Effective anti-mycobacterial treatment for BCG disease in patients with Mendelian Susceptibility to Mycobacterial Disease (MSMD): a case series.

BACKGROUND: Post-vaccination BCG disease typically attests to underlying inborn errors of immunity (IEIs), with the highest rates of complications in patients with Mendelian susceptibility to mycobacterial disease (MSMD). However, therapeutic protocols for the management of BCG-osis (disseminated) and persistent BCG-itis (localized) are still controversial. METHODS: Twenty-four Iranian patients with MSMD (BCG-osis or BCG-itis), followed from 2009 to 2020 in Tehran, were included in the study. Their medical records were retrospectively reviewed for demographics, clinical features, laboratory findings, and molecular diagnosis. The therapeutic protocol sheets were prepared to contain the types and duration of anti-mycobacterial agents. RESULTS: BCG disease either as BCG-itis (33.3%) or BCG-osis (66.7%) was confirmed in all patients by positive gastric washing test (54.2%), microbial smear and culture (58.3%), or purified protein derivative (PPD) test (4.2%). The duration between BCG-osis onset and MSMD diagnosis was 21.6 months. All except three patients were initiated on second-line anti-mycobacterial agents with either a fluoroquinolone (levofloxacin: 15 mg/kg/day, ciprofloxacin: 20 mg/kg/day, ofloxacin: 15 mg/kg/day), aminoglycoside (amikacin: 10-15 mg/kg/day, streptomycin: 15 mg/kg/day), and/or macrolide (clarithromycin: 15 mg/kg/day) along with oral rifampin (10 mg/kg/day), isoniazid (15 mg/kg/day), and ethambutol (20 mg/kg/day). Three patients showed a clinical response to rifampin, despite in vitro resistance. Fourteen (58.3%) patients received also adjuvant subcutaneous IFN-γ therapy, 50 µ/m2 every other day. At the end of survey, most patients (n = 22, 91.7%) were alive and two patients died following BCG-osis and respiratory failure. CONCLUSIONS: We recommend the early instigation of second-line anti-mycobacterial agents in MSMD patients with BCG disease.

Impaired IL-12- and IL-23-Mediated Immunity Due to IL-12Rß1 Deficiency in Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease.

PURPOSE: Inborn errors of IFN-γ-mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM). METHODS: In this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-γ, IL-12Rß1 expression on T cell blasts, and sequenced candidate genes. RESULTS: We report four patients from Isfahan, Iran, ranging from 3 months to 26 years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12Rß1 was completely abolished in the four patients with IL12RB1 mutations. CONCLUSIONS: IL-12Rß1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12Rß1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12Rß1-deficient patient, notified for the first time in this study.

Severe BCG-osis Misdiagnosed as Multidrug-Resistant Tuberculosis in an IL-12Rß1-Deficient Peruvian Girl.

PURPOSE: Mendelian suceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing to severe disease caused by mycobacteria and other intracellular pathogens. Delay in diagnosis can have an impact on the patient's prognosis. METHODS: We evaluated the IFN-γ circuit by studying IFN-γ production after mycobacterial challenge as well as IL-12Rß1 expression and STAT4 phosphorylation in response to IL-12p70 stimulation in whole blood of a 6-year-old Peruvian girl with disseminated recurrent mycobacterial infection diagnosed as multidrug-resistant tuberculosis. Genetic studies with Sanger sequencing were used to identify the causative mutation. Microbiological studies based on PCR reactions were used to diagnose the specific mycobacterial species. RESULTS: We identified a homozygous mutation in the IL12RB1 gene (p. Arg211*) causing abolished expression of IL-12Rß1 and IL-12 response. MSMD diagnosis led to a microbiological reevaluation of the patient, revealing a BCG vaccine-related infection instead of tuberculosis. Treatment was then adjusted, with good response. CONCLUSIONS: We report the first Peruvian patient with IL-12Rß1 deficiency. Specific mycobacterial species diagnosis within Mycobacterium tuberculosis complex is still challenging in countries with limited access to PCR-based microbiological diagnostic techniques. Awareness of MSMD warning signs and accurate microbiological diagnosis of mycobacterial infections are of the utmost importance for optimal diagnosis and management of affected patients.

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.

Clinical and Molecular Findings in Mendelian Susceptibility to Mycobacterial Diseases: Experience From India.

Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.

Pulmonary manifestations of urothelial carcinoma of the bladder.

Urothelial carcinoma (Transitional cell carcinoma) of the bladder is the pre-dominant histological type of bladder cancer in the United States and Europe. Patients with bladder cancer usually present with painless hematuria. The diagnosis is often delayed, as the symptoms are similar to various other benign conditions such as urinary tract infection, prostatitis or renal calculi. In some patients, the metastatic lesions will cause the initial presenting symptoms. We conducted a MedLine/PubMED search identifying all relevant articles with "pulmonary manifestations", "urothelial bladder cancer", "manifestations of bladder cancer" or a combination of these terms in the title. The pulmonary manifestations of urothelial carcinoma of the bladder include metastatic disease including cavitary lesions, endobronchial, pleural, or lymph node metastasis pleural effusion and chylothorax. Pulmonary embolism and tumor embolism is another manifestation of this cancer. Intravesical Bacillus Calmette-Gurin therapy for bladder cancer has been associated with a range of adverse effects including the systemic spread of Bacilli Calmette-Guérin immunotherapy affecting the lungs. Other drugs used to treat bladder cancer can be associated with drug-related pneumonitis. Other rare manifestations include a sarcoid like reaction and systemic granulomatous disease to Bacilli Calmette-Guérin therapy. In this review we discuss the various pulmonary manifestations of urothelial carcinoma of the bladder. A high index of suspicion with these presentations can lead to an early diagnosis and assist in instituting an appropriate intervention.

Systemic BCG-osis following intravesical BCG instillation for bladder carcinoma.

Intravesical instillation of Bacillus Calmette-Guérin (BCG) has been shown to be an effective form of immunotherapy for bladder cancer. This case report describes a patient who develops systemic BCG-osis following intravesical BCG instillation and demonstrates the importance of being aware of more severe complications associated with BCG immunotherapy.

Coexistence of early onset sarcoidosis and partial interferon-γ receptor 1 deficiency.

Pediatric sarcoidosis comprises a spectrum of childhood granulomatous inflammatory conditions. Pathological hallmark of the disease is granuloma formation that is seen in the affected tissues and almost any organ or system can be involved. There are two forms of pediatric sarcoidosis. One is seen in older children and the clinical picture is very similar to that of adult sarcoidosis and the other one is seen in early childhood. Sarcoidosis in early childhood can be divided as Blau syndrome (familial form) and early onset sarcoidosis (sporadic form). In both of the diseases there is a defect in the NOD2/CARD15 gene. The typical triad of early onset sarcoidosis is polyarthritis, dermatitis and uveitis. Interferon-γ receptor 1 deficiency is caused by defects in the IFNγR1 gene and non-tuberculosis mycobacterial pathogens are the leading causes of infections that start in early childhood. Herein we report a patient who presented with the symptoms of early onset sarcoidosis and also had partial interferon-γ receptor 1 deficiency that presented with BCG-osis. In addition to anti-mycobacterial treatment, methotrexate and prednisolone were used in therapy.