Intravesical BCG: Possible Protective Impact Against COVID-19 in NMIBC

Purpose: To determine the incidence of COVID 19 in a series of registered patients with non-muscle invasive bladder cancer, treated by TUR-BT and intravesical BCG. Patients and method: We analysed 127 patients with nonmuscle invasive bladder cancer, in the medium/high risk group, registered between 2001-2020. The patients and families have been contacted by phone. In this interval, 32 patients deceased (cardiovascular pathologies, non-urologic neoplasia, tumour progression), 95 patients are still alive, 24 women and 71 men. The average age was 61.7 (16-86), the majority being over 50, included in the high-risk group for COVID-19. The patients were resected endoscopically and received a cytostatic instillation within the fi rst 6 hours. Reresection of the tumour bed was practiced in pT1patients. The adjuvant treatment with BCG was used in the induction form at each relapse and maintenance (22 patients), respectively. Until 2005, we used the local strain (Cantacuzino Clinical Institute), after that, the strain from Bulgaria (Calgevax) and Medac (Germany). Results: 95 patients are still alive. Tumour relapses were registered in 34 patients. 3 patients registered tumour progression, resolved through radical cystectomy (2) and irradiation. In 3 cases, upper tract urothelial tumours were registered (nephroureterectomy with perimeatic cystectomy). 63 patients underwent induction treatment, while 22 underwent maintenance treatment. Complications: Intolerance to BCG in 4 patients, BCG cystitis in 5 patients, arthritis in 1 patient, septic status in 2 patients. In the analysed batch of patients, no COVID-19 cases have been registered. Conclusions: It appears that the intravesical administration of BCG represents an immunologic booster (confi rmable through PPD), resulting in a reduction of the COVID-19 infection incidence.


ORIGINAL PAPER
Th e patients or families have been contacted by phone. In this interval, 32 patients deceased (cardiovascular pathologies, non-urologic neoplasia, tumour pro gression), 95 patients are still alive, 24 women and 71 men. Th e average age was 61.7 (16-86), the majority being over 50, included in the high-risk group for COVID-19. Th e patients were resected endoscopically and received a cytostatic instillation within the fi rst 6 hours. Reresection of the tumour bed was practiced in pT1 patients. Th e adjuvant treatment with BCG was used in the induction form at every relapse and maintenance (22 patients), respectively. Until 2005, we used the local strain (Cantacuzino Clinical Institute), after that, the strain from Bulgaria (Calgevaz) and Medac (Germany).
Complications: intolerance to BCG in 4 patients, BCG cystitis in 5 patients, arthritis in 1 patient, sepsis in 2 patients.
In the analysed batch of patients, no COVID-19 cases have been registered.

DISCUSSIONS
In adults, BCG vaccination is unable to off er complete protection against pulmonary tuberculosis, with an effi ciency range between 0 and 80% 7-9 , which ex-

BCG -Bacillus Calmette-Guérin COVID-19 -Corona Virus Sars 2 NMIBC -Non muscle invasive bladder cancer PPD -Purifi ed Proteine Derivative TB -Tuberculosis
Bacillus Calmette-Guérin (BCG) has been used for almost a century (since 1921) to prevent the tuberculosis infection. Countries with a national BCG vaccination program for the entire population appear to have a reduced incidence and death rate due to COVID-19. Th is might be explained by the known benefi ts of the immunity acquired through BCG vaccination. In countries were the BCG vaccination program has been paused (Italy, France, Th e Netherlands) the morbidity due to COVID-19 is clearly diff erent from other countries, where the vaccination is commonly practiced (countries from the Eastern Europe).
COVID-19 incidence was 0,8/ millions inhabitants in countries with BCG vaccination programs and 34.8/ millions inhabitants in countries without vaccination programs. Also, the mortality amounted to 0.08 in countries with BCG vaccination and 34,8 in countries without vaccination program 1,2,3,4 .
In the absence of a specifi c vaccination against CO-VID-19, the BCG vaccination based on population may play a role in reducing the impact of such disease 5 .
Th e BCG vaccination decreases the rates of infection with pneumonia, staphylococcus aureus and plays an important role in the protection against viruses, such as infl uenza, yellow fever and herpes 6 .
Regarding patients who benefi t from intravesical BCG therapy for bladder cancer, the potential eff ects of this treatment on COVID-19 are not clear. Th e mechanism of action following the vaccination and intravesical administration diff ers signifi cantly 13,14 . BCG, apart from the local eff ect, appears to have a systemic eff ect with impact on the acquired immunity. Our hypothesis is that the intravesical instillations represent a clear booster inducing the control of the cytokine storm syndrome, involved in COVID-19 morbidity.
A BCG phial used for bladder cancer is 500 times higher than the dose necessary for vaccination, another quantitative element justifying the systemic answer. Approximatively 40% of patients with intravesical BCG induction become positive to the PPD test. Th ere are studies showing that for this reason, patients became immune to tuberculosis, due to BCG inductions. Webinar Ashim Kamat 22 .

CONCLUSIONS
It appears that the intravesical administration of BCG represents an immunologic booster (confi rmable through PPD), resulting in a reduction of the COVID-19 infection incidence. plains why TB is one of the major causes of mortality worldwide. Evidence suggests that the BCG vaccine may off er a long-term protection until 15-20 years 10,11 . Consequently, it was assumed that the protective eff ect of the BCG vaccine is likely to last for 15 years, without reducing the effi cacy of the vaccine within this period 12,13,14,15 .
BCG vaccination during childhood and teenage induces the immunologic memory to tuberculosis antigens, which are still present and measurable in the majority of vaccinated persons 16 . BCG protection may decrease in time since vaccination. A study from Norway, conducted over 41 years on patients between 12-50 years old, shows diff erent protection numbers: an average of 49% effi ciency of the BCG vaccination 18 .
In case of previously vaccinated persons, the recent studies showed that the re-vaccination is safe, well tolerated and is not associated with an increased frequency or severity of the local or systemic reactions, as compared to the primary BCG vaccination 11 . On the other hand, the revaccination might extend the protection duration against tuberculosis infection, off ered by BCG, assertion confi rmed through the tuberculin test.
Studies showed that anti TB antibodies titre (gamma interferon range) objectifi ed through the tuberculin test (PPD) and with role in the protection against tuberculosis infection, evolves extremely diff erent.
In children, it is maintained at 75%, in adults at 50% and may oscillate between 0 and 80%.
In countries at risk, boosters are carried out1-2 in teenagers and at 18 years old (fi rst vaccination is administrated during suckling).
Th ree new clinical trials started recruiting for testing the hypothesis according to which the BCG vaccination may protect against COVID-19 in healthcare workers. Clinical trials in Australia ("BRAVE"; PI Curtis), USA ("BADAS"; PI: Kamat, Dinardo) and the Netherlands (PI: Netea) intend to randomise cumulati-