Granulomatous prostatitis after bacille Calmette-Guérin instillation resembles prostate carcinoma:A case report and review of the literature

BACKGROUND Bacille Calmette-Guérin(BCG)instillation is recommended in patients with nonmuscle-invasive bladder cancer who have intermediate-risk and high-risk tumors.However,granulomatous prostatitis is a rare complication induced by BCG instillation,which can easily be misdiagnosed as prostate cancer.Here,we report a case of granulomatous prostatitis that resembled prostate cancer.CASE SUMMARY A 64-year-old Chinese man with bladder cancer received BCG instillation.Three days later,he stopped BCG instillation and received anti-infective therapy due to the urinary tract infection.Three months after BCG restart,he had rising total prostate-specific antigen(PSA)(9.14 ng/mL)and decreasing free PSA/total PSA(0.09).T2-weighted images of magnetic resonance imaging(MRI)showed a 28 mm×20 mm diffuse low signal abnormality in the right peripheral zone,which was markedly hyperintense on high b-value diffusion-weighted MRI and hypointense on apparent diffusion coefficient map images.Considering Prostate Imaging Reporting and Data System score of 5 and possibility of prostate cancer,a prostate biopsy was conducted.Histopathology showed typical features of granulomatous prostatitis.The nucleic acid test for tuberculosis was positive.He was finally diagnosed with BCG-induced granulomatous prostatitis.Thereafter,he stopped BCG instillation and received anti-tuberculosis treatment.During 10 mo follow-up,he had no evidence of tumor recurrence or symptoms of tuberculosis.CONCLUSION Temporarily elevated PSA and high followed by low signal abnormality on diffusion-weighted MRI are important indicators of BCG-induced granulomatous prostatitis.

Repeated inoculations of Mycobacterium bovis Bacille Calmette-Guérin (BCG) are needed to induce a strong humoral immune response against antigens expressed by the bacteria

The cellular immune response elicited by Mycobacterium bovis Bacille Calmette-Guérin (BCG) has been carefully investigated, but the humoral immune response has been partially neglected. BALB/c mice were immunized with BCG strain used to immunize humans. Anti-BCG antibodies, as assayed by ELISA, began to appear in the sera after the third week of immunization and plateaued three weeks after the 8th immunization. The total immunoglobulins (Igs) were purified by caprylic acid method from pooled serum collected after the 8th immunization. Anti-BCG antigen antibodies were detected in the total Igs preparation as well as in IgG, IgM, IgA, IgG1, IgG2a, and IgG2b, but not in the IgG3. Distinct BCG proteins were recognized the IgGs in Western blot analysis. Opsonization of BCG bacilli by the purified Igs potentiated internalization of the bacteria by murine Raw 264.7 macrophages. The intracellular BCG elimination coincided with the induction of NO production, which was more pronounced in cells infected with opsonized BCG compared to those infected with the non-opsonized bacteria. Coincidently, the production of NO was also higher in macrophages infected with opsonized BCG (maximal NO production at 48 h of incubation). The obtained results demonstrate that repeated inoculations of BCG effectively activate the humoral immune response, justifying the use of BCG as a live recombinant vaccine vector to insert genes encoding virulence factors controlled by antibodies.

Debate on Bacille Calmette-Guérin vaccination against COVID-19: Is it worth performing clinical trials?

The non-specific beneficial effects of Bacille Calmette-Guérin(BCG)vaccination suggest that this vaccine might play a role in protecting individuals against severe coronavirus disease 2019(COVID-19).Several studies propose that BCG vaccination may increase the body's immunity,thereby preventing respiratory infections caused by other respiratory pathogens.As the number of deaths due to COVID-19 is increasing rapidly and there is no specific treatment available to date,scientists are evaluating the effectiveness of already approved drugs as therapies against COVID-19,and the results were found to vary widely:from no significant effect being observed to a reduction in the time taken for clinical improvement.This study thus aims to evaluate whether it is worth performing clinical trials to examine the effects of the BCG vaccine on COVID-19.We herein emphasize the need to conduct phase III randomized controlled trials with adequate sample size and quality to investigate the effects of the BCG vaccine on COVID-19.In the event that BCG vaccination provides non-specific protection against COVID-19,administering it could be helpful in controlling the transmission of COVID-19 and other infectious diseases during future pandemics.

Septic Shock after Intravesical BCG Instillation—A Case Report

Bacillus Calmette-Guérin (BCG) is a live attenuated form of Mycobacterium bovis, initially used in medicine as a vaccination agent only. The discovery of its antineoplastic effects in bladder cancer has led to the widespread recognition of BCG intravesical instillation as a therapeutic option. Although sepsis following BCG intravesical instillation is rare, it is nonetheless a dreadful and potentially fatal complication. Therapy usually relies on antituberculous therapy and steroids, alongside with intensive care unit admission. The authors report a case of a 67-year-old male patient who developed septic shock with multiple organ dysfunction after intravesical BCG instillation and review the currently available knowledge concerning the risk factors, diagnosis, management and prevention of BCG sepsis.

BCG Infection after Bladder Cancer Treatment—3 Clinical Case Reports

Immunotherapy with Bacillus Calmette-Guérin (BCG) to treat non-muscle invasive bladder cancer has become an effective and superior alternative to chemotherapy. Intravesical treatment with BCG appears to be relatively safe;however, occasionally BCG infection complicates such treatment. In the present work we describe three patients in whom BCG infection occurred after intravesical BCG therapy. All patients had positive urine culture forMycobacterium tuberculosis complex, using AccuProbe culture identification and then Genotype Mycobacterium MTBC test identified Mycobacterium bovis BCG. The diagnosis is difficult and microbiologic study is usually negative, so high index of suspicion is essential.

Antitumor effects of human interferon-alpha 2b secreted by recombinant bacillus Calmette-Guérin vaccine on bladder cancer cells

Objective:Our objective was to construct a recombinant bacillus Calmette-Guérin vaccine(rBCG) that secretes human interferon-alpha 2b(IFNα-2b) and to study its immunogenicity and in vitro antitumor activity against human bladder cancer cell lines T24 and T5637.Methods:The signal sequence BCG Ag85B and the gene IFNα-2b were amplified from the genome of BCG and human peripheral blood,respectively,by polymerase chain reaction(PCR).The two genes were cloned in Escherichia coli-BCG shuttle-vector pMV261 to obtain a new recombinant plasmid pMV261-Ag85B-IFNα-2b.BCG was transformed with the recombinant plasmid by electroporation and designated rBCG-IFNα-2b.Mononuclear cells were isolated from human peripheral blood(PBMCs) and stimulated with rBCG-IFNα-2b or wild type BCG for 3 d,and then cultured with human bladder cancer cell lines T24 and T5637.Their cytotoxicities were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay.Results:BCG was successfully transformed with the recombinant plasmid pMV261-Ag85B-IFNα-2b by electroporation and the recombinant BCG(rBCG-IFNα-2b) was capable of synthesizing and secreting cytokine IFNα-2b.PBMC proliferation was enhanced significantly by rBCG-IFNα-2b,and the cytotoxicity of PBMCs stimulated by rBCG-IFNα-2b to T24 and T5627 was significantly stronger in comparison to wild type BCG.Conclusions:A recombinant BCG,secreting human IFNα-2b(rBCG-IFNα-2b),was constructed successfully and was superior to control wild type BCG in inducing immune responses and enhancing cytotoxicity to human bladder cancer cell lines T24 and T5637.This suggests that rBCG-IFNα-2b could be a promising agent for bladder cancer patients in terms of possible reductions in both clinical dosage and side effects of BCG immunotherapy.

Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more

Aim:Intravesical Bacille Calmette-Guérin(BCG)is the mainstay adjuvant treatment of non-muscle-invasive bladder cancer.However,one third of the patients on BCG regimen relapse within the first year of treatment.This study aimed at identifying biomarkers to predict response to BCG treatment.Methods:Gene expression was analyzed in blood cells of 58 patients treated with BCG through six consecutive weekly instillations and then at month 3,6,9,and 12.Cytokines tumor necrosis factor(TNF)-α,interleukin(IL)-10,interferon(IFN)-γ,IL-1β,IL-2,IL-4,and IL-6;chemokines CCL2,CCL3,CCL8,CXCL9,and IP-10;and mediators of cytotoxicity CTLA4,Fas-L,Perf,GNLY,NOS2A,and HMOX-1 were analyzed before the 1st and the 6th week instillation and 24 h after to assess fast(within 24 h)and prolonged changes resulting from treatment.Results:BCG instillation led to fast-increased expression of IL-1β,TNF-α,and IL-10 genes.When compared to relapsing patients,patients with no relapses within one year showed significantly lower expression of IL-1βat 1st week and less IFN-γ,HMOX-1,and GNLY at week 6.HMOX-1 and GNLY were independent predictive biomarkers,and values above the cut-off≥110 and≥13.0‰mRNA,respectively,were considered prejudicial factors.Patients with two HMOX-1 and GNLY factors had highest(66.7%)relapsing risk.Conclusion:Assessing immunomodulators’expression in blood allows the establishment of predictive cut-off values and identification of probabilities for patients’relapses after BCG treatment.

Candidate Vaccines against Tuberculosis and the Future of Novel TB Vaccine Research

Introduction: Tuberculosis (TB) continues to be a global health challenge and currently only one licensed vaccine is available. For nearly 100 years, the Bacillus Calmette-Guérin (BCG) vaccine has been in use. While it provides protection against disseminated TB in infants, its protection against adult and adolescent pulmonary tuberculosis (PTB) is variable. This literature review will provide an overview of the clinical status of candidate TB vaccines and discuss the challenges and future development trends of novel TB vaccine research, in combination with a general overview of the Tuberculosis (TB) disease and Mycobacterium tuberculosis itself. Methods: Bibliographic searches were carried out on medical journal databases, publishers, and aggregators. The most used databases were PubMed, NCBI and MDPI. Publications in English on these and other databases relating to novel TB vaccines were included in this review. Results: Currently, there are 12 main vaccine candidates in various phases of clinical trials, they include four protein or adjuvant vaccines, three viral-vectored vaccines, three mycobacterial whole cells or extract vaccines, and one each of the recombinant life and the attenuated Mycobacterium tuberculosis vaccine. Currently, the most likely candidate vaccines are the M72 + AS01E and Vaccae vaccines. M72 + AS01E is a recombinant fusion protein vaccine candidate, clinical trials showed that administering two doses of M72/AS01E was successful in reducing the development of active TB disease with 50% efficacy. Studies have also proven the efficacy of Vaccae (which is currently in phase III clinical trials) as an adjunctive therapy, with it being curative in conjunction with current therapy. Conclusion: Given the morbidity and mortality suffered globally by M. tuberculosis, it is time to realize the seriousness of the situation and accelerate our commitment and investment to the eradication of this infectious disease. With the number of vaccine candidates currently in clinical trials having promising results, it is imperative to continue these studies and accelerate towards phase III licensure trials if we are to achieve the milestone of “End TB Strategy” by 2035. Today, we are witnessing immense progress in both preclinical and clinical TB vaccine research despite disappointing results from some of the clinical efficacy trials like that of MVA85A. We can revisit the design of vaccines and learn from them. It is important not only to recognize and give credit to those that have tested well in human trials, such as M72 + AS01E, but to expedite and improve its efficacy through funding of its research.