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Sharma S, Moudgil A, Grewal J, Khatri P, Sharma V, Premkumar M, Bal A, Banerjee D, Patil AN. Development and validation of BCG vaccine-induced novel granulomatous liver injury preclinical animal model. Animal Model Exp Med 2025; 8:930-938. [PMID: 39968771 DOI: 10.1002/ame2.12559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/06/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Developing a granulomatous liver injury preclinical model may pave the way to understanding hepatic-TB (tuberculosis) and autoimmune granulomatous liver diseases. Antitubercular (ATT) and other drugs' metabolism in the presence of a specific type of liver injury is not well understood. The present study aimed to establish a preclinical model of granulomatous hepatitis by using the BCG (Bacillus Calmette-Guérin) vaccine, further studying it in the presence of ATT dosing, and analyze the pharmacokinetics of isoniazid, rifampicin, and their respective primary metabolites. METHODS We used 56 rats in seven equal groups. Group I functioned as a normal control (NC) receiving normal saline only. Groups II-IV received intravenous injections of low-, medium-, and high-dose BCG vaccine daily for 21 days. Groups V, VI, and VII received isoniazid (H) alone, rifampicin (R) alone, and isoniazid + rifampicin(HR) for a subsequent 15 days in addition to high dose BCG for the first 21 days, respectively. Liver function tests (LFT) were monitored on days 0, 21, 28, and 36. Rats were sacrificed later for oxidative stress and histopathological examination. RESULTS The study observed BCG dose-specific LFT derangements in groups II-IV compared to group I on day 21 (p < 0.05). Isoniazid, rifampicin, and combination intervention groups demonstrated normalization of the BCG-led LFT changes. Histology and oxidative stress parameters confirmed model development and biochemical changes. Isoniazid area under the curve (AUC) showed a reduction of 16.9% in BCG + HR group in comparison to the BCG + H group (p = 0.01). Des-acetyl-rifampicin AUC and maximum-concentration value demonstrated a significant rise in BCG + HR group in comparison to the BCG + R group (p = 0.001). CONCLUSION A novel preclinical model of granulomatous liver injury was developed using the BCG vaccine strain and validated with ATT response.
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Affiliation(s)
- Swati Sharma
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Abhishek Moudgil
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Jyoti Grewal
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Pankaj Khatri
- Department of Clinical Medicine and Medical Oncology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Amanjit Bal
- Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Dibyajyoti Banerjee
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Amol N Patil
- Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Deane K, Rodriguez P, Valentine D, Hathaway D, Hosseinzadeh F. Disseminated Mycobacterial Infection as a Sequelae of Bladder Biopsy. Cureus 2021; 13:e18711. [PMID: 34790466 PMCID: PMC8582617 DOI: 10.7759/cureus.18711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2021] [Indexed: 11/05/2022] Open
Abstract
Disseminated Mycobacterium infections have been commonly documented in the immunocompromised and patients who undergo treatment for non-muscle invasive bladder cancer with the Bacillus Calmette-Guerin vaccine; however, it was unique to our patient's case that she had no record of receiving vaccination in her native country, was immunocompetent, and had exposure to bovine livestock before immigrating to the United States. A 57-year-old woman with no significant medical history presented with complaints of abdominal pains and yellowing of her skin. Laboratory workup was consistent with cholestatic hepatitis. One month prior to presentation, she underwent biopsy and culture of an unspecified bladder mass, which turned out to be positive for Mycobacterium bovis. All antituberculosis medications were discontinued, without improvement of her symptoms and hepatic function tests. Subsequent liver biopsy showed the presence of granulomas with acid-fast bacilli; hence, disseminated infection was highly suspected. Multiple sputum cultures and quantiferon tests were negative, and other diagnostic tests were unremarkable. Initiation of appropriate antibiotics resulted in marked symptomatic improvement and gradual normalization of hepatic function parameters. Disseminated mycobacterial infection may present differently in patients; however, it is important to note that the source of primary infection may vary. Prompt diagnosis and treatment of these pathogens may lead to improved outcomes.
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Affiliation(s)
- Kitson Deane
- Medicine, Woodhull Medical Center, Brooklyn, USA
| | | | | | - Donald Hathaway
- Emergency Medicine, Lincoln Medical and Mental Health Center, Bronx, USA
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Oliveira AA, Morais J, Ribeiro J, Gouveia PF. Systemic infection following intravesical therapy with BCG. BMJ Case Rep 2021; 14:e243641. [PMID: 34753717 PMCID: PMC8578936 DOI: 10.1136/bcr-2021-243641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2021] [Indexed: 11/03/2022] Open
Abstract
Immunotherapy with BCG is an effective and widely used treatment for non-muscle-invasive bladder cancer. BCG sepsis is a rare but life-threatening and frequently not a straightforward complication of this treatment; in cases with a high index of suspicion, anti-bacillary treatment should not wait for laboratory confirmation and be instituted immediately. We report a severe case of BCG sepsis, in which timely diagnosis and initiation of antituberculosis agents enabled a full recovery.
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Affiliation(s)
| | - Joana Morais
- Department of Internal Medicine, Hospital de Braga, Braga, Portugal
| | - Jorge Ribeiro
- Department of Urology, Hospital de Braga, Braga, Portugal
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Granulomatous Hepatitis Following Intra-Vesical Instillation of Bacillus Calmette-Guérin for Treatment of Bladder Cancer. Infect Dis Rep 2021; 13:611-618. [PMID: 34287340 PMCID: PMC8293128 DOI: 10.3390/idr13030057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/25/2021] [Accepted: 06/28/2021] [Indexed: 11/17/2022] Open
Abstract
Intra-vesical instillation of bacillus Calmette–Guérin (BCG) is an important treatment modality of superficial bladder cancer. It is usually well tolerated, although some adverse reactions can occur. One possible yet rare complication is granulomatous hepatitis, that is thought to be caused either by BCG infection or a hypersensitivity reaction to the bacillus. We present a case of a 79-year-old apparently immunocompetent patient who developed granulomatous hepatitis a few months after BCG administration for bladder cancer immunotherapy. It is important to notice that acid-fast smears and cultures are often negative, and these should not exclude diagnosis nor delay treatment. Our case highlights the importance of clinical suspicion and prompt initiation of appropriate treatment.
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Siddique AS, Siddique O, Einstein M, Urtasun-Sotil E, Ligato S. Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience. World J Hepatol 2020; 12:207-219. [PMID: 32547688 PMCID: PMC7280859 DOI: 10.4254/wjh.v12.i5.207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/26/2020] [Accepted: 05/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Drug-induced liver injury (DILI) and herbal/dietary supplements (HDS) related liver injury present unique diagnostic challenges. Collaboration between the clinician and the pathologist is required for an accurate diagnosis and management. AIM To report our experience on the clinical-pathological findings of hepatic injury caused by drugs/HDS. METHODS A retrospective review of clinically proven cases of DILI/HDS who presented to our institution from January 1, 2013 to December 31, 2017 was performed. Slides were reviewed for histopathological patterns of injury and correlated with the causative agent. Out of 600 patients presenting with unexplained rise in liver enzymes undergoing biopsy, 107 were suspected to have DILI/HDS. Of these, 53 had a directly linked exposure to drug/herbal supplements. Fifteen patients were excluded for concurrent known liver disease. Thirty-eight patients with clinically proven DILI/HDS were finally included. RESULTS Thirty-eight cases of DILI/HDS with a male:female of 1:1.5 and mean age of 51 ± 3 years were identified. DILI was identified in 84.2% cases while HDS injury in 15.8%. Acute hepatitis (42.1%) was the most common pattern of injury while granulomatous hepatitis (2.6%) was the least common. We found one case of acute-cholestasis due to rivaroxaban and two cases of cholestatic-hepatitis due to rizatriptan and trimethobenzamide-hydrochloride that, to the best of our knowledge, have not been previously reported. One case of steatohepatitis due to trimethoprim-sulfamethoxazole and three unusual cases of cholestatic-hepatitis with bile duct injury and steatosis due to dronedarone, C4-Extreme and hydroxycut, were also seen. Of our cohort, 81.6% of the patients fared well with discontinuation of drug and 18.4% underwent transplant; of which 42.9% were deceased. CONCLUSION We describe the clinical findings, histopathological patterns of injury and clinical outcomes caused by drugs. In particular, we report a few previously unreported/ rarely observed clinical and histopathological patterns of hepatic injury.
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Affiliation(s)
- Ayesha S Siddique
- Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT 06102, United States.
| | - Osama Siddique
- Department of Gastroenterology and Hepatology, Hartford Hospital, University of Connecticut, Hartford, CT 06102, United States
| | - Michael Einstein
- Department of Gastroenterology and Hepatology, Hartford Hospital, University of Connecticut, Hartford, CT 06102, United States
| | - Eva Urtasun-Sotil
- Department of Gastroenterology and Hepatology, Hartford Hospital, University of Connecticut, Hartford, CT 06102, United States
| | - Saverio Ligato
- Department of Pathology and Laboratory Medicine, Hartford Hospital, Hartford, CT 06102, United States
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Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience. World J Hepatol 2020. [DOI: 10.4254/wjh.v12.i5.197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Guallar-Garrido S, Campo-Pérez V, Sánchez-Chardi A, Luquin M, Julián E. Each Mycobacterium Requires a Specific Culture Medium Composition for Triggering an Optimized Immunomodulatory and Antitumoral Effect. Microorganisms 2020; 8:microorganisms8050734. [PMID: 32423030 PMCID: PMC7284523 DOI: 10.3390/microorganisms8050734] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/01/2020] [Accepted: 05/13/2020] [Indexed: 11/30/2022] Open
Abstract
Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the first treatment option for non-muscle-invasive bladder cancer (BC) patients. In research laboratories, M. bovis BCG is mainly grown in commercially available media supplemented with animal-derived agents that favor its growth, while biomass production for patient treatment is performed in Sauton medium which lacks animal-derived components. However, there is not a standardized formulation of Sauton medium, which could affect mycobacterial characteristics. Here, the impact of culture composition on the immunomodulatory and antitumor capacity of M. bovis BCG and Mycolicibacterium brumae, recently described as efficacious for BC treatment, has been addressed. Both mycobacteria grown in Middlebrook and different Sauton formulations, differing in the source of nitrogen and amount of carbon source, were studied. Our results indicate the relevance of culture medium composition on the antitumor effect triggered by mycobacteria, indicating that the most productive culture medium is not necessarily the formulation that provides the most favorable immunomodulatory profile and the highest capacity to inhibit BC cell growth. Strikingly, each mycobacterial species requires a specific culture medium composition to provide the best profile as an immunotherapeutic agent for BC treatment. Our results highlight the relevance of meticulousness in mycobacteria production, providing insight into the application of these bacteria in BC research.
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Affiliation(s)
- Sandra Guallar-Garrido
- Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.G.-G.); (V.C.-P.); (M.L.)
| | - Víctor Campo-Pérez
- Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.G.-G.); (V.C.-P.); (M.L.)
- Bacterial Infections and Antimicrobial Therapies group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Alejandro Sánchez-Chardi
- Servei de Microscòpia, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain;
- Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Marina Luquin
- Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.G.-G.); (V.C.-P.); (M.L.)
| | - Esther Julián
- Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.G.-G.); (V.C.-P.); (M.L.)
- Correspondence: ; Tel.: +34-93-5814870
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Guallar-Garrido S, Julián E. Bacillus Calmette-Guérin (BCG) Therapy for Bladder Cancer: An Update. Immunotargets Ther 2020; 9:1-11. [PMID: 32104666 PMCID: PMC7025668 DOI: 10.2147/itt.s202006] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 01/28/2020] [Indexed: 01/02/2023] Open
Abstract
Physicians treating patients affected by nonmuscle-invasive bladder cancer (NMIBC) have been in shock during the last six years since manufacturing restrictions on the production of the first-option medicine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), have resulted in worldwide shortages. This shortage of BCG has led to a rethinking of the established treatment guidelines for the rationing of the administration of BCG. Some possible schedule modifications consist of a decrease in the length of maintenance treatment, a reduction in the dose of BCG in intravesical instillations or the use of different BCG substrains. All these strategies have been considered valuable in times of BCG shortage. In addition, the lack of availability of BCG has also led to the general recognition of the need to find new treatment options for these patients so that they are not dependent on a single treatment. Few alternatives are committed to definitively replacing BCG intravesical instillations, but several options are being evaluated to improve its efficacy or to combine it with other chemotherapeutic or immunotherapeutic options that can also improve its effect. In this article, we review the current state of the treatment with BCG in terms of all of the aforementioned aspects.
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Affiliation(s)
- Sandra Guallar-Garrido
- Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain
| | - Esther Julián
- Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain
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Larsen ES, Joensen UN, Poulsen AM, Goletti D, Johansen IS. Bacillus Calmette-Guérin immunotherapy for bladder cancer: a review of immunological aspects, clinical effects and BCG infections. APMIS 2020; 128:92-103. [PMID: 31755155 DOI: 10.1111/apm.13011] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 11/10/2019] [Indexed: 12/29/2022]
Abstract
Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer has been used since 1976 when the first evidence of its ability to lower recurrence and progression rates was published. Today, BCG immunotherapy is the choice of care for high-grade non-muscle invasive bladder cancer (NMIBC) after transurethral resection. This article presents indications and procedure of BCG instillations, and outlines the effects on recurrence and progression of NMIBC. The BCG-induced immunity in NMIBC is not yet fully understood. Animal studies point towards BCG inducing specific tumour immunity. We describe the current knowledge of how this immunity is induced, from internalization of BCG bacilli in urothelial cells, to cytokine- and chemokine-mediated recruitment of neutrophils, monocytes, macrophages, T cells, B cells and natural killer cells. In addition, we describe the process of trained immunity, the non-specific protective effects of BCG. Recent studies also indicate that dysbiosis of the urinary microbiome may cause lower urinary tract dysfunction. Side effects of BCG bladder instillations range from common, mild and transient symptoms, such as dysuria and flu-like symptoms, to more severe and rarely occurring life-threatening complications. We review the literature and give an overview of reported incidences and management of BCG infections after intravesical instillation.
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Affiliation(s)
| | - Ulla Nordström Joensen
- Department of Urology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Alicia Martin Poulsen
- Department of Urology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Delia Goletti
- Translational Research Unit, Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS L. Spallanzani, Rome, Italy
| | - Isik Somuncu Johansen
- Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Mycobacterial Centre for Research Southern Denmark - MyCRESD, Odense, Denmark
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Liu Y, Lu J, Huang Y, Ma L. Clinical Spectrum of Complications Induced by Intravesical Immunotherapy of Bacillus Calmette-Guérin for Bladder Cancer. JOURNAL OF ONCOLOGY 2019; 2019:6230409. [PMID: 30984262 PMCID: PMC6431507 DOI: 10.1155/2019/6230409] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 01/24/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Abstract
Because of its proven efficacy, intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is an important treatment for nonmuscle invasive bladder cancer at high risk of recurrence or progression. However, approximately 8% of patients have to stop BCG instillation as a result of its complications. Complications induced by BCG therapy can have a variety of clinical manifestations. These adverse reactions may occur in conjunction with BCG instillation or may not develop until months or years after BCG cessation. An essential step in the management complications arising from BCG is early establishment of diagnosis, particularly for distant, disseminated, and obscure infections. Therefore we reviewed the literature on the potential complications after intravesical BCG immunotherapy for bladder cancer and provide an overview on the incidence, diagnosis, and treatment modality of genitourinary and systemic BCG-induced complications.
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Affiliation(s)
- Yuqing Liu
- Urology Department, Peking University Third Hospital, Beijing, China
| | - Jian Lu
- Urology Department, Peking University Third Hospital, Beijing, China
| | - Yi Huang
- Urology Department, Peking University Third Hospital, Beijing, China
| | - Lulin Ma
- Urology Department, Peking University Third Hospital, Beijing, China
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