage
|
-0.331
|
0.085
|
Income
|
11.358
|
0.001
|
Current BCG policy status
|
-58.300
|
0.000
|
WHO – World Health Organization
BCG - Bacillus Calmette–Guérin vaccine
With regard to the linear regression performed for COVID-19 deaths per 100,000 population, the model was statistically significant (F(3,144)= 43.694, p<0.0005) and explained 46.6% of the variance observed. It identified a statistically significant effect on deaths, from the incidence of TB in >65-year old population, and an inverse effect from both the presence of BCG vaccination policy and WHO estimates of the BCG coverage of the population (Table 3).
Table 3 Linear regression analysis for COVID-19 deaths per 100,000 population
Covariate
|
Regression coefficient
|
Significance
|
(Constant)
|
8.633
|
0.000
|
TB incidence in 65 plus per 100,000
|
0.001
|
0.017
|
Current BCG policy status
|
-3.100
|
0.000
|
WHO estimates of BCG coverage
|
-0.054
|
0.000
|
TB - Tuberculosis
BCG - Bacillus Calmette–Guérin vaccine
WHO – World Health Organization
The linear regression analysis using the case fatality rate as the dependent variable did not provide a statistically significant result.