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PubMed2004

Neonatal BCG vaccine and response to the tuberculin test in BCG vaccinated children in contact with tuberculosis patients in Recife, Brazil.

This case-control study analyses the association between the tuberculin response and the neonatal BCG vaccine in 330 children under 15 who are home contacts of tuberculosis patients, taking into account risk factors for the transmission of infection. Interviews were conducted with 330 children, their parents or legal guardians. Chest X-rays were taken and the tuberculin test (TT) applied using 0.1 ml of PPD RT23, taking an induration reading of > or = 10 mm as the cut-off point for a positive test result. Prior BCG vaccination was ascertained by observing the presence of a scar on the deltoid region of the right arm. Six children were excluded because they had signs/symptoms of pulmonary tuberculosis, thereby reducing the final sample to 324 children. The multivariate analysis showed that being exposed to a patient with pulmonary lesions with cavities (OR = 3.14; CI: 1.59-6.20; p = 0.000), a positive sputum smear (OR = 3.65; CI: 1.52-8.78; p = 0.002) or a positive culture (OR = 4.42; CI: 1.39-14.1; p = 0.005), being under five (OR = 0.47; CI: 0.22-0.99; p = 0.045) are independently associated with a positive TT. The fact that a prior BCG scar is not associated with a positive response to the TT indicates the need to re-open discussion of the guidelines which exist in many poor countries where tuberculosis is still a serious public health problem. Such guidelines include those issued by the Brazilian Ministry of Health, which considers the child under 15 in contact with a tuberculosis case to be infected only if there is a TT of 10 mm or more and the child received no prior BCG vaccination.

Adolescent↗

PubMed1996

Identification of a 25-kilodalton protein of Mycobacterium bovis BCG to distinguish BCG strains from Mycobacterium tuberculosis.

Mycobacterium bovis BCG vaccine strains were compared with Mycobacterium tuberculosis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A 25-kDa protein observed in the BCG strains was absent in M. tuberculosis. Rabbit antibodies specific to the 25-kDa protein uniquely identified this protein in BCG strains but not in M. tuberculosis. It is suggested that the 25-kDa protein and polyclonal antibodies directed against this antigen can be exploited to distinguish BCG strains from M. tuberculosis.

Antibodies, Bacterial↗

PubMed1999

Mycobacterium bovis BCG causing vertebral osteomyelitis (Pott's disease) following intravesical BCG therapy.

We report a case of Mycobacterium bovis BCG vertebral osteomyelitis in a 79-year-old man 2.5 years after intravesical BCG therapy for bladder cancer. The recovered isolate resembled M. tuberculosis biochemically, but resistance to pyrazinamide (PZA) rendered that diagnosis suspect. High-pressure liquid chromatographic studies confirmed the diagnosis of M. bovis BCG infection. The patient was originally started on a four-drug antituberculous regimen of isoniazid, rifampin, ethambutol, and PZA. When susceptibility studies were reported, the regimen was changed to isoniazid and rifampin for 12 months. Subsequently, the patient was transferred to a skilled nursing facility for 3 months, where he underwent intensive physical therapy. Although extravesical adverse reactions are rare, clinicians and clinical microbiologists need to be aware of the possibility of disseminated infection by M. bovis BCG in the appropriate setting of clinical history, physical examination, and laboratory investigation.

Administration, Intravesical↗

PubMed1990

[A comparative clinical trial of UFT medication and intravesical BCG in the recurrence of superficial bladder cancer. Study Group of UFT and BCG adjuvant therapy for bladder cancer].

In sixty-four patients who had TUR-bt for superficial bladder cancer, the effect of intravesical BCG and UFT medication were compared. Group A (n = 20) were treated with BCG, group B (n = 22) were treated with UFT and group C (n = 22) were treated with both agents. The patients were followed up for more than 12 months by cystoscopy at a interval of 3 months, urinary cytology and bladder cold cup biopsy, if necessary. Thirteen of the 20 patients in group A and 13 of the 22 patients in group B were free of tumors, compared to 5 of the 22 patients in group C. Although the recurrence-free-rate in each group does not differ significantly, the combination therapy of intravesical BCG and UFT medication seems to decrease the rate of tumor recurrence for superficial bladder cancer. Side effects of BCG and UFT were tolerated well.

Administration, Intravesical↗

PubMed1987

BCG induced CD4+ cytotoxic T cells from BCG vaccinated healthy subjects: relation between cytotoxicity and suppression in vitro.

Mycobacterial antigen specific cytotoxic T cells killing antigen-pulsed antigen presenting cells (APC) were induced from peripheral blood mononuclear cells (PBMC) of BCG-vaccinated healthy subjects after activation in vitro with BCG. CD8+ depleted cells were as effective as PBMC, indicating that CD4+ cells play a dominant role in this phenomenon. CD4+ T cell clones raised against BCG also exhibited mycobacterial antigen specific cytotoxicity and suppressed BCG-driven selfproliferation. However, the same clones could either suppress or enhance the proliferation of other T cell clones from the same subject. The possible function in vivo of the cytotoxicity mediated by CD4+ T cells is discussed.

Antigens, Bacterial↗

PubMed1996

An audit of BCG immunisation and tuberculin skin testing in Scotland. Scottish BCG Study Group.

BACKGROUND: BCG vaccination of all tuberculin-negative schoolchildren has been undertaken in the United Kingdom since 1954. In light of the ten-fold decline in tuberculosis, mass vaccination may no longer be justified. Since most tuberculosis cases now occur among identifiable high-risk groups, restriction of vaccination to these groups may be more appropriate. Before such changes can be recommended, further information is required on current practice within Scotland. OBJECTIVE: To determine current BCG vaccination practice within Scotland, in order to inform planning of future immunisation services. DESIGN: Postal questionnaire survey. SETTING AND SUBJECTS: The questionnaires were posted to the Consultant in Public Health Medicine responsible for Communicable Disease Control in each of the fifteen Scottish Health Boards. RESULTS: Completed questionnaires were returned by all 15 Health Boards. Marked variations were reported in the vaccination of both schoolchildren and high-risk groups. Six (40%) Health Boards immunised all tuberculin-negative children, whereas the remainder excluded those with evidence of previous BCG vaccination. All Health Boards immunised contacts of tuberculosis cases, 11 offered it to healthcare workers and 11 to immigrants from countries with a high prevalence of tuberculosis. However, only 7 offered it to the offspring of high-risk ethnic groups, 5 to students and 4 to animal workers. CONCLUSION: There are marked variations in current BCG vaccination practice. Greater efforts are required to ensure that high-risk groups receive vaccination.

Adolescent↗

PubMed1997

[The need of prolonged BCG treatment in superficial bladder cancer is suggested by the development of a peripheral immune response induced by BCG].

Optimal duration of immunotherapy treatment by BCG for the prevention of recurrences of superficial bladder cancer is still unknown. We have studied the evolution and duration of the cellular immunity response at the peripheral level after BCG intravesical instillations. Our results show that immunity activation after BCG is of short duration and don't take more than 6 months. Our results support, strengthen and partially allow to explain the utility of maintenance treatment by BCG following 6-weekly instillations.

Adjuvants, Immunologic↗

PubMed1993

BCG-activated NK cells regulate the antibody response to SRBC and restore immune reactivity to PPD in BCG-infected mice.

C57B1/6 mice show a significant increase in the number of natural killer (NK) cells in the peritoneal cavity, four days after intraperitoneal infection with Mycobacterium bovis strain BCG. Cell transfer experiments demonstrated that BCG-induced NK cells are able to depress the induction of antibody response to an unrelated antigen (i.e., sheep red blood cells) in recipient mice. The involvement of macrophages, B and T cells in the phenomenon was ruled out by using different purification steps. In addition, BCG-induced NK cells were shown to be able of partially restoring the DTH response to PPD in recipient mice that were anergic to the latter antigen as a consequence of intravenous infection with large doses of BCG.

Animals↗

PubMed2006

Catalase-peroxidase of Mycobacterium bovis BCG converts isoniazid to isonicotinamide, but not to isonicotinic acid: differentiation parameter between enzymes of Mycobacterium bovis BCG and Mycobacterium tuberculosis.

Isonicotinic acid hydrazide (Isoniazid, INH) is one of the major drugs worldwide used in the chemotherapy of tuberculosis. Many investigators have emphasized that INH activation is associated with mycobacterial catalase-peroxidase (katG). However, INH activation mechanism is not completely understood. In this study, katG of M. bovis BCG was separated and purified into two katGs, katG I (named as relatively higher molecular weight than katG II) and katG II, indicating that there is some difference in protein structure between two katGs. The molecular weight of the enzymes of katG I and katG II was estimated to be approximately 150,000 Da by gel filtration, and its subunit was 75,000 Da as determined by SDS-PAGE, indicating that purified enzyme was composed of two identical subunits. The specific activity of the purified enzyme katG I was 991.1 (units/mg). The enzymes were then investigated in INH activation by using gas chromatography mass spectrometry (GC-MS). The analysis of GC-MS showed that the katG I from M. bovis BCG directly converted INH (Mr, 137) to isonicotinamide (Mr, 122), not to isonicotinic acid (Mr, 123), in the presence or absence of H2O2. Therefore, this is the first report that katG I, one of two katGs with almost same molecular weight existed in M. bovis BCG, converts INH to isonicotinamide and this study may give us important new light on the activation mechanism of INH by KatG between M. bovis BCG and M. tuberculosis.

Bacterial Proteins↗

PubMed1996

Mice that carry the resistance allele of the Bcg gene (Bcgr) develop a superior capacity to stabilize bacille Calmette-Guerin (BCG) infection in their lungs and spleen over a protracted period in the absence of specific immunity.

In mice, natural resistance to infection with BCG is under the influence of an autosomal gene designated Bcg. It is shown here in agreement with others that mice that possess the dominant resistant allele of the gene (Bcgr) are more capable than mice that possess the susceptible recessive allele (Bcgs) at restricting the growth of BCG in their lungs, as well as in their spleens, during the first 20 days of infection. It is shown, in addition, that in the absence of specific immunity the resistance difference between Bcgr and Bcgs mice became much more pronounced as infection progressed beyond day 20. Whereas T cell-depleted Bcgr mice developed a capacity after day 20 to cause infection in their lungs and spleens to stabilize and plateau for at least 40 days, T cell-depleted Bcgs mice were unable to prevent infection from progressing in these organs. On the other hand, both types of T cell-depleted mice were capable of causing infection to plateau in their livers and kidneys. Moreover, this T cell-independent mechanism of resistance was essentially abolished in all organs in which it was expressed by treating the mice with hydrocortisone. In the lungs of immunocompetent Bcgs mice, failure to stabilize infection was associated with heavily infected macrophages and failure to contain BCG at original sites of infection.

Animals↗

PubMed1988

Pleiotropic effects of the Bcg gene: III. Respiratory burst in Bcg-congenic macrophages.

Macrophage respiratory burst, as assessed by H2O2 and O2- production, and HMS and chemiluminescence activity was investigated in a variety of conditions in macrophages from Bcg-congenic mice. Measurement of HMS and chemiluminescence in splenic macrophages challenged in vitro with BCG showed that the Bcgr cells were more stimulated by the challenge than their Bcgs counterparts. H2O2 production was measured in Bcgr and Bcgs splenic macrophages. PMA-triggering and LK-triggering were shown to stimulate a similar degree of H2O2 production Bcgr and Bcgs macrophages. In contrast, in vitro phagocytosis of BCG was shown to trigger superior production of H2O2 and O2- in the Bcgr splenic macrophages as compared to their Bcgs congenics. Finally, following the in vivo infection with BCG Montreal, Bcgr splenic macrophages were superior producers of H2O2 (both spontaneous and PMA-triggered) in the early phase of infection.

Animals↗

PubMed1980

Alternating noncross-resistant combination chemotherapy and active nonspecific immunotherapy with BCG or MER-BCG for advanced breast carcinoma.

One hundred fifty-six evaluable patients with metastatic breast cancer were treated with vincristine, Adriamycin and cyclophosphamide alternating at fixed intervals with 5-FU and methotrexate. Immunotherapy with BCG or MER-BCG was administered to all patients in two consecutive treatment programs. Overall objective response rate and complete response rate were 67% and 20%, respectively. These were not significantly different between the two immunotherapeutic groups. The median time to progression was sixteen-and-a-half months from initiation of therapy. The median survival of all patients was 21 months and that of responders was 26 months. Response rates, time to progression, and survival showed no significant advantage over a recent historical control group treated with FAC-BCG. Toxicity related to the gastrointestinal tract and bone marrow was considerably higher in this protocol than in the FAC combinations. MER at the dose, route, and schedule administered in this protocol caused excessive local and systemic toxic reactions. The alternate use of these noncross-resistant combinations in advanced breast cancer is not superior to combination chemotherapy used in the traditional manner.

Adult↗

PubMed1985

Clinico-pathological aspects of immunotherapy by intralesional injection of BCG cell walls or live BCG in bovine ocular squamous cell carcinoma.

Bovine ocular squamous cell carcinoma (BOSCC) of clinical stage I, mostly situated in the third eyelid, was chosen as a therapy model for squamous cell carcinoma of the head and neck in humans. Block resection was found to be the best method of treatment. Regression was noticed in 19 out of 30 cows treated intratumourously with a single injection of live BCG or BCG cell wall vaccine, followed by recurrence in 8 cases. In 2 untreated cows, complete lasting regression occurred. Regression was significantly more frequently encountered in intratumourously treated cows than in controls. Regression was associated with a high mitotic index, severe infiltrating growth and small amounts of cellular (lymphoid) infiltration. Metastasis was found in 14 out of 50 cows: 5 in 10 untreated controls, 8 in 30 BCG treated cows and 1 in 10 surgically treated cows. The growth rate of progressively growing untreated and of some treated tumours was not associated with the mitotic index nor with other morphological characteristics tested. The mitotic index was found to be higher in the deep infiltrating layer than in the superficial layer of the primary tumour, suggesting that a single biopsy is not sufficiently representative for cell kinetic studies.

Animals↗

PubMed2006

Immunogenicity of Danish-SSI 1331 BCG vaccine in the UK: comparison with Glaxo-Evans 1077 BCG vaccine.

The immunogenicity and reactogenicity, in British schoolchildren, of the newly introduced Danish-SSI 1331 BCG vaccine was compared with that of the previously used Glaxo-Evans 1077 BCG vaccine. Interferon-gamma (IFN-gamma) response to M. tuberculosis purified protein derivative (M.tb PPD) in a 6-day whole blood assay and delayed type hypersensitivity (DTH) to tuberculin PPD were determined before and 1 year after receiving BCG or no vaccination. Scar size was measured 1 year after vaccination. There was no evidence of a difference in immunogenicity (IFN-gamma and DTH conversion rates) but evidence of lower reactogenicity (scar size) with Danish-SSI 1331 compared to Glaxo-Evans 1077 vaccines.

BCG Vaccine↗

PubMed2003

Spectrum of bacille Calmette-Guérin (BCG) infection after intravesical BCG immunotherapy.

Intravesical instillation of bacille Calmette-Guérin (BCG) effectively treats transitional cell carcinoma of the bladder. Occasionally, BCG infection complicates such treatment. In some patients, infection appears early (within 3 months after instillation) and is characterized by generalized symptoms, with pneumonitis and hepatitis. Late-presentation disease occurs >1 year after the first BCG treatment and usually involves focal infection of the genitourinary tract (the site at which bacteria were introduced) and/or other sites that are typical for reactivation of mycobacterial disease, such as the vertebral spine or the retroperitoneal tissues. Noncaseating granulomas are found in the majority of cases, whether early or late. Most patients respond to treatment with antituberculous drugs; in early-presentation disease, when features of hypersensitivity predominate, glucocorticosteroids are sometimes added. Late localized infection often requires surgical resection.

Adult↗

PubMed1978

Effect of BCG on alloimmune cell-mediated cytotoxicity in (C57BL/6Jfemale x A/Jmale)F1 mice. II. Correlation with BCG activity in syngeneic tumor systems.

The effectiveness of selected BCG regimens to produce an activation of cell-mediated cytotoxicity (CMC) in an allogeneic tumor system was compared with its ability to cause tumor regression in syngeneic tumor systems. In the tumor system selected in both inbred LEW rats and inbred C57BL/6J and (C57BL/6Jfemale x A/Jmale)F1 mice, a correlation was observed in that BCG treatments that caused marked CMC activation in the allogeneic tumor systems also effectively caused tumor regression and increased animal survival in syngeneic systems. It was concluded that the allogeneic CMC reaction can be used to predict the capacity of BCG to cause tumor rejection.

Animals↗

PubMed1979

Immunotherapy of guinea pigs with a transplanted hepatoma: comparison of intralesionally administered killed BCG cells and BCG cell walls.

Heat-killed whole BCG cells (KC) and BCG cell walls (CW) were each tested in emulsified form for their potency to cause regression of a transplanted guinea pig hepatoma. On a weight basis, KC were at least as effective as CW in causing tumor regression and elimination of microscopic lymph node metastasis, and they, as well as purified protein derivative of mycobacteria, provoked delayed cutaneous hypersensitivity reactions in animals immunized with CW or with KC. On a weight basis, KC were as active as CW in eliciting delayed cutaneous hypersensitivity in sensitized guinea pigs whether the animals were immunized with CW or with KC. In unimmunized animals the inflammatory response to intradermally administered KC was similar to that induced by CW. Because KC are easier to prepare than CW, it is suggested that whole killed BCG might be used instead of CW in clinical trials of cancer treatment requiring administration of nonliving mycobacteria.

Animals↗

PubMed2004

BCG lymphadenopathy detected in a BCG-vaccinated infant.

Large-scale vaccination with BCG, the live attenuated strain of Mycobacterium bovis, is being adopted around the world, although sporadic complications have occurred after the procedure. Lymphadenopathy is not uncommon especially in babies under one year (0.73% of vaccinated infants), but the swelling subsides within 2 months in most cases, with no medical or surgical treatment. Brazil adopted BCG vaccination program earlier in the seventies and by 1995 more than 96% of the infant population received this immunization. We report here the occurrence of lymphadenopathy in a two-year-old child vaccinated with the Brazilian BCG strain. The diagnosis was made using a lymph node biopsy and intestinal aspirates that yielded a positive mycobacterial culture. The isolate was resistant to isoniazid, rifampicin, pyrazinamide and thiophen-2-carbonic acid hydrazide, sensitive to streptomycin, ethambutol, and p-nitrobenzoic acid, and reacted positively to cyclo-serine and negatively to niacin. The pncA gene involved in bacterial activation of pyrazinamide contains in M. bovis a point mutation that renders pyrazinamidase unable to catalyze drug activation. Therefore, this polymorphism is a good option for developing methods to differentiate M. bovis and M. tuberculosis. Taking advantage of this difference we further analyzed the isolates by single-stranded conformation polymorphism electrophoresis of DNA following PCR of the pncA gene. The isolate identity was confirmed by RFLP electrophoretic analysis of the amplified fragment following Eco065I digestion, which selectively cleaves M. tuberculosis DNA. From this result it is proposed that RFLP of pncA gene represents an alternative for differential diagnosis of M. bovis.

Amidohydrolases↗