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MYCOBACTERIUM BCG PROTECTS NON-MUSCLE INVASIVE BLADDER CANCER PATIENTS FROM SEVERE COVID-19 PROGRESSION

May 2021 Covid-19 Dominique Vrouwenvelder

The Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is an active compound for tuberculosis that has also been described to protect against other respiratory infections. BCG is being used as a standard of care in patients with intermediate-high risk, non-muscle invasive bladder cancer (NMIBC). Héctor Gallegos and colleagues performed a cohort study to establish the role of BCG instillations in the incidence and mortality of coronavirus disease 2019 (COVID-19) in NMIBC patients.1

BACKGROUND

Albeit being a live attenuated vaccine for tuberculosis, BCG is used as a form of immunotherapy in NMIBC patients. Intravesical BCG treatment has shown a 32% reduction in bladder tumor recurrence risk and a 27% reduction in odds of progression in patients with NMIBC.2 It induces a systemic effect with increased levels of IgG and produces various pro-inflammatory cytokines, such as IL-1β, tumor necrosis factor and IL-6, which explains the BCG vaccine’s protective effect against other pathogens.3 BCG has been described to reduce contagiousness, severity and even mortality of other respiratory infections. The association between BCG and infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and subsequent COVID-19, has until now, not yet been fully explored.

Various observational studies, however, have shown that countries with BCG vaccination programs against tuberculosis present lower mortality rates from COVID-19 than countries without vaccination.4 Countries without a vaccination program, such as Italy and USA, have experienced higher mortality associated with COVID-19 than countries with long-standing universal BCG vaccination policies, like South Korea and Japan.5 Ozdemir et al., in April 2020, demonstrated that mean cases per habitants is significantly lower in BCG-vaccinated countries than in BCG-non-vaccinated countries (p < 0,0001).6 Moreover, mean death is significantly lower in BCG-vaccinated countries compared to BCG-non-vaccinated countries (p < 0,0001).

NMIBC WITH BCG

During this study, Gallegos and colleagues observed NMIBC patients receiving intravesical BCG-therapy (induction of maintenance) during the COVID-19 pandemic. By determining the cumulative incidence (cases/total patients) and the case fatality rate (deaths/cases) in NMIBC patients receiving BCG instillation and comparing these data with the national statistics for the same age group, the authors aimed to observe whether intravesical BCG has a protective role in COVID-19 in terms of a less aggressive presentation of the disease.

This cohort included 175 NMIBC-BCG patients of which 43 were diagnosed with COVID-19 during the study period (cumulative incidence = 24,6%). There was no statistically significant difference between COVID-19 and No-COVID patients in age (72,9 years vs. 73,1 years, p=0,899), gender (83,7% vs. 72,0%, p=0,157), and the proportion of patients with maintenance therapy completed (62,8% vs. 75,0%, p=0,170, respectively). One hundred sixty-seven patients (95,4%) had complete induction.

During follow-up, in the group of COVID-infected patients, only one patient died from the disease (case fatality rate = 2,3%), two patients (4,6%) required hospitalization, and two patients (4,6%) had COVID pneumonia. Most patients presented upper respiratory symptoms, compatible with a flu.

In the same period of time, a non-NMIBC control group (age group 70-79 years) had a cumulative incidence of COVID-19 infection of 6,3% (40,629 COVID-19 confirmed cases, 643,423 people in the 70-79 age group), and a case fatality rate of 14% (5,671 deaths due to COVID-19, 40,629 confirmed cases, according official statistics of Chile).7

CONCLUSION AND CLINICAL IMPLICATIONS

According to these results, patients with NMIBC in BCG bladder instillations had lower case fatality rate than same age overall population (2.3% vs. 14%, respectively), but had more cumulative incidence (24,6% to NMIBC and 6,3% to overall population).

Recent evidence suggests that patients with cancer are at higher risk of infection for SARS-CoV-2 and may have poorer outcomes.8 It has been proposed to defer instillations with BCG by at least 3 weeks due to the risk of increased severity in patients with COVID-19.9 However, according to these data, intravesical BCG would be beneficial in case of infection, since it could protect against aggressive presentation of COVID-19 and mortality.

References

  1. Gallegos, H, Rojas, PA, Sepúlveda, F, et al. Protective role of intravesical BCG in COVID-19 severity. BMC Urol. 2021;21(1):50.
  2. Babjuk M, Burger M, Compérat EM, et al. European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ)—2019 update. Eur Urol. 2019;76(5):639-57.
  3. Kleinnijenhuis J, van Crevel R, Netea MG. Trained immunity: consequences for the heterologous effects of BCG vaccination. Trans R Soc Trop Med Hyg. 2015;109(1):29-35.
  4. Miyasaka M. Is BCG vaccination causally related to reduced COVID-19 mortality? EMBO Mol Med. 2020;12(6):e12661.
  5. Redelman-Sidi G. Could BCG be used to protect against COVID-19? Nat Rev Urol. 2020;17(6):316-7.
  6. Ozdemir C, Kucuksezer UC, Tamay ZU. Is BCG vaccination affecting the spread and severity of COVID-19? Allergy. 2020;75(7):1824-7.
  7. Ministerio de ciencias. Reporte epidemiológico de Ministerio de Salud Febrero 2021. https://www.gob.cl/coronavirus/cifrasoficiales/ (Online Resource). Accessed 23 Feb 2021.
  8. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21:335-7.
  9. Lenfant L, Seisen T, Loriot Y, Rouprêt M. Adjustments in the use of intravesical instillations of bacillus Calmette–Guérin for high-risk non-muscle-invasive bladder cancer during the COVID-19 pandemic. Eur Urol. 2020;78(1):1-3.
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