To our knowledge, this is the first report of acute tuberculosis infection superimposed on COVID-19 pneumonia. The association of these two infections has been previously described in 3 patients, but none of them developed an acute tuberculous disease, even because two of them were under treatment with quadruple anti-tuberculosis therapy, which was able to prevent the reactivation of the disease6.
Interestingly, our patient had a history of BCG vaccination, a life attenuated vaccine for tuberculosis that contains a weakened strain of Mycobacterium bovis. It is given to children in their first year of life in several countries, conferring protection against active tuberculosis in about 60% of treated individuals7. BCG increases immune response also to other pathogens, conferring a nonspecific protection against a wide range of bacterial, protozoa and viral infections, throughout the activation of the innate immune system8. Also induces the innate immune system to develop a "memory", which is called "trained immunity", through epigenetic reprogramming of monocytes, macrophages and natural killer cells9,10. Trained immunity induced by BCG may affect different microorganisms other than Mycobacterium tuberculosis. In a recent study carried out in healthy volunteers, vaccination with BCG was shown to reduce viremia in response to the yellow fever vaccine (live attenuated vaccine). This response was associated with epigenetic changes in monocytes which were related to a better antiviral response11. The broad immunomodulatory capacity of BCG on respiratory tract pathogens was supported by a study in Guinea-Bissau showing that BCG reduced the incidence of respiratory syncytial virus infection12, while a similar protective effect of BCG on infections respiratory tract has been reported in elderly subjects in Indonesia13.
It has been hypothesized that trained immunity can exert protective actions also against COVID-19. In countries that do not have a universal vaccination policy against the BCG, such as Italy and the United States, a higher mortality associated with COVID-19 has been reported as compared with nations with long-standing universal vaccination policies with BCG, such as South Korea and Japan14.
BCG confers immunity against mycobacterium tuberculosis for about 10 years although some reports describe a duration of immunity up to 20 years15.
This case suggests that in some individuals the immune response to BCG vaccination may be defective as supported by the findings that results of QuantiFERON assay were indeterminate indicating a condition of non-responsiveness of T lymphocytes to the antigenic stimuli. Moreover, the effect of the BCG vaccination on trained immunity seems to be limited to one year in most cases. Thus, it is conceivable that in our patient, BCG vaccination did not induce a trained immunity capable to provide protection against either tuberculosis infection or COVID-19 infections. Indeed, the patient’s immune system was unable to react to mycobacterium tuberculosis infection by generating a latent infection that subsequently was flared up under a stressful condition induced by viral superinfection with coronavirus-1916.
Clinical trials are underway to investigate the effect of BCG vaccination to protect the elderly individuals from infections, and to explore the possibility to prevent serious COVID-19 infection in healthcare professionals. The current case report argues against the possibility that vaccine with BCG exerts long-lasting protection from Coronavirus-19 infection, and highlights the importance of further research aimed to explore the role of trained immunity induced by BCG vaccination in COVID-19 management17.