Assistance of next-generation sequencing for diagnosis of disseminated Bacillus Calmette-Guerin disease with X-SCID in an infant: a case report and literature review.

Bacille Calmette-Guérin (BCG) is a live strain of Mycobacterium bovis (M.bovis) for use as an attenuated vaccine to prevent tuberculosis (TB) infection, while it could also lead to an infection in immunodeficient patients. M.bovis could infect patients with immunodeficiency via BCG vaccination. Disseminated BCG disease (BCGosis) is extremely rare and has a high mortality rate. This article presents a case of a 3-month-old patient with disseminated BCG infection who was initially diagnosed with hemophagocytic syndrome (HPS) and eventually found to have X-linked severe combined immunodeficiency (X-SCID). M.bovis and its drug resistance genes were identified by metagenomics next-generation sequencing (mNGS) combined with targeted next-generation sequencing (tNGS) in blood and cerebrospinal fluid. Whole exome sequencing (WES) revealed a pathogenic variant in the common γ-chain gene (IL2RG), confirming X-SCID. Finally, antituberculosis therapy and umbilical cord blood transplantation were given to the patient. He was successfully cured of BCGosis, and his immune function was restored. The mNGS combined with the tNGS provided effective methods for diagnosing rare BCG infections in children. Their combined application significantly improved the sensitivity and specificity of the detection of M.bovis.

Metagenomic sequencing expedites diagnosis of disseminated BCG in an infant with BRAFV600E mutation.

INTRODUCTION: Disseminated bacillus Calmette-Guérin (BCG) disease is a rare but serious BCG complication in children. Early diagnosis and timely interventions are essential to improve prognosis. However, its manifestations can closely mimic those of Langerhans cell histiocytosis (LCH), which usually leads to a high rate of misdiagnoses. Herein we report the first case of successful application of biopsy tissue metagenomic next-generation sequencing (mNGS) in the differential diagnosis of disseminated BCG disease and LCH. CASE STUDY: A 5-month-old female infant was transferred to our center for the treatment of paroxysmal cough, intermittent hematochezia and trunk rash. Examination on admission showed moderate anemia, erythropenia, thrombocytopenia and hepatosplenomegaly. The immunohistochemistry of her intestinal biopsy samples showed CD1a (+) and Langerin (+). Genetic testing of both peripheral blood and bone marrow samples suggested BRAFV600E mutation. Hence, she was initially diagnosed with LCH. However, no improvement was observed after a course of systemic chemotherapy. The left axillary lymph node and colonic mucosal biopsy specimens were sent for mNGS which resulted in sequence reads of Mycobacterium bovis-BCG. Triple antimycobacterial therapy was started according to the diagnosis. RESULTS: The diagnosis of this case was corrected as disseminated BCG disease by mNGS. Currently, she is doing well clinically and continues to follow-up at our outpatient clinic. CONCLUSIONS: This case suggests that mNGS is a valuable tool in the differential diagnosis of disseminated BCG disease and LCH, which can improve the early diagnosis rate of disseminated BCG disease.

[Guillain-Barré syndrome caused by intravesical instillation of Bacillus Calmette-Guérin]. / Bacillus Calmette­Guérin intravesicalis instillációja által okozott Guillain­Barré-szindróma.

Introduction - Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy. In the vast majority of patients, 1-4 weeks before the onset of GBS-related symptoms, an event such as upper respiratory tract or gastrointestinal tract infection, surgical intervention or vaccination is present. To the best of our knowledge, this is the first case of GBS that occurred after intravesical Bacillus Calmette-Guérin (BCG) therapy in the absence of tuberculosis or any other infection in the English literature.
Case report – A 65-year-old male patient, who had no systemic disorders except hypertension and coronary artery disease, underwent transurethral resection of a bladder tumour further to imaging studies investigating macroscopic haematuria. A pathologic examination revealed a non-muscle-invasive high-grade (pT1HG) transitional cell carcinoma. Immediately after the fourth cycle of intravesical BCG, which was administered 2 months after surgery, the patient experienced numbness and weakness in his lower and upper extremities, respectively. There were no signs or symptoms related to an acute cranial pathology or infectious disease. Nerve conduction studies, which were carried out on the 7th day after the onset of the neurologic symptoms, revealed a demyelinating sensorimotor polyneuropathy with mild secondary axonal damage in upper and lower limbs with a sural sparing pattern.
Conclusion - Without tuberculosis infection, GBS can occur secondary to increased immune response and antibodies triggered by intravesical BCG therapy. However, considering the worldwide use of BCG vaccination and thousands of intravesical BCG therapies, this is a very rare adverse effect. 

Granulomatous myocarditis arising from intravesical Bacillus Calmette-Guérin therapy leading to death diagnosed by postmortem examination: a case report.

BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) is used as a standard adjuvant therapy for non-muscle invasive urothelial cancer. Most patients tolerate the treatment well, with mild side effects. Systemic complications are extremely rare, occur due to BCG dissemination and are associated with immunocompromised state and urothelial breach. CASE PRESENTATION: We present a case of a 78-year-old male, a former smoker, with history of non-muscle invasive urothelial carcinoma status post partial resection followed by intravesical BCG therapy. An autopsy was performed due to the sudden nature of his death. Autopsy showed multiple necrotizing granulomas in the brain, atrium, ventricles, lungs, kidneys, and urinary bladder. Stains for acid-fast bacilli and fungi were negative. In addition, bilateral lungs showed evidence of bronchopneumonia secondary to cytomegalovirus. CONCLUSION: Granulomatous myocarditis arising from BCG therapy is extremely rare. Our patient with urothelial cancer treated with BCG developed multiorgan granulomas, most likely due to a hypersensitivity reaction to intravesical BCG. Arrhythmia induced by granulomatous myocarditis was the cause of his death. Although there have been few cases of systemic BCG-osis causing fatal sepsis leading to death, a cardiac cause of death is unique.

The spectrum of cytological findings in patients with BCG lymphadenitis: A series of 13 cases.

CONTEXT: Bacillus Calmette-Guérin (BCG) vaccine has been used to prevent tuberculosis and/or its severe complications for long. BCG lymphadenitis is a common complication of the vaccine, which is sometimes subjected to cytological examination. The aim of the study is to describe the cytological findings of BCG lymphadenitis. SETTINGS: The study was conducted in a tertiary care hospital in the western part of India from January 2021 to December 2022. DESIGN: The study was performed on archived material of all patients who were referred to the fine needle aspiration clinic for cytology examination. Clinical and pathological data of cases were retrieved, and cases of BCG lymphadenitis were selected in the study based on these data. Slides of cases were retrieved, and cytological findings were studied. MATERIALS AND METHODS: Papanicolaou, Giemsa, and Hematoxylin & eosin-stained smears, as well as Ziehl-Neelson stain (Z.N. stain) smears of all BCG lymphadenitis cases, were retrieved. Cases were reviewed for individual cytological features and overall cytological diagnostic categories. Z.N. stain smears were evaluated for acid-fast bacilli. RESULTS AND CONCLUSIONS: Diagnostic categories observed in BCG lymphadenitis include suppurative lymphadenitis/abscess (15 %), necrotizing lymphadenitis (23 %), necrotizing granulomatous lymphadenitis (46 %), suppurative granulomatous lymphadenitis (8 %), non-necrotizing granulomatous lymphadenitis (8 %). Acid-fast bacilli were detected by Z.N. stain in 8 cases (62 %). The cytological findings of BCG lymphadenitis closely overlap with those of tuberculous lymphadenitis. So, clinical context is very important while reporting isolated axillary lymphadenopathy, specifically in recently vaccinated infants, to avoid misdiagnosis as tuberculous lymphadenitis.

Erdafitinib in BCG-treated high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette-Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. PATIENTS AND METHODS: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. RESULTS: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2 : 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. CONCLUSIONS: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.

Device-assisted intravesical chemotherapy versus bacillus Calmette-Guerin for intermediate or high-risk non-muscle invasive bladder cancer: a systematic reviewer and meta-analysis.

PURPOSE: To investigate the effectiveness and safety of device-assisted intravesical chemotherapy compared to Bacillus Calmette-Guerin (BCG) in the treatment of patients with intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). METHODS: In February 2023, a systematic search was conducted on the PubMed, Cochrane, and Embase databases. Following the PRISMA guidelines, a systematic review and meta-analysis of the primary outcomes of interest were performed. The review was prospectively registered on PROSPERO under the registration number CRD42023398559. RESULTS: A total of 10 studies involving 1160 patients were included. The results of the meta-analysis showed that compared to BCG, device-assisted chemotherapy had a lower recurrence rate (OR: 0.63, 95% CI: 0.48-0.84, p = 0.001), longer recurrence-free survival (OR: 0.64, 95% CI: 0.47-0.88, p = 0.006), and lower incidence of fever (OR: 0.18, 95% CI: 0.08-0.44, p = 0.0002). However, no significant differences were observed between the two groups in terms of progression, overall survival, progression-free survival, disease-free survival, overall adverse events, serious adverse events, hematuria, allergy, and general discomfort. Subgroup analysis revealed that neither chemohyperthermia (CHT) nor electromotive drug administration (EMDA) showed statistically significant differences in oncological outcomes compared to BCG. Regarding adverse events, both CHT and EMDA groups showed lower rates of fever compared to the BCG group (OR: 0.26, 95% CI: 0.10-0.67, p = 0.005, and OR: 0.14, 95% CI: 0.05-0.37, p < 0.0001, respectively). No significant differences were observed in the remaining adverse events between either the CHT or EMDA group and the BCG group. CONCLUSION: Device-assisted intravesical chemotherapy appears to be a safe and viable alternative to BCG for patients with intermediate and high-risk NMIBC, showing comparable oncological outcomes and adverse events.

Reactive arthritis as a rare complication of intravesical bacillus Calmette-Guérin treatment: Report of two cases.

Intravesical bacillus Calmette-Guérin (BCG) immunotherapy is recommended for non-muscle-invasive bladder cancer after transurethral resection. BCG-associated musculoskeletal adverse events are rare. We report two cases of BCG reactive arthritis that were unusually severe and refractory. These describe two male patients who presented with polyarthritis after BCG exposure. Ultrasonography-guided glucocorticoid injections, high-dose systemic glucocorticoids and the institution of sulfasalazine were required for achievement of remission. Bacillus Calmette-Guérin reactive arthritis can present as polyarthritis of small and medium joints or as mono-oligoarthritis of asymmetrical ankles and knees, frequently associated with tenosynovitis and enthesitis. The mechanism by which BCG promotes arthralgia and arthritis is poorly understood. The most well-accepted theory is that the BCG antigens migrate to different peripheral tissues, including the joints. There is also a lack of knowledge regarding risk factors, with possible genetic factors playing a role. As the two presented cases show, BCG-induced reactive arthritis should be considered in the differential diagnosis of arthritis and refractory tenosynovitis in BCG-exposed patients.

[Thoracic Endovascular Aortic Repair for Mycotic Thoracic Aortic Aneurysm After BCG Intravesical Therapy].

Bacille Calmette-Guérin( BCG) intravesical therapy is an effective and safe treatment for bladder cancer; however, mycotic aneurysms have been reported as a rare complication. Case 1:A 64-year-old man with a history of BCG intravesical therapy underwent emergent thoracic endovascular aortic repair (TEVAR) for a ruptured thoracic aortic aneurysm (TAA). He was diagnosed with BCG infection by hemosputum specimen culture five months later;then, antituberculous therapy was initiated. However, his follow-up computed tomography scan revealed stent-graft infection and new aneurysm formation. Therefore, we performed a repeated TEVAR with abdominal 4-vessel debranching. There was no recurrence of infection for six years while continuing postoperative antituberculous therapy. Case 2:A 72-year-old man who had undergone BCG intravesical therapy underwent TEVAR for a rapidly enlarging mycotic TAA. He received anti-tuberculous therapy for one year with no recurrent infection for one year. TEVAR may be an effective alternative to the open surgical procedure;however, multidisciplinary treatment including anti-tuberculous therapy and careful long-term follow up are required.

Double BCG vaccination in a neonate: implications, management and prevention.

Tuberculosis is a common cause of morbidity and mortality especially in low-income and middle-income countries like India. BCG vaccination is recommended for all neonates after birth in areas with a high tuberculosis disease burden. Here, we describe a case where a neonate received two doses of the BCG (Chennai strain) vaccine within a span of 4 days after birth due to a vaccination error. Parents were informed about the event. The infant was managed conservatively and followed up till 12 months of life for any possible complication. There were no serious adverse effects apart from the localised reaction and a double scar on the left arm. Measures to avoid any such error in the future and the need for reporting medication error has been highlighted. Parental concerns are frequent in such scenarios and should be actively addressed.

Intravesical Ty21a treatment of non-muscle invasive bladder cancer induces immune responses that correlate with safety and may be associated to therapy potential.

BACKGROUND: Standard of care treatment of non-muscle invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette Guérin (BCG) is associated with side effects, disease recurrence/progression and supply shortages. We recently showed in a phase I trial (NCT03421236) that intravesical instillation in patients with NMIBC with the maximal tolerated dose of Ty21a/Vivotif, the oral vaccine against typhoid fever, might have a better safety profile. In the present report, we assessed the immunogenicity of intravesical Ty21a in patients of the clinical trial that had received the maximal tolerated dose and compared it with data obtained in patients that had received standard BCG. METHODS: Urinary cytokines and immune cells of patients with NMIBC treated with intravesical instillations of Ty21a (n=13, groups A and F in NCT03421236) or with standard BCG in a concomitant observational study (n=12, UROV1) were determined by Luminex and flow cytometry, respectively. Serum anti-lipopolysaccharide Typhi antibodies and circulating Ty21a-specific T-cell responses were also determined in the Ty21a patients. Multiple comparisons of different paired variables were performed with a mixed-effect analysis, followed by Sidak post-test. Single comparisons were performed with a paired or an unpaired Student's t-test. RESULTS: As compared with BCG, Ty21a induced lower levels of inflammatory urinary cytokines, which correlated to the milder adverse events (AEs) observed in Ty21a patients. However, both Ty21a and BCG induced a Th1 tumor environment. Peripheral Ty21a-specific T-cell responses and/or antibodies were observed in most Ty21a patients, pointing the bladder as an efficient local immune inductive site. Besides, Ty21a-mediated stimulation of unconventional Vδ2 T cells was also observed, which turned out more efficient than BCG. Finally, few Ty21a instillations were sufficient for increasing urinary infiltration of dendritic cells and T cells, which were previously associated with therapeutic efficacy in the orthotopic mouse model of NMIBC. CONCLUSIONS: Ty21a immunotherapy of patient with NMIBC is promising with fewer inflammatory cytokines and mild AE, but induction of immune responses with possible antitumor potentials. Future phase II clinical trials are necessary to explore possible efficacy of intravesical Ty21a.

Optimal interval timing between transurethral resection of bladder tumors and Bacillus Calmette-Guerin perfusion.

OBJECTIVE: There is no consensus regarding the best interval time between transurethral resection of a bladder tumor and Bacillus Calmette-Guerin (BCG) perfusion. This study was to explore whether the interval time has an impact on the prognosis and adverse effects. METHODS: We retrospectively reviewed the clinical data of patients who received BCG intravesical perfusion at Sun Yat-sen University Cancer Center (SYSUCC) from September 2015 to October 2021. Recurrence-free survival (RFS) and progression-free survival were the primary endpoints. Cox regression was used to explore independent predictors. The association between interval time and adverse effect grade was detected by logistic regression. Propensity score matching (PSM) was performed. RESULTS: A total of 403 patients were enrolled, the median interval time was 24 days (6-163 days), and the follow-up was 28 months (7-82 months). Eighty-eight (20.9%) patients relapsed, and 40 patients (10.0%) suffered progression. The multivariate Cox regression analysis confirmed that interval time was an independent predictor of RFS (p = 0.017). Notably, when the interval time was less than or equal to 26 days, there was a trend toward better RFS, PSM resulted in 65 matched pairs in each group, and Kaplan-Meier analysis showed that there was a significant difference in RFS between groups (p = 0.009). The logistic regression analysis showed that there was no correlation between interval time and adverse effects and their grades (p > 0.05). CONCLUSIONS: We considered that the first BCG perfusion could be performed within 2-4 weeks after surgery.

Bacillus Calmette-Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 × 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.

[Miliary Pulmonary Tuberculosis After Intravesical BCG Instillation in a Patient with High-Grade Bladder Cancer]. / Intravezikal BCG Uygulamasi Sonrasi Olusan Miliyer Akciger Tüberkülozu Olgusu.

Intravesical administration of Bacillus Calmette-Guerin (BCG) vaccine is used in the treatment of superficial bladder cancer. In clinical practice, intravesical BCG immunotherapy after transurethral tumor resection is a highly effective treatment option in preventing tumor recurrence and progression in medium and high risk superficial bladder tumors. Since patients are given live tuberculosis (TB) bacillus, serious side effects such as pneumonia, sepsis and even death can be seen. Lung involvement occurs in less than 1% of patients and most commonly presents as interstitial pneumonia or miliary TB. Miliary TB is difficult to diagnose and is usually based on high clinical suspicion, as Mycobacterium bovis is not isolated in most cases. Treatment is not completely standardized. However, in severe cases, a combination of antituberculosis drugs and corticosteroids is recommended. In this report, a case of miliary tuberculosis, a very rare complication after instillation of BCG into the bladder in a patient with a diagnosis of superficial bladder cancer, was presented. A 73-year-old male patient diagnosed with bladder tumor underwent transurethral resection of bladder tumor, and then weekly intravesical injection of BCG-MEDAC for six weeks had no adverse effects. Three weeks of intravesical BCG supplementation was planned for the patient who had no signs of recurrence when checked three months later by cystoscopy. Two hours after the first dose, the patient, who applied to the emergency department with the complaint of chills and shivering, was hospitalized for further follow-up and treatment. Afterwards, repeat cultures were taken from the patient whose fever continued on the seventh day of treatment with broad-spectrum antibiotics (meropenem and teicoplanin). In addition, when abdominal and thorax computed tomography (CT) were performed, multiple miliary nodular lesions were detected in both lungs and were evaluated in favor of miliary TB. With these findings, the patient was started on miliary TB therapy [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM)] targeting Mycobacterium bovis, since it was an infection that developed after BCG injection. In the third week of the treatment, the patient's fever was under control, and he was discharged on the 25th day of his hospitalization because of significant improvement in infection markers [C-reactive protein(CRP)-procalcitonin]. At the end of two months, there was clear regression of pulmonary abnormalities on control thorax CT. In conclusion, miliary TB developing after intravesical BCG instillation is a very rare condition, the cause of which is not fully understood, the etiology of fever can be easily missed, and the diagnosis is difficult. In addition, this case is presented to draw attention to a critical disease that requires long treatment and follow-up and requires attention.

Real-world efficacy of adjuvant single-agent intravesical gemcitabine for non-muscle invasive bladder cancer.

INTRODUCTION: Failure, intolerance, or shortage of bacillus Calmette-Guerin (BCG) treatment for patients with high-risk (HR) non-muscle invasive bladder cancer (NMIBC) leave many facing the prospect of radical cystectomy (RC). However, despite the lack of large-scale randomized controlled studies with single-agent intravesical gemcitabine (Gem), it has emerged as a popular salvage agent after BCG failure or even a treatment alternative to BCG. AREAS COVERED: 1. Characterization of treatment regimen details pertaining to single-agent intravesical adjuvant Gem use among disease states of NMIBC characterized by risk and BCG exposure. 2. Comparison of safety and efficacy of Gem according to risk category, type of tumor (papillary vs. carcinoma in situ (CIS)), and tumor grades. EXPERT OPINION: Two randomized studies in early BCG failure disease demonstrate that single-agent Gem has superior efficacy versus repeated BCG therapy or mitomycin C. Studies enrolling patients with predominantly papillary disease without CIS, intermediate-risk (IR) disease, and less BCG exposure appear to derive the highest benefits from adjuvant Gem in terms of recurrence and progression. However, studies with cohorts enriched for a predominance of CIS, HR disease and/or more extensive BCG failure have poorer 2-year recurrence free survival and a somewhat higher risk of progression and RC.