Rapid Diagnosis of Hemophagocytic Lymphohistiocytosis Triggered by Disseminated BCG Infection in Infants With Severe Combined Immunodeficiency: Case Report.

Hemophagocytic lymphohistiocytosis triggered by disseminated Bacillus Calmette-Guerin infection is rare. Targeted next-generation sequencing for tuberculosis can rapidly identify different strains of Mycobacterium tuberculosis complex as well as drug resistance genes. Herein we report 2 cases of hemophagocytic lymphohistiocytosis in whom targeted next-generation sequencing rapidly identified Bacillus Calmette-Guerin as the infectious trigger.

BCG Aortitis, a Rare Complication of BCG Therapy.

Introduction: Intravesical Bacillus Calmette-Guerin (BCG) is an effective treatment for in situ bladder carcinomas; however, extravesical BCG infection may occur in remote organs in patients with underlying primary immunodeficiency and is a potentially serious complication in 3-5% of cases. It includes granulomatous pneumonia, hepatitis as well as specific dermatological, ophthalmic, and haematopoietic manifestations. Diagnosis is difficult and often based on high clinical suspicion as in many cases Mycobacterium bovis is not isolated. This report presents a rare case of BCGaortitis treated in a tertiary care centre. Report: A 74 year old man, with a history of bladder cancer treated with BCG therapy over a year ago, presented with malaise, abdominal pain, anorexia, and significant weight loss for several months associated with acute on chronic renal failure and a tender aneurysm. He was diagnosed with hepatic BCGitis and pararenal BCGaortitis. He was considered too high risk for open surgery after a multidisciplinary team meeting and was treated with a four vessel physician modified endograft (PMEG) and antituberculous therapy. At seven month follow up, he was clinically well and control computed tomography showed a patent endograft with complete exclusion of the aortic aneurysm. Discussion: Infectious BCG complications after intravesical BCG administration for in situ bladder carcinomas can lead to severe early and late complications. In the present case, the patient presented with both liver and aortic BCG infection. The lack of positive microbiological data should not discourage clinicians from considering BCG infection even if several months have passed since the last BCG instillation.

Multiple Lytic Bone Lesions Mimicking Langerhans Cell Histiocytosis: A Case of Infantile Mendelian Susceptibility to Mycobacterial Disease due to STAT1 Deficiency.

We present the first infantile disseminated Bacillus Calmette-Guérin (BCG) disease case with STAT1 deficiency, which is manifested by multiple Langerhans cell histiocytosis-like osteolytic lesions. The diagnosis of BCG-induced osteomyelitis was not initially considered until the additional biopsy revealing granulomatous inflammation, a key pathological diagnostic component for mycobacterial infection.

Two cases of disseminated BCG disease following vaccination in the same family: case reports and review of the literature in China.

Disseminated bacillus Calmette-Guérin (BCG) disease is a rare and serious adverse event following immunization (AEFI) with BCG. Here, we reported two cases of disseminated BCG disease in the same family and reviewed the literature to identify another 35 cases in China. The average age at onset was 3.7 ± 2.1 months among the 37 cases and only 21 cases (56.8%) were laboratory confirmed. Of the 37 cases, 22 were evaluated for immunodeficiency; definite immunodeficiency was observed in 16 cases (72.7%) and could not be excluded in the other six cases (27.3%). Following treatment, 20 of the 37 cases died (54.1%), one case developed sequelae (2.7%), four cases had progressive disease (10.8%), nine cases had stable disease (24.3%), and only three cases were cured (8.1%). Vaccination of infants with BCG is cost-effective and should not be stopped because of the possibility of rare disseminated BCG disease, especially in countries with high tuberculosis burdens such as China. However, infants with a family history of immunodeficiency should be vaccinated after excluding immunodeficiency-related diseases to minimize the risk of disseminated BCG disease. Furthermore, government should strengthen proactive surveillance programs to detect and treat rare AEFIs early and improve disease outcomes.

Development of a Multiplex Real-Time PCR Assay for Mycobacterium bovis BCG and Validation in a Clinical Laboratory.

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a live attenuated vaccine which can result in local or disseminated infection, most commonly in immunocompromised individuals. Differentiation of BCG from other members of the Mycobacterium tuberculosis complex (MTBC) is required to diagnose BCG disease, which requires specific management. Current methods for BCG diagnosis are based on mycobacterial culture and conventional PCR; the former is time-consuming and the latter often unavailable. Further, there are reports that certain BCG strains may be associated with a higher rate of adverse events. This study describes the development of a two-step multiplex real-time PCR assay which uses single nucleotide polymorphisms to detect BCG and identify early or late BCG strains. The assay has a limit of detection of 1 pg BCG boiled lysate DNA and was shown to detect BCG in both pure cultures and experimentally infected tissue. Its performance was assessed on 19 suspected BCG clinical isolates at Christian Medical College in Vellore, India, taken from January 2018 to August 2020. Of these 19 isolates, 10 were identified as BCG (6 early and 4 late strains), and 9 were identified as other MTBC members. Taken together, the results demonstrate the ability of this assay to identify and characterize BCG disease from cultures and infected tissue. The capacity to identify BCG may improve patient management, and the ability to discriminate between BCG strains may enable BCG vaccine pharmacovigilance. IMPORTANCE Vaccination against tuberculosis with bacillus Calmette-Guérin (BCG) can lead to adverse events, including a rare but life-threatening complication of disseminated BCG. This complication often occurs in young children with immunodeficiencies and is associated with an ∼60% mortality rate. A rapid method of reliably identifying BCG infection is important because BCG requires treatment unique to tuberculosis. BCG is resistant to the first-line antituberculosis drug pyrazinamide. Additionally, diagnosis of BCG disease would lead to further investigation of a possible underlying immune condition. We have developed a diagnostic assay to identify BCG which improves upon previously published methods and can reliably identify BCG from bacterial culture or directly from infected tissue. This assay can also differentiate between strains of BCG, which have been suggested to be associated with different rates of adverse events. This assay was validated on 19 clinical isolates collected at Christian Medical College in Vellore, India.

Case Report: BCG-Triggered Hemophagocytic Lymphohistiocytosis in an Infant With X-Linked Recessive Mendelian Susceptibility to Mycobacterial Disease Due to a Variant of Chronic Granulomatous Disease.

In the United Arab Emirates, BCG (Bacillus Calmette-Guérin) is administered to all newborns. We present here a young infant with an inborn error of immunity (IEI) who developed fatal adverse events to this live-attenuated vaccine. This male infant received BCG (Serum Institute of India Pvt., Ltd., India) on Day 11 of life. On Day 25, he developed fever, followed by cervical lymphadenitis and bilateral otitis media with fluid drainage. On Day 118, he was admitted with severe hemophagocytic lymphohistiocytosis (HLH), and passed away on Day 145. The diagnostic exome sequencing test identified a hemizygous nonsense variant, NM_000397.3(CYBB):c.676C>T, p.Arg226* (rs137854592). Pathogenic variants of CYBB [cytochrome b(-245), beta subunit; Mendelian Inheritance in Man [MIM] accession code, 300481] are known to cause "immunodeficiency 34, mycobacteriosis, X-linked" (IMD34, MIM#300645) and "chronic granulomatous disease, X-linked" (CGDX, MIM#306400). The natural history of his illness is consistent with "X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD)." This entity is responsible for his BCG disease and is a likely trigger of his HLH. This disastrous event underlines the importance of developing worldwide policies that target BCG disease prevention, especially in communities with high prevalence of IEI. Moreover, screening for genetic causes of MSMD in the community could pave the way, at least partially, for scale-up of tuberculosis (TB) prevention.

Phylogenomic and epidemiological insights into two clinical Mycobacterium bovis BCG strains circulating in South Africa.

BACKGROUND: Mycobacterium bovis BCG is a live, attenuated tuberculosis vaccine. While the vaccine protects infants from tuberculosis, complications including disseminated infections have been reported following vaccination. Genetically diverse BCG sub-strains now exist following continuous passaging of the original Pasteur strain for vaccine manufacture. This genetic diversity reportedly influences the severity of disseminated BCG infections and the efficacy of BCG immunization. METHODS: M. bovis BCG was isolated from infants suspected of being infected with tuberculosis. The whole genome of the clinical isolates and BCG Moscow were sequenced using Illumina Miseq and the sequences were analysed using CLC Genomics Workbench 7.0, PhyResSE v1.0, and Parsnp. RESULTS AND CONCLUSIONS: Genetic variations between the clinical strains and the reference BCG Copenhagen were identified. The clinical strains shared only one mutation in a secretion protein. Mutations were identified in various antibiotic resistance genes in the BCG isolates, which suggests their potential as multidrug-resistant (MDR) phenotypes. Phylogenetic analysis showed that the two isolates were distantly related, and the M1_S48 clinical isolate was closely related to M. bovis BCG Moscow. The phylogenomics results imply that two different BCG strains may be circulating in South Africa. However, it is difficult to associate the BCG vaccine strain administered and the BCG strain supplied with specific adverse events, as BCGiosis is under-reported. This study presents background genomic information for future surveillance and tracking of the distribution of BCGiosis-associated mycobacteria. It is also the first to report on the genomes of clinical BCG strains in Africa.

Genetic and Clinical Profiles of Disseminated Bacillus Calmette-Guérin Disease and Chronic Granulomatous Disease in China.

Background: Disseminated Bacillus Calmette-Guérin disease (D-BCG) in children with chronic granulomatous disease (CGD) can be fatal, while its clinical characteristics remain unclear because both diseases are extremely rare. The patients with CGD receive BCG vaccination, because BCG vaccination is usually performed within 24 h after delivery in China. Methods: We prospectively followed-up Chinese patients with CGD who developed D-BCG to characterize their clinical and genetic characteristics. The diagnoses were based on the patients' clinical, genetic, and microbiological characteristics. Results: Between September 2009 and September 2016, we identified 23 patients with CGD who developed D-BCG. Their overall 10-year survival rate was 34%. We created a simple dissemination score to evaluate the number of infected organ systems and the survival probabilities after 8 years were 62 and 17% among patients with simple dissemination scores of ≤3 and >3, respectively (p = 0.0424). Survival was not significantly associated with the CGD stimulation index or interferon-γ treatment. Eight patients underwent umbilical cord blood transplantation and 5 of them were successfully treated. The genetic analyses found mutations in CYBB (19 patients), CYBA (1 patient), NCF1 (1 patient), and NCF2 (1 patient). We identified 6 novel highly likely pathogenic mutations, including 4 mutations in CYBB and 2 mutations in NCF1. Conclusions: D-BCG is a deadly complication of CGD. The extent of BCG spreading is strongly associated with clinical outcomes, and hematopoietic stem cell transplantation may be a therapeutic option for this condition.

Disseminated Mycobacterium bovis Infection Complicating Intravesical BCG Instillation for the Treatment of Superficial Transitional Cell Carcinoma of the Bladder.

BACKGROUND: Intravesical instillation of Bacillus Calmette-Guérin (BCG) remains a first-line treatment for superficial transitional cell carcinoma of the bladder. Although its use is relatively safe, severe complications such as granulomatous hepatitis, osteomyelitis, pneumonitis, and sepsis occur in few patients. Complications of intravesical instillation of BCG can be local or systemic, with early or late presentation. CASE PRESENTATION: Here, we report an 88-year-old man who developed fever, rigors, and episodes of syncope following fourth intravesical BCG instillation for the treatment of superficial transitional cell carcinoma of the bladder. Pancytopenia, disseminated intravascular coagulation, ground glass appearance on computerized tomography of the chest scan in addition to multiple bone marrow granulomas, suggested the diagnosis of disseminated BCG infection. All these features recovered on antituberculosis treatment. CONCLUSION: Our case study highlights the importance of early recognition and prompt treatment of patients with disseminated BCG infection following intravesical instillation. Although isolation of mycobacterium is desirable to make the diagnosis, it is not unusual to have negative smears and cultures and this should not be used to dismiss the possibility of BCG infection.

Clinical and laboratory observation of Bacillus Calmette-Guérin infections.

OBJECTIVE: To study the clinical features of BCG infection in children. METHODS: 51 cases confirmed with BCG infection from all over China were enrolled and followed up for at least 6 months. All cases were treated with anti-tuberculosis drugs. A random, open, group control study was designed in non-disseminated cases to evaluate curative effects of anti-tuberculosis drugs for early stage BCG infection. Disseminated cases were also closely monitored, and patients were given combined anti-tuberculosis drug therapy. RESULTS: In 34 (66.7%) non-disseminated cases, 19 children with local infections were treated with Isoniazid (Group A) and 15 were treated with Isoniazid and Rifampin (Group B). In the first 3 months, Group B responded better to anti- tuberculosis drug therapy than Group A (P<0.05). At the end of 6 months drug therapy, improvement rate was 100% of Group B vs. 89.5% of Group A (P<0.05). 33.3% children were admitted with disseminated BCG disease and were initially treated with Isoniazid and Rifampin. Most of these children responded poorly to drug therapies: Both isolated strains and BCG vaccination strain showed resistance to isoniazid, but susceptible to other First-line anti-tuberculosis drugs (Rifampin, Ethambutol and Streptomycin). CONCLUSION: INH does not perform well for treating BCG Chinese infections. Multiple drug regimens are necessary for treatment and preventing Drug-Resistance. Even for non-disseminated cases, preventive therapy using mono-isoniazid regimen is not suitable. BCG infections also occur in children without clear immunodeficiency, so parental education and awareness of health-care workers is essential for promptly recognition and handling BCG infections.