Maternal BCG scars and mortality risk for male and female newborns: observational study from Guinea-Bissau.

BACKGROUND: Maternal priming with Bacille Calmette-Guérin (BCG) has been associated with reduced mortality in male offspring. We investigated this association in a cohort of healthy BCG-vaccinated neonates. METHODS: Observational study within a randomized controlled trial comparing different BCG strains conducted in Guinea-Bissau from 2017-2020. As part of trial inclusion procedures, on the day of discharge from the maternity ward, maternal BCG scar status was evaluated by visual inspection, followed by offspring BCG and polio vaccination. Through mortality data collected at telephone interviews at six weeks and six months of age, we assessed all-cause mortality risk in Cox Proportional Hazards models adjusted for maternal schooling and BCG strain, providing adjusted Mortality Rate Ratios (aMRRs). RESULTS: 64% (11,070/17,275) of mothers had a BCG scar, which for females and overall was not associated with neither admission risk, admission severity nor all-cause mortality. By six months of age, the mortality rate (MR) was 4.1 (200 deaths/4,919 person-years) for the maternal BCG scar cohort and 5.2 (139 deaths/2,661 person-years) for no maternal scar, aMRR=0.86 (0.69-1.06). In males, six-month MRs were 4.3 (109/2,531) for maternal BCG scar vs 6.3 (87/1,376) for no scar, the maternal scar/no scar aMRR being 0.74 (0.56-0.99). In females, six-month MRs were 3.8 (91/2,388) vs 4.0 (52(1,286), the aMRR being 1.04 (0.74-1.47), p for interaction with sex=0.16. CONCLUSION: While we cannot rule out an association in females, being born to a mother with a BCG scar reduced the risk of death during early infancy for BCG-vaccinated males, reproducing findings from previous studies.

Mortality Risk Among Frail Neonates and Maternal BCG Vaccine Scar Status: Observational Study From Guinea-Bissau.

BACKGROUND: Maternal priming with the Bacille Calmette-Guérin (BCG) vaccine has been associated with reduced offspring mortality rates. We investigated this association in a cohort of frail neonates. METHODS: We performed an observational study within a randomized BCG trial conducted at the neonatal intensive care unit (NICU) in Guinea-Bissau from 2015 to 2017. At NICU admission and after informed consent, the maternal scar status was evaluated by visual inspection before neonates were randomized 1:1 to receive BCG + oral polio vaccine immediately or at hospital discharge. Stratified by maternal scar status, we assessed overall in-hospital and postdischarge mortality rates through 42 days of age in Cox proportional hazards models providing adjusted mortality rate ratios (aMRRs). RESULTS: Overall, 62% of mothers (903 of 1451) had a BCG vaccine scar. During NICU admission, the mortality risk was 1.7% (15 of 903) for neonates born to mothers with a scar versus 3.3% (18 of 548) for those born to mothers with no scar; the aMRR for maternal scar versus no scar was 0.53 (95% CI, .26-1.05), 0.39 (95% CI, .13-1.05) for unvaccinated and 0.70 (95% CI, .26-1.87) for vaccinated neonates. CONCLUSIONS: This small study indicates that maternal BCG vaccine might be associated with reduced all-cause NICU mortality rate. If confirmed elsewhere, this finding would have substantial ramifications for global health.

[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. 

The impact of BCG dose and revaccination on trained immunity.

The innate immune system can display heterologous memory-like responses termed trained immunity after stimulation by certain vaccinations or infections. In this randomized, placebo-controlled trial, we investigated the modulation of Bacille Calmette-Guérin (BCG)-induced trained immunity by BCG revaccination or high-dose BCG administration, in comparison to a standard dose. We show that monocytes from all groups of BCG-vaccinated individuals exerted increased TNFα production after ex-vivo stimulation with various unrelated pathogens. Similarly, we observed increased amounts of T-cell-derived IFNγ after M. tuberculosis exposure, regardless of the BCG intervention. NK cell cytokine production, especially after heterologous stimulation with the fungal pathogen Candida albicans, was predominantly boosted after high dose BCG administration. Cytokine production capacity before vaccination was inversely correlated with trained immunity. While the induction of a trained immunity profile is largely dose- or frequency independent, baseline cytokine production capacity is associated with the magnitude of the innate immune memory response after BCG vaccination.

Clinical and Genetic Characteristics of BCG Disease in Chinese Children: a Retrospective Study.

PURPOSE: Summarize the characteristics of a large cohort of BCG disease and compare differences in clinical characteristics and outcomes among different genotypes and between primary immunodeficiency disease (PID) and patients without identified genetic etiology. METHODS: We collected information on patients with BCG disease in our center from January 2015 to December 2020 and divided them into four groups: chronic granulomatous disease (CGD), Mendelian susceptibility to mycobacterial disease (MSMD), severe combined immunodeficiency disease (SCID), and gene negative group. RESULTS: A total of 134 patients were reviewed, and most of them had PID. A total of 111 (82.8%) patients had 18 different types of pathogenic gene mutations, most of whom (91.0%) were classified with CGD, MSMD, and SCID. CYBB was the most common gene mutation (52/111). BCG disease behaves differently in individuals with different PIDs. Significant differences in sex (P < 0.001), age at diagnosis (P = 0.013), frequency of recurrent fever (P = 0.007), and vaccination-homolateral axillary lymph node enlargement (P = 0.039) and infection severity (P = 0.006) were noted among the four groups. The CGD group had the highest rate of males and the oldest age at diagnosis. The MSMD group had the highest probability of disseminated infection (48.3%). The course of anti-tuberculosis treatment and the survival time between patients with PID and without identified genetic etiology were similar. CONCLUSION: Greater than 80% of BCG patients have PID; accordingly, gene sequencing should be performed in patients with BCG disease for early diagnosis. BCG disease behaves differently in patients with different types of PID. Patients without identified genetic etiology had similar outcomes to PID patients, which hints that they may have pathogenic gene mutations that need to be discovered.

Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients.

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confirmatory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults.

Safety and Immunogenicity of Recombinant Bacille Calmette-Guérin Strain VPM1002 and Its Derivatives in a Goat Model.

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats' health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4+, CD8+, and γδ T cells showed that CD4+ T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats.

Inborn Errors of Immunity in Patients with Adverse Events Following BCG Vaccination in Brazil.

OBJECTIVE: The Bacille Calmette-Guérin (BCG) vaccine is routinely applied in Brazil. Adverse events (AE) may occur in patients with inborn or acquired immunodeficiencies, varying between local (BCGitis) or disseminated (BCGosis) reactions. We evaluated 53 individuals with local or disseminated adverse events to BCG vaccination to assess if they had inborn errors of immunity (IEI). METHODS: Patients diagnosed with an adverse event following BCG vaccination between 2014 and 2017 were included in the study. We collected clinical data, immunophenotyped T and B lymphocytes, and natural killer cells (NK), assessed oxidative function of neutrophils through dihydrorhodamine (DHR) 123 testing, and genotyped 361 genes related to IEI through targeted (panel) sequencing. RESULTS: The median age of the 53 individuals was four months (IQ 1.5-12), and 52.8% were male. Forty-eight (90.6%) individuals presented only locoregional AE and five (9.4%) presented both locoregional and disseminated AE. Nine (16.9%) patients were diagnosed with an IEI. Four of them presented BCGitis and five presented BCGosis after BCG vaccination. Clinically, four presented chronic granulomatous disease (CGD), three Mendelian susceptibility to mycobacterial disease (MSMD), and two severe combined immunodeficiency (SCID). Patients with IEI had a higher frequency of systemic symptomatology (p = 0.002), history of other infections (p < 0.001), parental consanguinity (p = 0.01), familial history of sick siblings (p < 0.001), or early deaths in the family (p < 0.01). CONCLUSION: There is a high frequency of IEI in patients with locoregional and disseminated adverse events to BCG vaccination, revealing the need for the investigation of IEI accompanied by clinical and familial inquiry.

Predictive value of immunological markers after bacille Calmette-Guérin induction in bladder cancer.

OBJECTIVES: To investigate the predictive value of different immunological markers on treatment outcomes after bacille Calmette-Guérin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients who underwent transurethral resection of bladder tumour for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before first dose of induction) and after induction (4 h after last [sixth] dose). Urine samples were evaluated for interleukin (IL)-2 and IL-10 by solid-phase enzyme-linked immunosorbent assay. Blood samples were evaluated for tumour necrosis factor α (TNF-α), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and transcription factors (TFs) (GATA-binding protein 3 [GATA3], T-box expressed in T cells [T-bet], and forkhead box protein 3 [FoxP3]) using quantitative reverse transcriptase-polymerase chain reaction analysis. Change pattern and fold change of each evaluable marker was assessed in relation to different treatment outcomes (initial complete response [ICR]/recurrence/progression). RESULTS: Between July 2013 and May 2019, 204 patients were included. Among evaluable markers, urinary IL-2 and serum TNF-α increased in all patients, serum CTLA-4 and FoxP3+ showed a predominant decreased pattern in 188 (92.2%) and 192 (94.1%) patients, respectively. An ICR was achieved in 186 (91.2%) patients. Serum TNF-α fold change and urinary IL-10 change pattern were significantly associated with an ICR (P = 0.001 and P = 0.03, respectively). At a median (range) follow-up of 37 (20-88) months, 104 (56%) patients developed recurrence. Urinary IL-10, serum CTLA-4, T-bet+ , FoxP3+ change patterns and GATA3+ /T-bet+ ratio were significantly associated with tumour recurrence (P = 0.001, P = 0.001, P = 0.02, P = 0.009 and P = 0.001, respectively). Tumour progression occurred in 34 (18.3%) patients. Urinary IL-10, serum CTLA-4, serum T-bet+ change patterns and GATA3+ /T-bet+ ratio were independent predictors of tumour progression (P = 0.001, P = 0.001, P = 0.02 and P = 0.001, respectively). CONCLUSIONS: Urinary IL-10 and serum TNF-α can significantly predict ICR. Moreover, change pattern of urinary IL-10, serum CTLA-4, TFs (GATA3, T-bet and FoxP3) and GATA3+ /T-bet+ ratio after BCG induction can independently predict further BCG response. These markers could be implemented in clinical practice when management options are discussed or in systems with severe BCG shortage.

Should patients with non-muscle-invasive bladder cancer discontinue fibrin clot inhibitors during bacille Calmette-Guérin?

OBJECTIVE: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate bacille Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence- and progression-free survival were analysed using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence- or progression-free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. CONCLUSION: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy.

Does bacillus Calmette-Guérin vaccine prevent herpes simplex virus recurrences? A systematic review.

Recurrent infections with herpes simplex virus (HSV) in the orofacial (cold sores), ocular or genital region are common and sometimes disabling, calling for an effective preventive intervention. The bacillus Calmette-Guérin (BCG) vaccine has beneficial off-target effects that might impact recurrence of HSV infections. In this systematic review, Medline, EMBASE, and PubMed were searched in June 2020; 16 articles were deemed relevant comprising eight animal and eight human studies (301 patients). In animals, BCG administration led to a 1.9 to 5.5-fold increase in survival rate following HSV challenge (vaginal, corneal, or intraperitoneal inoculation). This beneficial effect was influenced by the dose of BCG (higher better), mode of administration (intradermal better than intraperitoneal), and the interval between vaccination and viral challenge (at least 6 days required). In nonrandomized human studies (that failed to control for a placebo effect), BCG vaccination appeared beneficial in 78% of adults with recurrent herpes genitalis or labialis, with 37% being recurrence-free for an extended period, 41% experiencing less frequent or severe episodes, and only 22% reporting no change. This clinical benefit is consistent with the findings of immunological sub-studies. In the two studies restricted to recurrent herpes labialis, 94% appeared to benefit from BCG. The one randomized controlled trial used an intervention in the control group that has immunomodulatory effects thus limiting interpretation. In conclusion, BCG vaccine is a potential, safe, affordable and readily available candidate intervention to decrease the high burden of disease associated with HSV infection and recurrences, but properly controlled randomized trials are required.

Quality of Life, Efficacy, and Safety of Sequential Intravesical Gemcitabine + Docetaxel versus BCG for Non-Muscle Invasive Urinary Bladder Cancer: A Pilot Study.

PURPOSE: Bacille Calmette-Guerin (BCG) is considered the most effective agent for non-muscle invasive bladder cancer (NMIBC). However, due to BCG-related toxicity, multiple studies have suggested the role of newer chemotherapeutic drugs. The aim of our study was to evaluate intravesical gemcitabine + docetaxel (Gem/Doce) versus BCG with respect to quality of life (QOL), safety, and efficacy in NMIBC. METHODS: A total of 60 patients with NMIBC were evaluated between July 2019 and December 2020 in a prospective manner. The sample size calculation was done, keeping in mind the incidence of intravesical BCG-related complications of up to 50-60% and 20-30% for Gem/Doce combination. The p value of 0.05 was kept as statistically significant. The enrollment ratio was kept at 1, and power of study was aimed at 80%. The study population was alternatively assigned to two groups (BCG vs. Gem/Doce) of 30 patients each. Both the groups received 6 weekly doses of induction therapy followed by 6 monthly doses of maintenance therapy if no recurrence was noted at interim follow-up. QOL scores, safety, and efficacy were assessed at beginning of intravesical therapy, end of induction, and 6 months of maintenance therapy. Cystoscopy examination and cytology were performed at the end of induction therapy and 3-monthly thereafter. RESULT: The preliminary results at the end of 6 months following maintenance therapy showed that the demographic profile, histological stage, and grade were comparable between two groups. The QOL scores using QLQ-30 and QLQ-BLS-24 showed statistically significant differences with the Gem/Doce arm showing better outcomes. There were no progressions to higher stage, while one recurrence each was seen in both groups. Patient-related side effects measured by CTCAE (Common Terminology Criteria for Adverse Events)version 5 showed that the BCG group had higher toxicity profile as compared to Gem/Doce group. CONCLUSION: Gem/Doce combination intravesical therapy is a promising alternative to BCG for treatment of NMIBC, showing better QOL measures and lesser side effects.

The Association Between Bacille Calmette-Guérin Vaccination and Nontuberculous Mycobacterial Pulmonary Disease.

This study aimed to investigate the association between Bacille Calmette-Guérin (BCG) vaccination and nontuberculous mycobacterial pulmonary disease (NTM-PD). Patients in the prospective NTM-PD cohort were matched to healthy controls to measure the association between BCG and NTM-PD development. The clinical course of NTM-PD patients was also evaluated to investigate the association between BCG and NTM-PD progression. BCG scars were not associated with NTM-PD development (adjusted odds ratio [OR], 2.04; 95% confidence interval [CI], 0.96-4.34) or progression (adjusted OR, 1.61; 95% CI, 0.92-2.81). In conclusion, BCG vaccination was not associated with the development or progression of NTM-PD.

Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.

Immediate Bacille Calmette-Guérin Vaccination to Neonates Requiring Perinatal Treatment at the Maternity Ward in Guinea-Bissau: A Randomized Controlled Trial.

BACKGROUND: Randomized controlled trials (RCTs) indicate that bacille Calmette-Guérin (BCG) vaccination provides broad beneficial "nonspecific" protection against infections. We investigated the effect on in-hospital mortality of providing BCG immediately upon admission to a neonatal intensive care unit (NICU), rather than BCG-at-discharge. The pretrial NICU mortality was 13% and we hypothesized that BCG would reduce mortality by 40%. METHODS: Parallel-group, open-label RCT was initiated in 2013 in Guinea-Bissau. Neonatal intensive care unit-admitted neonates were randomized 1:1 to BCG + oral polio vaccine (OPV) immediately (intervention) versus BCG + OPV at hospital discharge (control; usual practice). The trial was discontinued due to decreasing in-hospital mortality and major NICU restructuring. We assessed overall and disease-specific mortality by randomization allocation in cox proportional hazards models providing mortality rate ratios (MRRs). RESULTS: We recruited 3353 neonates, and the overall mortality was 3.1% (52 of 1676) for BCG-vaccinated neonates versus 3.3% (55 of 1677) for controls (MRR = 0.94; 0.64-1.36). For noninfectious causes of death, the MRR was 1.20 (0.70-2.07), and there tended to be fewer deaths from infections in the BCG group (N = 14) than among controls (N = 21) (MRR = 0.65; 0.33-1.28). CONCLUSIONS: Providing BCG + OPV to frail neonates was safe and might protect against fatal infection in the immediate newborn period. Deaths due to prematurity and perinatal complications were unaffected by BCG.

Time interval from transurethral resection of bladder tumour to bacille Calmette-Guérin induction does not impact therapeutic response.

OBJECTIVES: To investigate bacille Calmette-Guérin (BCG) tolerability and response with respect to the timing of BCG administration after transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A review of patients with NMIBC at our institution managed with at least 'adequate BCG' (defined by the United States Food and Drug Administration as at least five of six induction instillations, with two additional instillations comprising either maintenance or repeat induction) at our institution from 2000 to 2018 was performed. Time from TURBT to first instillation of induction BCG was stratified by quartile and analysed as a continuous variable. Kaplan-Meier and log-rank tests analysed differences in recurrence-free (RFS) and progression-free survival (PFS). Cox proportional hazards regression models identified associations between risk factors and survival outcomes. RESULTS: A total of 518 patients received adequate BCG at a median (range) of 26 (6-188) days from TURBT. Overall, 45 patients (9%) developed BCG intolerance at a median (range) 12 (7-33) instillations. When time from TURBT to BCG was stratified into quartiles, there was no difference with respect BCG intolerance (P = 0.966), RFS (P = 0.632) or PFS (P = 0.789). On both uni- and multivariate regression analysis for RFS and PFS, time from TURBT to BCG was not a significant predictor when analysed by quartile or as a continuous variable (the hazard ratio for RFS was 1.00, 95% confidence interval [CI] 0.99-1.00, P = 0.449; and for PFS was 0.99, 95% CI 0.98-1.00, P = 0.074). CONCLUSION: The rates of tolerability and response to adequate BCG are not predicated by the timing of induction BCG instillation after TURBT. Early administration in properly selected patients is safe and delays do not affect therapeutic response.

Worldwide inverse correlation between Bacille Calmette-Guérin (BCG) immunization and COVID-19 mortality.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has spread to all countries in the world, and different countries have been impacted differently. The study aims to understand what factors contribute to different COVID-19 impacts at the country level. METHODS: Multivariate statistical analyses were used to evaluate COVID-19 deaths and cases relative to nine other demographic and socioeconomic factors in all countries and regions of the world using data as of August 1, 2020. The factors analyzed in the study include a country's total COVID-19 deaths and cases per million population, per capita gross domestic product (GDP), population density, virus tests per million population, median age, government response stringency index, hospital beds availability per thousand population, extreme poverty rate, Bacille Calmette-Guérin (BCG) vaccination rate, and diphtheria-tetanus-pertussis (DTP3) immunization rate. RESULTS: The study reveals that COVID-19 deaths per million population in a country most significantly correlates, inversely, with the country's BCG vaccination rate (r = - 0.50, p = 5.3e-5), and also significantly correlates a country's per capita GDP (r = 0.39, p = 7.4e-3) and median age (r = 0.30, p = 0.042), while COVID-19 cases per million population significantly correlate with per capita GDP and tests per thousand population. To control for possible confounding effects of age, the correlation was assessed in countries propensity score matched for age. The inverse correlation between BCG vaccination rates and COVID-19 case (r = - 0.30, p = 0.02) and death (r = - 0.42, p = 0.0007) remained significant among the top 61 countries with the highest median age. CONCLUSION: This study contributes to a growing body of evidence supporting the notion that BCG vaccination may be protective against COVID-19 mortality.

The role of surgical management of BCG vaccine-induced regional suppurative lymphadenitis in children: a 7 years' experience from one medical center.

BACKGROUND: The management strategy of Bacille Calmette-Guérin (BCG) vaccine-induced regional suppurative lymphadenitis in children is still controversial and more clinical studies are needed. We therefore present a surgical case series to explore the role of surgical management for this dilemma. METHODS: From January 2013 to June 2020, data from 65 patients diagnosed with BCG vaccine-induced regional suppurative lymphadenitis were retrospectively reviewed. Clinical characteristics, ultrasonographic findings, surgical procedures, perioperative management, and outcome were analyzed. The association between postoperative seroma and symptom duration, skin involvement, and postoperative hospital stay were compared using Yates's corrected Chi-square test and Student's t-test for statistical analysis. The follow-up period ranged from three to six months. RESULTS: Of the 65 cases, the median age at presentation was 3.4 months. All patients were full-term with normal range of birth weight and received a BCG vaccination in the first 24 h of life. All patients underwent surgical excision of the abscess with the involved lymph node(s). Postoperative seroma formation was found in 20 patients and fine needle aspiration was needed. There was no significant association between postoperative seroma formation with symptom duration, skin involvement, and postoperative hospital stay. No oral anti-tubercular agents were given postoperatively. The mean length of postoperative hospital stay was 6.02 ± 1.62 days. Sixty-four cases (98.46%) received only one procedure and recovered. One patient required a second procedure due to postoperative sinus. CONCLUSIONS: The present study showed that surgical excision of the abscess with involved lymph node(s) is one of the choices for BCG vaccine-induced suppurative lymphadenitis, but special attention should be paid to controlling the surgical indications. Intraoperative meticulous manipulation and postoperative care are crucial to achieve a good outcome.

The frequency and related factors of non-tuberculosis mycobacteria infections among patients with cystic fibrosis.

BACKGROUND: Non-tuberculous mycobacteria (NTM) can cause chronic lung infection particularly in patients who have structural lung disease such as cystic fibrosis (CF). We evaluated the incidence and management of NTM infections in patients with CF in our center. METHODS: A retrospective cohort study was carried out on CF patients having at least one positive NTM isolate between 2012 and 2020. RESULTS: Ten patients (2.1%) had at least one positive NTM culture from respiratory samples. All of them were vaccinated with Bacille Calmette-Guérin (BCG) vaccine, which is in the national vaccination program in our country. Eight patients had the Mycobacterium abscessus complex, one had Mycobacterium avium, and one had Mycobacterium szulgai growth in their respiratory samples. Three patients had transient NTM infection, two had persistent, and five had active NTM infection (NTM pulmonary disease). Patients with NTM pulmonary disease received antibiogram-directed antimycobacterial therapy. In patients with NTM pulmonary disease, the median ppFEV1 and BMI decreased by 17% and 1%, respectively, at the time of the first NTM isolation when compared with the values one year before the first NTM isolation. Culture conversion was not seen in any patient infected with Mycobacteriunm abscessus complex. CONCLUSIONS: The NTM infection incidence is lower in our country than in those countries where the BCG vaccine is not routinely applied. The BCG vaccine may be a protective factor for NTM infection. Further studies are needed about the prevalence of NTM infections, facilitating and protective factors, and appropriate management of NTM infections in patients with CF.

Need for BCG Vaccination to Prevent TB in High-Incidence Countries and Populations.

An estimated one quarter of persons worldwide are infected with Mycobacterium tuberculosis. In 2018, the World Health Organization issued revised guidance on BCG vaccine for high-risk groups. The World Health Organization should consider guiding countries on a case-by-case basis in developing appropriate BCG policies to deliver equitable healthcare and protect public health.