Acute Tuberculosis pneumonia and COVID-19 in a patient vaccinated with Bacille Calmette-Guérin (BCG)


 COVID-19 is a respiratory tract infection caused by the new coronavirus SARS-COV2, that can be complicated by acute distress respiratory syndrome and multiorgan failure. In light of the high rate of mortality associated with COVID-19, pharmacological and non-pharmacological strategies to prevent the infection are currently being tested. Among non-pharmacological preventive measures, vaccines represent one of the main resources for public health. It has been suggested that Bacille Calmette-Guérin (BCG) vaccine may protect individuals against infection from COVID-19 virus, and two clinical trials addressing this question are underway. Here, we report the case of a 32-year old woman, vaccinated with BCG when she was 1 year old, who was diagnosed with apical tuberculous pneumonia of the right lung along with COVID 19 pneumonia.


Introduction
COVID-19 is a respiratory tract infection caused by the coronavirus SARS-COV2. This virus was rst reported in Wuhan (China) with rapid spread worldwide causing a pandemic 1 with over 300,000 deaths to date 2 . Non-pharmacological strategies have been adopted to prevent infection diffusion, including quarantine, social distancing, and personal protective equipment. COVID-19 clinical features include a spectrum of manifestations, ranging from absence of symptoms, gastro-intestinal disorders, and u-like symptoms including fever, cough, and astenia 3 . In older patients with comorbidities, SARS-COV 2 leads to interstitial pneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and, eventually, death. COVID-19 can be complicated by bacterial superinfections. Antibiotics, immunosuppressants, low weight heparin, and antiviral drugs were used to treat patients 3,4 . Among preventive measures, vaccine represent a major resource for public health. It was suggested that Bacille Calmette-Guérin (BCG) vaccine may protect individuals against COVID-19 infection, and two clinical trials addressing this hypothesis are underway 5 .
Here, we report the case of a 32-old year woman simultaneously affected by COVID-19 and tuberculous pneumonia although she was vaccinated with BCG.

Case Presentation
A 32-years old woman with history of BCG vaccination at one year of age was hospitalized on 29 th March 2020 for high fever, and muscle pain. The patient had a positive epidemiological link for travel to Milan, an area in Italy severely hit by COVID-19, and was treated with amoxicillin/clavulanic acid 1000 mg/BID and paracetamol 1000 mg/day.
The rst nasopharyngeal swab RNA test for SARS-CoV2 genes resulted undetermined, while two subsequent tests were negative. High resolution chest computer tomography (HRCT) revealed parenchymal consolidation of 54 x 25mm, with air bronchogram in context, at the apical segment of the right upper lobe (RUL). Other consolidation areas with the same feature were located in the posterior segment of the same lobe in the parascissural site, in the middle lobe in the paramediastinal site, and contralaterally to the anterior segment of the left upper lobe (LUL) in the subpleural area. Large right pleural effusion leading to atelectasis of the right lower lobe (RLL) was also detected.
Three days later a new nasopharyngeal swab RNA test for SARS-CoV2 genes resulted positive, despite the fact that both IgG and IgM antibodies assays were negative. The patient was transferred to a dedicated COVID-19 unit, where hydroxychloroquine and antiviral therapy with lopinavir/ritonavir were initiated. A rst measurement of the QuantiFERON gave an indeterminate result with the indication to repeat the exam because of insu cient production of gamma interferon upon stimulation with the mitogen. HIV test was negative. Seven days later, Linezolid 500 mg/BID was introduced by replacing the previous antibiotic therapies due to the lack of clinical improvement. Thoracentesis was performed with removal of one liter of citrine yellow liquid. The chemical-physical and cytological analyses of the pleural uid were consistent with exudative effusion, while culture tests for common germs and real-time polymerase chain reaction assay (RT-PCR) of KB were both negative. Due to rapid relapse of large pleural effusion, pleural drainage with pigtail catheter was inserted. A second assay for the QuantiFERON gave an indeterminate result. Due to the uncertain interpretation of chest CT images despite the reduction of pleural effusion, a lung CT biopsy procedure was performed with histological examination showing multiple areas of caseous necrosis delimited by a brous wall, and giant multinucleated cells suggestive for tuberculosis infection. RT-PCR performed on histological samples resulted positive for KB.
The patient repeated three nasopharyngeal swab RNA tests for SARS-CoV2 genes which were negative, while clinical conditions improved. The antiviral therapy was rst stopped followed by the hydroxychloroquine treatment. After discharge, the patient observed a 14-day quarantine period, and due to positive tests for tuberculosis, a combined therapy with isoniazid and rifampicin was introduced.

Discussion
To our knowledge, this is the rst 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 disease 6 .
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 rst year of life in several countries, conferring protection against active tuberculosis in about 60% of treated individuals 7 . BCG increases immune response also to other pathogens, conferring a nonspeci c protection against a wide range of bacterial, protozoa and viral infections, throughout the activation of the innate immune system 8 . Also induces the innate immune system to develop a "memory", which is called "trained immunity", through epigenetic reprogramming of monocytes, macrophages and natural killer cells 9,10 . 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 response 11 . 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 infection 12 , while a similar protective effect of BCG on infections respiratory tract has been reported in elderly subjects in Indonesia 13 .
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 Japan 14 .
BCG confers immunity against mycobacterium tuberculosis for about 10 years although some reports describe a duration of immunity up to 20 years 15 .
This case suggests that in some individuals the immune response to BCG vaccination may be defective as supported by the ndings 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 ared up under a stressful condition induced by viral superinfection with coronavirus-19 16 .
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 longlasting 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 management 17 .

Con icts of interest
None of the authors have any con ict of interest.

Funding
None.

Consent
Written informed consent was obtained by patient for publication of this case report and accompanying images.

Author contribution
Dr Luciani participated in article preparation.

Figure 1
First HRCT showing parenchymal consolidation with air bronchogram at the right apical segment (1A). Other consolidation areas were located in the posterior segment of the RUL and contralaterally (1B and 1C) . Large right pleural effusion leading to atelectasis of RLL was also detected (1D). Second HRCT performed after two weeks showing reduction of parenchymal consolidation (2A, B and C) and resolution of pleural effusion (2D).