Bacille Calmette-Guérin Disease Research Articles

Stem Cell Transplant in Immune-deficiency-associated Vaccine-derived Poliovirus.

Patients with severe primary immunodeficiency are at risk for complications from live-attenuated vaccines. Here, we report a case of a vaccine-associated paralytic polio and Bacille Calmette-Guérin disease in a 6-month-old girl with severe combined immunodeficiency resulting from homozygous recombinant activating gene 1 deficiency. The patient was successfully treated with intravenous immunoglobulins and oral pocapavir for poliovirus, and antimycobacterial therapy for regional Bacille Calmette-Guérin disease, allowing stem cell transplant. Following transplantation, poliovirus type 3 with 13 mutations was detected from cerebrospinal fluid but not from stool, indicating ongoing viral evolution in the central nervous system despite pocapavir treatment. Clinical improvement and immune reconstitution allowed the patient to be successfully discharged with no further detection of poliovirus.

Mycobacterium Tuberculosis Complex in Children Clinical, Radiological Features, Management, Outcome and Susceptibility Pattern

Introduction Mycobacterium tuberculosis complex MTC is a major cause of morbidity and mortality globally. The Bacille Calmette-Guérin (BCG) vaccine is most commonly used worldwide. Disseminated BCG disease is one of the vaccine complications that may occur in immunocompromised children. Methods Retrospective study from January 2009 to December 2022. Results We evaluated 66 patients with microbiologically documented M. tuberculosis complex. Immunocompetent were 28 while 38 were immunocompromised. Our data include 46 patients with BCG-related infections. The majority of 26 patients were diagnosed with disseminated BCGiosis, and local BCGitis was found in 20 out of 46. Remaining 20 patients constitute non-BCG-related infections. Chest radiography done in 58 patients and 10.6% had abnormal findings specific for TB. Other image was mainly done for disseminated BCGiosis. The overall acid-fast bacillus AFB smear was positive in 42.4%, polymerase chain reaction (PCR) positive in 75.8% and positive cultures in 97%. Susceptibility of all samples showed high resistance of pyrazinamide 78.2%, and INH 57.8%, while low resistance to RIF and ethambutol. A further subanalysis of the non-BCG group only showed a drop of resistance to 30% for the related group; all strains were pyrazinamide resistant in the same line with the fact that BCG strain is intrinsically resistant to pyrazinamide, all our patients were 100% resistant. We observed four medications showed some advantage over three-drug regimens with respect to mortality in immunocompromised group. The overall outcome in all patients showed 10.6% mortality. Majority were in disseminated BCGiosis, in which 19.2% died. Conclusion: Our center is the main referral hospital in the kingdom with a large number of patients that will help in understanding local data more. Performance of smear and PCR showed variation in relation to different TB diagnoses and sensitivity patterns, giving us insight into different MTB complex strain characteristics that would help in treatment. Sensitivity pattern data will help in keeping updated treatment protocol locally. We recommend managing disseminated BCGiosis with at least four antimycobacterial agents.

The Spectrum of Bacille Calmette-Guérin Diseases in Children-A Decade of Data from Neonatal Vaccination Settings.

In this paper, we present a multicentre record-based descriptive study used to estimate the incidence and characterize the spectrum of confirmed bacille Calmette–Guérin (BCG) vaccine-related disease among children in Oman. This study included all children (age ≤ 14 years) who had culture and/or polymerase chain reaction (PCR)-confirmed BCG disease from January 2006 to December 2018, as identified from Central Public Health Laboratory data and International Classification of Diseases coding of an electronic patient information system. In total, 88 children confirmed to have BCG disease were included in the study, making an average incidence of 9.2 cases per 100,000 vaccinated neonates. The males comprised 65.9%, Omanis 93.2%, and the median age of presentation was 4 months in children with BCG disease. The most common type of disease was BCG abscesses (72.4%). Children with immunodeficiency and those presenting within 6 months were found to have a more severe and disseminated disease. In total, 28 children had immunodeficiency. The age of presentation and type of BCG disease was significantly associated with immunodeficiency status. The majority of cases required therapy (both medical and surgical) and recovered well. The incidence of laboratory-confirmed BCG vaccine-related disease was low in Oman supporting continuing the use of the BCG vaccination practice at birth.

Investigation of adverse events following bacille Calmette-Guérin immunization using immunization safety surveillance system in Korea Centers for Disease Control and Prevention.

PurposeThe report of adverse events following immunization (AEFI) in Korea has continued since 1994, and the most frequently reported cases of AEFI of Korea Centers for Disease Control and Prevention (KCDC) is bacille Calmette-Guérin (BCG). Meanwhile, various inoculation methods and strains have been used in the past 6 years in Korea. Therefore, we investigated AEFI of BCG by strain types and inoculation methods using immunization safety surveillance of KCDC.Materials and MethodsWe reviewed BCG AEFIs registered in the KCDC from January 2013 to June 2018.ResultsThere were 336 AEFI cases during the period, and average time interval from vaccination to symptom onset was within 2 months. AEFI proportion was 6.4 cases per 100,000 doses for BCG percutaneous Tokyo strain, 41.6 cases per 100,000 doses of BCG intradermal Danish strain, and 25.9 cases per 100,000 doses of BCG intradermal Tokyo strain. Intradermal type was more reported AEFI than percutaneous type in the same strain. The most common adverse events were local reaction like BCG lymphadenitis and severe adverse reactions such as osteomyelitis or disseminated BCG disease were 0.1 to 0.2 cases per 100,000 doses which are correlated with the range of World Health Organization published AEFI rates.ConclusionThe AEFI reporting rate does not equal the actual proportion of AEFI occurrence. Because AEFI monitoring is a passive surveillance system, various factors might influence the number of events reported. Nevertheless, it is important to analyze BCG AEFI by vaccine strains and inoculation method using surveillance data of KCDC.

Life-Threatening Infections Due to Live-Attenuated Vaccines: Early Manifestations of Inborn Errors of Immunity.

Live-attenuated vaccines (LAVs) can protect humans against 12 viral and three bacterial diseases. By definition, any clinical infection caused by a LAV that is sufficiently severe to require medical intervention attests to an inherited or acquired immunodeficiency that must be diagnosed or identified. Self-healing infections can also result from milder forms of immunodeficiency. We review here the inherited forms of immunodeficiency underlying severe infections of LAVs. Inborn errors of immunity (IEIs) underlying bacille Calmette-Guérin (BCG), oral poliovirus (OPV), vaccine measles virus (vMeV), and oral rotavirus vaccine (ORV) disease have been described from 1951, 1963, 1966, and 2009 onward, respectively. For each of these four LAVs, the underlying IEIs show immunological homogeneity despite genetic heterogeneity. Specifically, BCG disease is due to inborn errors of IFN-γ immunity, OPV disease to inborn errors of B cell immunity, vMeV disease to inborn errors of IFN-α/β and IFN-λ immunity, and ORV disease to adaptive immunity. Severe reactions to the other 11 LAVs have been described yet remain "idiopathic," in the absence of known underlying inherited or acquired immunodeficiencies, and are warranted to be the focus of research efforts. The study of IEIs underlying life-threatening LAV infections is clinically important for the affected patients and their families, as well as immunologically, for the study of the molecular and cellular basis of host defense against both attenuated and parental pathogens.

Disseminated Bacille Calmette-Guérin Infection in Immunodeficient Infants: Report of Two Cases

Introduction: The Bacille Calmette-Guerin (BCG), a live attenuated Mycobacterium bovis vaccine, is administered to all the newborns in Tunisia in order to prevent Tuberculosis (TB). Complications of this vaccine are uncommon. However, it poses a risk for children with unknown immunodeficiency. Case Presentation: We report on disseminated BCG disease in two infants, respectively, with severe combined immunodeficiency and human immunodeficiency virus (HIV). Evolution was fatal for both, despite adequate anti-tuberculosis treatment. Conclusions: Molecular methods are available to respond to the urgent need for rapid and specific diagnosis of local/regional or systemic BCG disease, using available commercial kits GenoType® MTBC and GenoType® MTBDRplus. These tests allow prevention of inoculation of live vaccines such as BCG among the next siblings until appropriate screening tests exclude primary or secondary immunodeficiency syndromes.

Disseminated BCG disease with unusual manifestations

Abstract Bacille Calmette–Guerin (BCG) vaccine – although considered safe in infants, is associated with complications – ranging from local and regional complications to the disseminated form of BCG disease. We report an interesting case of fever of unknown origin in an infant, closely mimicking hematological malignancy and Langerhans cell histiocytosis (LCH). Investigations revealed disseminated BCG disease with underlying immunodeficiency.

Bécégites de l’enfant : diagnostic, classification et exploration

The Bacille Calmette-Guérin (BCG) vaccine is used extensively worldwide, and more than 100 million children are vaccinated each year. This is a live vaccine that protects against severe tuberculosis in children. However, BCG complications, specific to the BCG vaccine, do occur, although the epidemiology differs from one country to another. Nevertheless, these complications are considered to be rare and range from benign local BCGitis to BCGosis, a potentially lethal disseminated disease. Etiologies of BCGitis/BCGosis can be related to the vaccine itself (technical errors, vaccinal strain) or to the patient. Indeed, it is well established that some immunodeficiencies, primary or acquired, can expose the patient to BCG disease. The diagnosis of a BCG disease lies on clinical examination and laboratory results. Recent advances in molecular biology help to distinguish BCG disease from other mycobacterial infections, especially from tuberculosis. When BCG complications have been confirmed, the underlying defect should be investigated, particularly if other features of immunodeficiency are reported, such as recurrent infection, failure to thrive, etc. Prognosis largely depends on the immune status, but also on the management of the BCG disease. Although the therapeutic protocols are still controversial, there are more and more publications on the diagnosis and management guidelines of the disease.

IRF8Mutations and Human Dendritic-Cell Immunodeficiency

The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).

Diffuse bony involvement in disseminated BCG disease in a patient with possible severe combined immune deficiency (SCID)

BCG (bacille Calmette-Guerin) vaccination is carried out worldwide to prevent tuberculosis. It is considered to be very effective and has an excellent safety profile, but complications do occur. These may range from erythema and abscess at the site of inoculation to extensive disseminated disease including regional and distant lymphadenopathy, lymphadenitis, musculoskeletal lesions and non-fatal and fatal disseminated infections, depending upon the immune status of the patient. Osteomyelitis is a rare but serious complication that may have a fatal outcome. We report a case of severe tuberculous osteomyelitis secondary to BCG vaccination in a child with possible severe combined immune deficiency.

Bacille Calmette–Guérin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families

Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-γ production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guérin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-γ. The β1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti-mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23-IFN-γ axis.

Disseminated bacille Calmette–Guérin infection in two patients with CD8+ T-cell lymphopenia

To the Editors: Intravesical bacille Calmette–Guerin (BCG) therapy is an effective treatment for high-risk superficial bladder cancer. A nonspecific immune response is expected after instillation of BCG, an alive but attenuated strain of Mycobacterium bovis . Disseminated BCG disease is a rare but well known complication of this therapy. It occurs in approximately 1% of cases 1. Severe complications could occur with hepatitis and pneumonitis but bone marrow involvement is exceptional. There are limited data on factors associated with the risk of BCG infection. The role of CD4+ T-cells in controlling mycobacteria infection is well established and the susceptibility of HIV-infected individuals for tuberculosis is an argument for this 2. Nevertheless, CD8+ T-cells play a significant role in this control, in particular secreting interferon (IFN)-γ and killing infected cells given their cytotoxic potential 3. Furthermore, experimental studies have shown that CD8+ T-cells play an important role in the early control of mycobacteria infection in older mice 4, suggesting that this may be occurring in elderly people. The present study describes two disseminated BCG infections, including bone marrow involvement, in elderly patients. Severe CD8+ T-cell depletion was found in the two patients, which illustrates the importance of CD8+ T-cells in the early control of mycobacterial infection in humans. The first patient was a 74-yr-old male, admitted in our department for fever and chills. He had concomitant weight loss of 6 kg and intense fatigue over the last 15 days. 3 months earlier he had undergone a trans-urethral resection for superficial bladder cancer. Treatment was completed by weekly instillation of BCG. A few days after the second instillation, the patient noted gradual onset of fever. 3 weeks after the onset of fever, he was referred to our hospital. Clinical examination gave no conclusive results but the biological results showed elevated C-reactive protein …

Disseminated bacille Calmette-Guerin disease in HIV-infected South African infants

To determine the population-based incidence of disseminated bacille Calmette-Guérin (BCG) disease in HIV-infected infants (aged <or= 1 year) in a setting with a high burden of tuberculosis and HIV infection coupled with a well-functioning programme for the prevention of HIV infection in infants. The numerator, or number of new cases of disseminated BCG disease, was derived from multicentre surveillance data collected prospectively on infants with a confirmed HIV infection during 2004-2006. The denominator, or total number of HIV-infected infants who were BCG-vaccinated, was derived from population-based estimates of the number of live infants and from reported maternal HIV infection prevalence, vertical HIV transmission rates and BCG vaccination rates. The estimated incidences of disseminated BCG disease per 100 000 BCG-vaccinated, HIV-infected infants were as follows: 778 (95% confidence interval, CI: 361-1319) in 2004 (vertical HIV transmission rate: 10.4%); 1300 (95% CI: 587-2290) in 2005 (transmission rate: 6.1%); and 1013 (95% CI: 377-1895) in 2006 (transmission rate: 5.4%). The pooled incidence over the study period was 992 (95% CI: 567-1495) per 100 000. Multicentre surveillance data showed that the risk of disseminated BCG disease in HIV-infected infants is considerably higher than previously estimated, although likely to be under-estimated. There is an urgent need for data on the risk-benefit ratio of BCG vaccination in HIV-infected infants to inform decision-making in settings where HIV infection and tuberculosis burdens are high. Safe and effective tuberculosis prevention strategies are needed for HIV-infected infants.

Bacille Calmette–Guerin vaccine-induced disease in HIV-infected and HIV-uninfected children

Bacille Calmette-Guerin (BCG)--a live attenuated vaccine--is routinely given to neonates in settings where tuberculosis is endemic irrespective of human immunodeficiency virus (HIV) exposure. HIV infected infants and other immunodeficient infants are at risk of BCG-related complications. We report the presentation treatment and mortality of children who develop BCG disease with emphasis on HIV-infected children. In addition we present a revised classification of BCG disease in children and propose standard diagnostic and management guidelines. This retrospective hospital-based study was conducted in the Western Cape Province South Africa. Mycobacterium tuberculosis complex isolates recovered from children aged < 13 years during the period of August 2002 through January 2005 were speciated by polymerase chain reaction to confirm Mycobacterium bovis BCG. Clinical data were collected through medical file review. BCG disease was classified according to standard and revised disease classifications. Mortality was assessed at the end of the study period. BCG disease was diagnosed in 25 children; 22 (88%) had local disease and 8 (32%) had distant or disseminated disease; 5 children (20%) had both local and distant or disseminated disease. Seventeen children were HIV infected; 2 children had other immunodeficiencies. All 8 children with distant or disseminated disease were immunodeficient; 6 were HIV infected. The mortality rate was 75% for children with distant or disseminated disease. BCG vaccination poses a risk to infants perinatally infected with HIV and to other primary immunodeficient children. The proposed pediatric BCG disease classification reflects clinically relevant disease categories in HIV-infected children. The suggested diagnostic and treatment guidelines should improve existing case management and surveillance. Prospective evaluation of management strategies for BCG disease in HIV infected and HIV-uninfected children is essential. (authors)

The risk of disseminated Bacille Calmette-Guerin (BCG) disease in HIV-infected children

Objectives Bacille Calmette-Guerin (BCG), a live attenuated Mycobacterium bovis vaccine, poses a risk to human immunodeficiency virus (HIV)-infected children; this risk has not been well quantified. We estimate the risk of disseminated BCG disease in HIV-infected children in a setting highly endemic for tuberculosis and HIV. Design and methods We conducted a prospective hospital-based surveillance study in the Western Cape Province, South Africa. Clinical and laboratory-confirmed cases of disseminated BCG disease in children <1 year of age from January 2002 to December 2004 at a referral hospital were used as numerator data. Denominator data for calculations of disseminated BCG risk were obtained through estimating the total number of HIV-infected infants receiving BCG based on the known vaccination coverage in the study setting, combined with population data on the total number of children <1 year of age, the known HIV prevalence amongst women attending public antenatal care facilities and different scenarios (5–15%) for the rate of vertical HIV transmission. Results Nine cases of disseminated BCG disease were identified over the study period, seven of these were in HIV-infected infants. The estimated risk for HIV-infected infants to develop disseminated BCG disease, given a 95% BCG coverage and an HIV prevalence of 12.4–15.4% amongst women, were as follows for different scenarios of vertical HIV transmission: 329–417/100,000 vaccinees (assuming 5% vertical HIV transmission), 164–208/100,000 vaccinees (assuming 10% vertical HIV transmission) and 110–139/100,000 vaccinees (assuming 15% vertical HIV transmission). Conclusions The risk of disseminated BCG disease is increased several hundred fold in HIV-infected infants compared to the documented risk in HIV-uninfected infants. Data on the protective effect of BCG in HIV-exposed and infected children is lacking. Population- and hospital-based surveillance is vitally important to more accurately estimate the safety and benefits of BCG in HIV-exposed and infected infants.

Bacille Calmette-Guerin Vaccine--Induced Disease in HIV-Infected and HIV-Uninfected Children

Bacille Calmette-Guérin (BCG)--a live, attenuated vaccine--is routinely given to neonates in settings where tuberculosis is endemic, irrespective of human immunodeficiency virus (HIV) exposure. HIV-infected infants and other immunodeficient infants are at risk of BCG-related complications. We report the presentation, treatment, and mortality of children who develop BCG disease, with emphasis on HIV-infected children. In addition, we present a revised classification of BCG disease in children and propose standard diagnostic and management guidelines. This retrospective, hospital-based study was conducted in the Western Cape Province, South Africa. Mycobacterium tuberculosis complex isolates recovered from children aged <13 years during the period of August 2002 through January 2005 were speciated by polymerase chain reaction to confirm Mycobacterium bovis BCG. Clinical data were collected through medical file review. BCG disease was classified according to standard and revised disease classifications. Mortality was assessed at the end of the study period. BCG disease was diagnosed in 25 children; 22 (88%) had local disease, and 8 (32%) had distant or disseminated disease; 5 children (20%) had both local and distant or disseminated disease. Seventeen children were HIV infected; 2 children had other immunodeficiencies. All 8 children with distant or disseminated disease were immunodeficient; 6 were HIV infected. The mortality rate was 75% for children with distant or disseminated disease. BCG vaccination poses a risk to infants perinatally infected with HIV and to other primary immunodeficient children. The proposed pediatric BCG disease classification reflects clinically relevant disease categories in HIV-infected children. The suggested diagnostic and treatment guidelines should improve existing case management and surveillance. Prospective evaluation of management strategies for BCG disease in HIV-infected and HIV-uninfected children is essential.

Danish bacille Calmette-Guérin vaccine-induced disease in human immunodeficiency virus-infected children.

An analysis of isolates of Mycobacterium tuberculosis complex was performed to determine the prevalence of bacille Calmette-Guérin (BCG) disease among human immunodeficiency virus (HIV)-infected children. Speciation was done with polymerase chain reaction; 183 isolates from mycobacterial cultures for 49 HIV-infected patients were analyzed. The Danish Mycobacterium bovis BCG strain was isolated from 5 patients. No cases of Tokyo M. bovis BCG strain disease were detected. All patients were asymptomatic at birth, <12 months of age, and severely immunodeficient at presentation. Four patients had regional axillary adenitis ipsilateral to the vaccination site, and 2 had pulmonary BCG disease. Two patients with regional BCG disease had simultaneous pulmonary M. tuberculosis infection. Although chest radiographic features were similar to those seen in patients with tuberculosis, BCG disease should be considered in HIV-infected infants with right axillary adenitis ipsilateral to the vaccination site. Young, symptomatic, HIV-infected infants are at risk for BCG-related complications. Controlled, population-based studies are needed to assess the risk of BCG in HIV-infected children.

Clinical Features and Outcome of Eleven Patients with Disseminated Bacille Calmette-Guérin (BCG) Infection

Disseminated BCG infection is a very rare complication of BCG vaccination. This study presents 11 patients with such complication. The underlying disease in eight of the 11 patients was primary imm...