Bacillus Calmette-Guérin Infection Research Articles

Plasma Metagenomic Sequencing Expedites Diagnosis of Disseminated BCG in an Infant With IKBKB Mutation.

Infants with inborn errors of immunity (IEI), born in countries where Bacillus-Calmette-Guerin (BCG) vaccination is recommended at birth, are at risk of developing infectious complications following vaccination. A prompt diagnosis of disseminated BCG infection in these infants is essential, as many will require stem cell transplantation (SCT) for the immunologic cure. In patients with IEI, the mortality risk from disseminated mycobacterial infection is high, both before and following SCT. A 7-month-old Qatari infant with an IEI, homozygous IKBKB gene mutation, was evaluated at our institution for SCT. He had a history of recurrent pneumonias, but pretransplant evaluation revealed negative cultures from bronchoalveolar fluid, blood and urine. At 8 months of age, the infant developed skin nodules of unclear etiology, prompting additional evaluation. Given his profound immunosuppression and receipt of broad-spectrum antimicrobials, plasma metagenomic next-generation sequencing (mNGS) was obtained and identified Mycobacterium tuberculosis complex within 72 hours. A skin biopsy was performed, and antimycobacterial therapy was initiated. Mycobacterium bovis-BCG was confirmed from cultures 3 weeks later. Treatment was complicated by elevated serum liver transaminases and aminoglycoside-associated high-frequency hearing loss. The infant completed 14 months of treatment from engraftment. Evaluation for active BCG infection after SCT was negative. In an infant with a unique IEI, plasma mNGS provided the first diagnosis of disseminated BCG infection. We believe that early initiation of antimycobacterial treatment improved the infant's clinical outcome. Plasma mNGS testing should be considered as a noninvasive screen for infectious pathogens in children with IEIs before SCT.

Bacillus Calmette-Guerin Vaccine-Associated Lymphadenitis in Children

Background: Tuberculosis (TB) is one of the most important infectious diseases worldwide. Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine, entered into the childhood immunization program by the World Health Organization (WHO) in 1974 to prevent TB. One of the relatively common complications of BCG vaccination is regional lymphadenitis. Objectives: This study aimed to determine the lymphadenitis incidence in BCG-vaccinated children in southwest Iran. Methods: In a prospective descriptive study, infants born from March to June 2017 were evaluated for BCG vaccine complications at two, four, six, nine, and 12 months of age in Ahvaz, southwestern Iran. Results: The study enrolled 1,506 infants (794 males and 712 females). Among the vaccinated infants, four (0.26%) had injection site reactions, and 106 (7.03%) presented lymphadenitis (66 males and 40 females). The lymphadenitis rate was significantly higher in males than in females (P = 0.024). The mean age at presentation was 4.28 ± 0.79 months. Suppurative lymphadenitis was seen in 53 (50%) cases and nonsuppurative lymphadenitis in 53 (50%) cases. About 80% of nonsuppurative lymphadenitis resolved entirely or partially after a one-year follow-up. Of 53 cases with suppurative lymphadenitis, 46 (43.4%) developed spontaneous drainage, and seven (6.6%) were drained by needle aspiration. No significant relationship was found between the BCG inoculation site and lymphadenitis rate. No other complications such as osteomyelitis or disseminated BCG infection were observed after one year of follow-up. Conclusions: The relatively high incidence of BCG lymphadenitis in this study may be due to the vaccine strain, young vaccinees, and improper vaccination techniques. In most cases, nonsuppurative lymphadenitis regressed spontaneously, and suppurative lymphadenitis was drained spontaneously or by needle aspiration.

Knockdown of GBP1 inhibits BCG-induced apoptosis in macrophage RAW 264.7 cells via p38/JNK pathway.

Alveolar macrophage apoptosis induced by Mycobacterium tuberculosis (Mtb) plays a significant role in mediating the pathogenesis of tuberculosis. There is growing evidence that guanylate-binding proteins (GBPs) are associated with different pathological processes such as microbial infection. However, it remains unclear whether GBPs can regulate the apoptosis of macrophages induced by Mtb. In this study, we investigated the potential effect of GBP1 on RAW 264.7 cell apoptosis during Bacillus Calmette-Guerin (BCG) infection. The results demonstrated that BCG could induce macrophage apoptosis and GBP1 upregulation. In addition, we explored the role of GBP1 in regulating BCG-induced RAW 264.7 cell apoptosis using small interfering RNAs targeting GBP1. The results showed that knockdown of GBP1 could attenuate BCG-induced apoptosis in RAW 264.7 cells. Moreover, we found that GBP1 knockdown decreased the levels of cleaved-Caspase 3 and cleaved-PARP-1, while decreased those of cleaved-Caspase 9, BAX, Cytochrome C and APAF1. These findings imply that GBP1 knockdown can prevent BCG-induced apoptosis through an endogenous apoptosis pathway. In addition, the mitochondrial membrane potential of macrophages was significantly increased after BCG infection, and GBP1 knockdown could alleviate this phenomenon. Furthermore, downregulation of GBP1 also attenuated BCG-induced accumulation of reactive oxygen species in macrophages. Mechanistically, GBP1 suppressed the phosphorylation of the target molecules in p38/JNK pathway, thus regulating the apoptosis of BGC-infected macrophages. Collectively, these findings reveal a significant role of GBP1 in mediating cell apoptosis in macrophages infected with BCG, and the molecular mechanism underlying its suppressive effect on BCG-induced apoptosis.

Evaluating the effects of Cyclosporine A immunosuppression on Mycobacterial infection by inhaling of Cyclosporine A administrated BALB/c mice with live Bacillus Calmette Guérin

Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and treatment of autoimmune diseases. Effects of CsA on determining the direction of the immune response and pathogenesis of infections by altering immune responses particulary T cells functions have always been questionable. We evaluated the effect of different doses of CsA on course of infection in BALB/c mice infected with live Bacillus Calmette Guérin (BCG) (as an example of Mycobacterial infections). Four groups of mice (n = 5) receiving 5, 25, 125, and 0 mg/kg of CsA, three times a week, were infected with BCG aerosolly. Before BCG inhalation and 40-/60- days post-infection, cell proliferation and CD4+CD25+ cell percentage were evaluated in splenocytes of mice after culture and stimulation with PHA or BCG lysate. The histopathological alterations and bacterial burden were assessed in lung tissue. Cells showed a dose-dependent decrease in proliferation and the percentage of CD4+ CD25+ cells. After BCG infection, in presence of dose 125 mg/kg, there were some exceptions. The number of bacteria and histopathological lesions and inflammation in lung tissues increased in a dose-dependent manner. CsA immunosuppressed BCG infected mice can be used as a safe model for studying Mycobacterium species pathogenesis and related cellular immune responses.

Endovascular Repair of a Mycotic Aortic Aneurysm Infected With Bacillus Calmette-Guérin After Treatment of Bladder Cancer

Bacillus Calmette-Guérin (BCG) is an attenuated form of Mycobacterium bovis used for intravesical therapy for bladder carcinoma. Disseminated infection is uncommon. Aortic involvement with aneurysmal degeneration is even rarer, with <30 cases reported. Prior reports documented aggressive open surgical repair. We have detailed a case of mycotic aortic pseudoaneurysm and para-aortic abscess from disseminated BCG treated with endovascular repair and percutaneous drainage. A 73-year-old man was found to have an infrarenal mycotic aortic pseudoaneurysm with para-aortic and iliopsoas abscess on computed tomography after complaining of persistent abdominal pain. His history was noTable for recurrent in situ bladder carcinoma treated with two sessions of intravesical BCG. He eventually underwent cystoprostatectomy with an ileal conduit and cecectomy. His postoperative course was complicated by bowel perforation requiring a diverting ileostomy and reversal—all performed several months before the current episode. Fine needle aspiration was positive for acid fast bacilli, raising concerns for BCG infection. Antibiotics were started, and he was offered surgical repair. Given the hostile abdomen, we decided to proceed with EVAR. With the patient under general anesthesia, a rifampin-soaked 22 × 94-mm thoracic endograft (Medtronic, Dublin, Ireland) was deployed across the pseudoaneurysm. This case was performed before the company recall of their device. The procedure was performed with a single access site, using an 18F Gore sheath (W.L. Gore & Associates, Flagstaff, Ariz) with a buddied pigtail catheter. A completion aortogram revealed an excellent seal. The procedure was well-tolerated, and the patient discharged on the second postoperative day after retroperitoneal drain placement by the radiology staff. He was seen in follow-up at 1 month, at which time his drain was removed and a computed tomography scan demonstrated resolution of his pseudoaneurysm and abscess. Aortic infection from disseminated BCG is a rare clinical entity. The few reported cases have mostly included open surgical repair. We have described the case of a patient treated with an endograft who had had clinical and radiologic resolution at short-term follow-up. The long-term prognosis has not yet been determined. However, our patient's favorable early outcome shows promise for the technique.

LncRNA MIAT regulates autophagy and apoptosis of macrophage infected by Mycobacterium tuberculosis through the miR-665/ULK1 signaling axis

Accumulating lines of evidence have revealed the involvement of long non-coding RNAs (lncRNAs) in the control and elimination of invading Mycobacterium tuberculosis (Mtb) by macrophage. In this study, we sought to elucidate the role of MIAT on autophagy and apoptosis of Mtb-infected macrophage and to reveal the molecular mechanism. We observed that the expression of MIAT was heightened while miR-665 level was declined in THP-1 cells with Bacillus Calmette-Guerin (BCG) infection in a time-dependent manner. Functionally, disruption of MIAT effectively facilitated cell viability and restricted apoptosis ability concomitant with the downregulation of Bax and cleaved caspase-3 along with an accumulation of Bcl-2 in BCG-infected THP-1 cells. Concurrently, the interference of MIAT dramatically disinhibited macrophage autophagy as characterized by diminution of autophagy related markers LC3-II and Beclin-1 as well as increment of p62 in THP-1 cells following BCG infection. Concordantly, depletion of MIAT was found to noticeably aggrandize Mtb survival. Importantly, MIAT served as a ceRNA for sponging miR-665 and negatively regulated its expression. ULK1 was identified as an authentic target of miR-665 and modulated by MIAT. Mechanistically, the functional role of MIAT depletion in macrophage apoptosis and autophagy were tremendously abrogated by the depression of miR-665 and enrichment of ULK1. Overall, the preceding observations clearly illuminated that MIAT was elevated in human macrophage response to BCG infection, and functioned as a negative regulator in autophagy and antimicrobial effects by manipulating miR-665/ULK1 axis during Mtb infection, which may provide a promising target for developing an anti-bacterial against TB.

MyD88-dependent BCG immunotherapy reduces tumor and regulates tumor microenvironment in bladder cancer murine model

Bacillus Calmette-Guerin (BCG) is the only FDA approved first line therapy for patients with nonmuscle invasive bladder cancer. The purpose of this study is to better understand the role of innate immune pathways involved in BCG immunotherapy against murine bladder tumor. We first characterized the immunological profile induced by the MB49 mouse urothelial carcinoma cell line. MB49 cells were not able to activate an inflammatory response (TNF-α, IL-6, CXCL-10 or IFN-β) after the stimulus with different agonists or BCG infection, unlike macrophages. Although MB49 cells are not able to induce an efficient immune response, BCG treatment could activate other cells in the tumor microenvironment (TME). We evaluated BCG intratumoral treatment in animals deficient for different innate immune molecules (STING−/−, cGAS−/−, TLR2−/−, TLR3−/−, TLR4−/−, TLR7−/−, TLR9−/−, TLR3/7/9−/−, MyD88−/−, IL-1R−/−, Caspase1/11−/−, Gasdermin-D−/− and IFNAR−/−) using the MB49 subcutaneous mouse model. Only MyD88−/− partially responded to BCG treatment compared to wild type (WT) mice, suggesting a role played by this adaptor molecule. Additionally, BCG intratumoral treatment regulates cellular infiltrate in TME with an increase of inflammatory macrophages, neutrophils and CD8+ T lymphocytes, suggesting an immune response activation that favors tumor remission in WT mice but not in MyD88−/−. The experiments using MB49 cells infected with BCG and co-cultured with macrophages also demonstrated that MyD88 is essential for an efficient immune response. Our data suggests that BCG immunotherapy depends partially on the MyD88-related innate immune pathway.

The role of IL-32 in Bacillus Calmette-Guérin (BCG)-induced trained immunity in infections caused by different Leishmania spp.

BackgroundCells of the innate immune system undergo long-term functional reprogramming in response to Bacillus Calmette-Guérin (BCG) exposure via a process called trained immunity, conferring nonspecific protection to unrelated infections. Here, we investigate whether BCG-induced trained immunity is able to protect against infections caused by different Leishmania spp., protozoa that cause cutaneous and mucosal or visceral lesions. MethodsWe used training models of human monocytes with BCG and subsequent infection by L. braziliensis, L. amazonensis and L. infantum, and the vaccination of wild-type and transgenic mice for IL-32γ before in vivo challenge with parasites. ResultsWe demonstrated that monocytes trained with BCG presented enhanced ability to kill L. braziliensis, L. amazonensis and L. infantum through increased production of reactive oxygen species. Interleukin (IL)-32 appears to play an essential role in the development of trained immunity. Indeed, BCG exposure induced IL-32 production in human primary monocytes, both mRNA and protein. We have used a human IL-32γ transgenic mouse model (IL-32γTg) to study the effect of BCG vaccination in different Leishmania infection models. BCG vaccination decreased lesion size and parasite load in infections caused by L. braziliensis and reduced the spread of L. amazonensis to other organs in both infected wild-type (WT) and IL-32γTg mice. In addition, BCG reduced the parasite load in the spleen, liver and bone marrow of both WT and IL-32γTg mice infected with L. infantum. BCG vaccination increased inflammatory infiltrate in infected tissues caused by different Leishmania spp. In all infections, the presence of IL-32γ was not mandatory, but it increased the protective and inflammatory effects of BCG-induced training. ConclusionsBCG's ability to train innate immune cells, providing protection against leishmaniasis, as well as the participation of IL-32γ in this process, pave the way for new treatment strategies for this neglected infectious disease.

BCG vaccine–related complications in patients with primary immunodeficiencies after allogeneic hematopoietic stem cell transplantation

BCG (Bacillus Calmette–Guérin) vaccine is widely used for the vaccination of newborns within the first few days of life to prevent mycobacterial infections. However, complications occurring after BCG vaccination in patients with primary immunodeficiencies (PIDs) can lead to serious consequences for their health and life. BCG vaccine-related complications occurring in patients with severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD) after hematopoietic stem cell transplantation (HSCT) constitute an important problem. The article presents a retrospective observational analysis of 45 patients with SCID and CGD who received BCG vaccination and underwent HSCT. In the post-transplant period, 33 (73.3%) patients had BCG-related complications, either localized or generalized. The presence of BCG vaccine-related complications in the pre-transplant period was a significant predictor of the development of post-transplant complications. The most severe and long-term BCG vaccine-related complications were observed in the patients with SCID: the median time to the resolution of symptoms of BCG infection was 30 days and 100 days in the CGD patients and the SCID patients, respectively (p&lt; 0.001). The severity of BCG vaccine-related complications, the nature of the primary disease and the presence of pre-transplant BCG vaccine-related complications did not affect the overall survival (OS) of the patients: OS for the entire study group was 79.5 ± 6.6%. Non-compliance with antimycobacterial prophylaxis prior to HSCT resulted in severe infections in a number of patients. The treatment of BCG vaccine-related complications included a combination of several antimycobacterial agents, and anti-inflammatory drugs (such as glucocorticoids, interleukin-1 and 6 receptor antagonists) in cases of immune reconstitution inflammatory syndrome (n= 18). The only effective method of prophylaxis of BCG-related infections in patients with SCID and CGD in the pre- and post-transplant period is the exemption of newborns from BCG vaccination based on their family history. Uninterrupted antimycobacterial prophylaxis in vaccinated patients in the pre- and post-transplant period is also important. Furthermore, an effective uniform strategy for the prevention and treatment of BCG vaccine-related complications in PID patients both before and after HSCT is needed.

Prosthetic hip joint infection by Bacillus Calmette-Guerin therapy following intravesical instillation for bladder cancer identified using whole-genome sequencing: a case report

BackgroundJoint replacement is an effective intervention and prosthetic joint infection (PJI) is one of the most serious complications of such surgery. Diagnosis of PJI is often complex and requires multiple modalities of investigation. We describe a rare cause of PJI which highlights these challenges and the role of whole-genome sequencing to achieve a rapid microbiological diagnosis to facilitate prompt and appropriate management.Case presentationA 79-year-old man developed chronic hip pain associated with a soft-tissue mass, fluid collection and sinus adjacent to his eight-year-old hip prosthesis. His symptoms started after intravesical Bacillus Calmette-Guerin (BCG) therapy for bladder cancer. Synovasure™ and 16S polymerase chain reaction (PCR) tests were negative, but culture of the periarticular mass and genome sequencing diagnosed BCG infection. He underwent a two-stage joint revision and a prolonged duration of antibiotic therapy which was curative.ConclusionsBCG PJI after therapeutic exposure can have serious consequences, and awareness of this potential complication, identified from patient history, is essential. In addition, requesting appropriate testing is required, together with recognition that traditional diagnostics may be negative in non-pyogenic PJI. Advanced molecular techniques have a role to enhance the timely management of these infections.

Bacillus Calmette-Guérin vaccine-related complications in children in Oman.

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccine-related complications are frequently observed in children in Oman. There are a few regional studies on BCG complications, but none from Oman.OBJECTIVE: Evaluate the spectrum of BCG-vaccine related complications and immune status in Omani children.DESIGN: Retrospective cross-sectional study.SETTING: Referral tertiary hospital.METHODS: Children aged younger than 13 years old and with complications of BCG vaccination recorded from 2006-2018 were included in this study. Clinical characteristics, treatment, immune workup and outcome were reviewed from hospital records.MAIN OUTCOME MEASURES: Different BCG vaccine-related complications categorized by the site of involvement.SAMPLE SIZE: 226.RESULTS: Of the 226 children had BCG-vaccine related complications, 99% received BCG vaccine immediately after birth. The median age of presentation was 4 months. The most common complication was isolated BCG lymphadenitis (85%, n=192), followed by BCG-related osteomyelitis (10.2%, n=23) and disseminated BCG infection (4.9%, n=11). The median age of presentation of disseminated BCG was 5 months, with different organs involved. Out of 11 children with disseminated BCG infection, 72.7% (n=8) had primary immune deficiency (PID), including chronic granulomatous disease (CGD, n=5), severe combined immunodeficiency (SCID) (n=2); 1 patient had Mendelian susceptibility to mycobacterial disease (IFNGR2 deficiency); 2 patients with PID not yet identified and the 1 with a non-specific PID had blood or saliva samples sent for whole-exome sequencing.CONCLUSION: Because of the spectrum of BCG vaccine-related complications, including the most severe in children with PID, we suggest that delaying the BCG vaccine from birth to 6 months may prevent disseminated BCG diseases and their complications in children with PID because any PID will have been identified before 6 months. Further studies are needed to guide this recommendation.LIMITATIONS: Single center-based study that may not provide a full overview of all BCG vaccine-related complications in Oman. Unavailability of details of some microbiological results and an inability to determine the detailed management for all patients.CONFLICT OF INTEREST: None.

Bacillus Calmette-Guérin (BCG) Infections at High Frequency in Both AR-CGD and X-CGD Patients Following BCG Vaccination.

Patients with chronic granulomatous disease (CGD) develop severe infections, including Bacillus Calmette-Guérin (BCG). Although the autosomal recessive CGD (AR-CGD) patients should hypothetically develop relatively fewer infections compared to the X-linked CGD (X-CGD) patients due to more residual reactive oxygen intermediates, the impacts of BCG vaccination on AR-CGD and X-CGD patients are unclear. Herein, we demonstrated the clinical features of BCG infections, treatments, and genetic factors in CGD patients after BCG vaccination under the Japanese immunization program. We collected data retrospectively from 43 patients with CGD and assessed their history of initial infection, age at diagnosis of CGD, BCG vaccination history, clinical course, treatment for BCG infections, and genetic mutations associated with CGD. Fourteen CGD patients avoided BCG vaccination because of other preceding infections and family history. Of 29 patients with CGD who received BCG vaccination, 20 patients developed BCG infections. Although the age at onset of initial infection in X-CGD patients was significantly younger than that in AR-CGD patients (P < .01), the onset and frequency of BCG infections were similar in X-CGD and AR-CGD patients. In X-CGD patients, BCG infections equally developed in the patients carrying missense, insertion, deletion, nonsense, and splice mutations of CYBB. All CGD patients with BCG infections were successfully treated with anti-tuberculous drugs. Although X-CGD patients develop severe infections at a younger age than AR-CGD patients, our data suggested that BCG infections develop at high frequency in both AR-CGD and X-CGD patients, regardless of genotype and mutant forms.

A rare case of synchronous bilateral epididymal and testicular metastases of urothelial carcinoma of the bladder after intravesical bacillus Calmette-Guérin.

A 68-year-old man was diagnosed with non-muscle-invasive bladder cancer and underwent transurethral resection of the bladder tumor (TURBT) in June 2014. The pathological diagnosis was urothelial carcinoma (UC), Grade 2, pT1. He was treated with intravesical bacillus Calmette-Guérin (BCG) instillation after TURBT. In February 2016, he received anti-tuberculosis treatment for systemic BCG infection, and tuberculosis treatment was continued. In September 2018, he presented with bilateral scrotum swelling and underwent bilateral orchiectomy following a diagnosis of antituberculotics-resistant epididymitis. The pathological findings were metastatic UC of the bilateral epididymis and testis. One months later, fluorodeoxyglucose-positron emission tomography/computed tomography showed para-aortic lymph node and peritoneal metastases. He was treated with chemotherapy of gemcitabine and cisplatin. We herein report a very rare case of synchronous metastatic UC of the bilateral epididymis and testis after intravesical BCG treatment.

Knockdown of fatty acid binding protein 4 exacerbates Bacillus Calmette-Guerin infection-induced RAW264.7 cell apoptosis via the endoplasmic reticulum stress pathway.

Mycobacterial infection can induce alveolar macrophage apoptosis, which plays a vital role in the pathogenesis of tuberculosis. Accumulating evidence has demonstrated that fatty acid oxidation is involved in apoptosis during various pathological processes, including bacterial infection. However, whether fatty acid oxidation regulates mycobacterial infection-induced macrophage apoptosis remains unclear. Hence, the present study aimed to investigate the role of fatty acid binding protein 4 (FABP4) which is a carrier protein for fatty acids, in regulating apoptosis in RAW264.7 cells infected with Bacillus Calmette-Guerin (BCG). In our study, the impact of BCG infection on apoptosis and fatty acid oxidation in RAW264.7 cells was examined. Notably, we found that FABP4 was overexpressed during this process. Furthermore, small interfering RNAs targeting FABP4 were used to investigate the role of FABP4 in regulating apoptosis and fatty acid oxidation in BCG-infected RAW264.7 cells. The results indicated that mycobacterial infection promoted apoptosis and enhanced fatty acid oxidation in RAW264.7 cells. Moreover, FABP4 knockdown exacerbated BCG-induced apoptosis and upregulated the expression of p-PERK, p-eIF2α and chop, which are endoplasmic reticulum (ER) stress markers. In addition, FABP4 knockdown promoted fatty acid oxidation and ROS production, which result in the activation of ER stress. Our data suggested that FABP4 knockdown exacerbated BCG-induced apoptosis in RAW264.7 cells via the ER stress pathway.

Primary Immunodeficiency Diseases and Bacillus Calmette-Guérin (BCG)-Vaccine–Derived Complications: A Systematic Review

Bacillus Calmette-Guérin (BCG) vaccine is a live attenuated bacterial vaccine derived from Mycobacterium bovis, which is mostly administered to neonates in regions where tuberculosis is endemic. Adverse reactions after BCG vaccination are rare; however, immunocompromised individuals and in particular patients with primary immunodeficiencies (PIDs) are prone to develop vaccine-derived complications. To systematically review demographic, clinical, immunologic, and genetic data of PIDs that present with BCG vaccine complications. Moreover, we performed a meta-analysis aiming to determine the BCG-vaccine complications rate for patients with PID. We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (1966 to September 2018) introducing terms related to PIDs, BCG vaccination, and BCG vaccine complications. Studies with human subjects with confirmed PID, BCG vaccination history, and vaccine-associated complications (VACs) were included. A total of 46 PIDs associated with BCG-VAC were identified. Severe combined immunodeficiency was the most common (466 cases) and also showed the highest BCG-related mortality. Most BCG infection cases in patients with PID were reported from Iran (n= 219 [18.8%]). The overall frequency of BCG-VAC in the included 1691 PID cases was 41.5% (95% CI, 29.9-53.2; I2= 98.3%), based on the results of the random-effect method used in this meta-analysis. Patients with Mendelian susceptibility to mycobacterial diseases had the highest frequency of BCG-VACs with a pooled frequency of 90.6% (95% CI, 79.7-1.0; I2= 81.1%). Several PID entities are susceptible to BCG-VACs. Systemic neonatal PID screening programs may help to prevent a substantial amount of BCG vaccination complications.

Bacillus Calmette-Guérin immunotherapy for bladder cancer: a review of immunological aspects, clinical effects and BCG infections.

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.

Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China.

Although many studies have investigated Mendelian susceptibility to mycobacterial disease (MSMD) worldwide, there is no report of the long-term clinical management and prognosis for MSMD in China. This is a cohort study from January 2000 to June 2018. Three hundred and twenty-four patients with bacillus Calmette-Guérin (BCG) infection were diagnosed during this period, and those with MSMD diagnosed by genetic and functional experiments were enrolled in the study. The clinical and genetic characteristics and management of these MSMD patients were summarized. Thirty patients diagnosed with MSMD were followed up. The age at the follow-up end point ranged from 5 to 173months. Among the patients, IL12RB1 mutations were identified in 22, IFNGR1 mutations in 5, STAT1 mutations in 2, and IFNGR2 mutation in 1. The medium age at onset was 3months. BCG infection involved multiple organs, including regional infection (8/30; 26.7%) or distant or disseminated infection (22/30; 73.3%). Ten percent (30/324) of patients with BCG infection had a confirmed MSMD diagnosis. Protein expression of IL12RB1 or IFNGR1 was decreased in all patients with IL12RB1 or IFNGR1 mutation, respectively, as indicated by flow cytometry. In addition, 77.8% of patients received rhIFN-γ treatment, which can improve the prognosis of patients with IL12RB1 deficiency. Two patients received stem cell transplantation. Twenty-five patients remained alive at the time of publication. MSMD is an important cause of BCG infection. Flow cytometric detection of IL12RB1 and IFNGR1 expression is very useful for rapid MSMD diagnosis. rhIFN-γ therapy is effective in patients with MSMD, particularly improving prognosis in those with IL12RB1 deficiency.

Disseminated Mycobacterium Sepsis with Bone Marrow, Liver, and Lung Involvement Following Intravesical Bacillus Calmette-Guerin (BCG) Therapy

Introduction: BCG therapy is first line therapy for high grade non-muscle invasive bladder cancer (NMIBC).Case Presentation: A 54-year-old male presented with fevers, rigors and hematuria one week following intravesical BCG administration for treatment of NMIBC. He developed fever, pancytopenia, elevated liver enzymes and pulmonary infiltrates with progression of symptoms despite broad spectrum antimicrobial therapy. A bone marrow biopsy showed granulomatous infiltration; cultures of urine demonstrated growth of Mycobacterium bovis. A diagnosis of disseminated BCG infection secondary to intravesical administration was made; rifampin, isoniazid, ethambutol, and high dose prednisone were initiated.Conclusion: Adverse events associated with BCG administration have been attributed to both the primary mycobacterium infection and to hypersensitivity reactions. Timely collection of histopathology can lead to early treatment of disseminated BCG with good outcomes. Internists should have a high index of suspicion for patients presenting with organ dysfunction with an immediate or remote history of intravesical BCG administration.

A retrospective study on tolerability and complications of bacillus Calmette-Guérin (BCG) instillations for non-muscle-invasive bladder cancer

Objectives: The objective was to evaluate the tolerability of BCG treatment and to evaluate the effects of interruption on treatment outcomes. The incidence and characteristics of severe complications were observed.Methods: From hospital records, all bladder carcinoma patients treated with BCG instillations in the institution from 2009–2015 were retrospectively identified. The reasons for interruption, treatment outcome, number of instillations, and diagnosis of BCG infection were recorded.Results: Of the 418 patients who started BCG instillation therapy, 176 (42.1%) interrupted BCG treatment. Of those, 23 (5.5%) patients interrupted because of suspected BCG infection. Systemic BCG infection was found in seven (1.7%), and local infection in five (1.2%) patients. Interruption of treatment was due to other adverse effects in 71 patients (17.0%), BCG failure in 46 patients (11.0%), and other reasons in 36 patients (8.6%). Fifty percent of interruptions due to adverse effects occurred within the first 6 months. The probabilities of tumor recurrence (20.0% vs 10.7%, p = 0.014, OR = 2.077, CI95% = 1.149–3.753) and disease progression (5.4% vs 1.2%, p = 0.018, OR = 4.534, CI95% = 1.152–17.840) were higher among patients whose BCG treatment was interrupted.Conclusions: Severe complications were encountered in only <5% of patients. Adverse effects requiring treatment interruption were more likely to happen within the first year of treatment. Interrupting BCG treatment due to adverse effects increased the risk of disease progression and tumor recurrence.

Myeloid cell TNFR1 signaling dependent liver injury and inflammation upon BCG infection

TNF plays a critical role in mononuclear cell recruitment during acute Bacillus Calmette-Guérin (BCG) infection leading to an effective immune response with granuloma formation, but may also cause tissue injury mediated by TNFR1 or TNFR2. Here we investigated the role of myeloid and T cell specific TNFR1 and R2 expression, and show that absence of TNFR1 in myeloid cells attenuated liver granuloma formation and liver injury in response to acute BCG infection, while TNFR2 expressed in myeloid cells contributed only to liver injury. TNFR1 was the main receptor controlling cytokine production by liver mononuclear cells after antigenic specific response, modified CD4/CD8 ratio and NK, NKT and regulatory T cell recruitment. Further analysis of CD11b+CD3+ phagocytic cells revealed a TCRαβ expressing subpopulation of unknown function, which increased in response to BCG infection dependent of TNFR1 expression on myeloid cells. In conclusion, TNFR1 expressed by myeloid cells plays a critical role in mononuclear cell recruitment and injury of the liver after BCG infection.