Received BCG Vaccination Research Articles

Cluster of human tuberculosis caused by Mycobacterium bovis: evidence for person-to-person transmission in the UK

Despite a recent resurgence in the incidence of bovine tuberculosis in UK cattle herds, no associated rise in the number of cases in man has been noted. Disease due to human Mycobacterium bovis infection usually occurs in older patients, in whom drinking unpasteurised milk in the past is the probable source of infection. Person-to-person transmission is very rare. After identification of two epidemiologically-linked cases of human M bovis infection through routine laboratory and surveillance activities, all patients identified with M bovis infection in the Midlands from 2001-05 (n=20) were assessed by DNA fingerprinting (MIRU-VNTR and spoligotyping), with additional interviews for patients with a clustered strain. A cluster of six cases was identified. All clustered cases were young and UK-born; five patients had pulmonary disease, and one patient died due to M bovis meningitis, with four patients possessing factors predisposing to tuberculosis. All patients had common social links through visits to bars in two different areas. With the exception of the first case, there was an absence of zoonotic links or consumption of unpasteurised dairy products, suggesting that person-to-person transmission had occurred. This report of several instances of M bovis transmission between people in a modern urban setting emphasises the need to maintain control measures for human and bovine tuberculosis. Transmission and subsequent disease was probably due to a combination of host and environmental factors. Prospective surveillance and DNA fingerprinting identified the cluster, enabling health protection teams to set up control measures and prevent further transmission.

Mycobacterium bovis tuberculosis: forgotten, but not gone

In today?s Lancet Jason Evans and colleagues report on a cluster of six patients with tuberculosis caused by Mycobacterium bovis. All were young people born and living in the UK who had documented social links to at least one other person in the cluster. Only one had a history of zoonotic exposure and consumption of unpasteurised dairy products. Five had pulmonary disease; five received BCG vaccine as children including one patient who developed meningitis and died. All M bovis isolates were identical by genotyping. These findings strongly support the authors? contention that several events of person-to-person transmission occurred. Moreover they emphasise that human tuberculosis caused by M bovis persists and might be an underappreciated cause of morbidity and mortality. (excerpt)

Editorial: ‘Non‐specific effects of vaccines’– an important analytical insight, and call for a workshop

keywords vaccines, mortality, analysis, bias, non-specificThis issue of the TMIH journal carries two papers by Aabyand his colleagues on the ‘non-specific effects’ of vaccines.They discuss a methodological issue that might explaininconsistent findings in papers published in recent yearswith respect to non-specific effects of DPT vaccination onchild mortality. In particular they point out that somecommonly applied methods of analysis may introducesubstantial bias in the estimation of such effects.It has long been known that vaccines can have effectsother than reducing the risk of the disease against whichthey are targeted. Perhaps most obvious are the adversereactions that, albeit rarely, can occur as a consequence ofvaccination – ranging from anaphylaxis attributable toparticular components (e.g. egg albumen) to pericarditisfrom smallpox vaccines. The pathogenesis of many of theseadverse effects is reasonably well understood, and warn-ings regarding the risk of such effects are described inpackage inserts of all vaccines. Less widely appreciated isthe fact that vaccines may have unanticipated beneficialeffects, other than on the target disease. For example, BCGvaccines, originally given for their protective effect againsttuberculosis, also protect against a variety of mycobacterialinfections (including Mycobacterium leprae and Myco-bacterium intracellulare). Beyond these examples is thepossibility that some vaccines may have less preciselydefined effects, perhaps mediated through the immunesystem, that manifest as a general increase, or decrease, inmorbidity or mortality attributable to a variety of causes ordiseases. It is with reference to such effects of vaccines thatthe term ‘non-specific’ is increasingly used.A striking example of an apparent non-specific effectwas described 15 years ago in the context of studiesevaluating the efficacy of high titre measles vaccines. Thesevaccines, carrying more than 10

Tuberculosis contact investigation with a new, specific blood test in a low-incidence population containing a high proportion of BCG-vaccinated persons

BackgroundBCG-vaccination can confound tuberculin skin test (TST) reactions in the diagnosis of latent tuberculosis infection.MethodsWe compared the TST with a Mycobacterium tuberculosis specific whole blood interferon-gamma assay (QuantiFERON®-TB-Gold In Tube; QFT-G) during ongoing investigations among close contacts of sputum smear positive source cases in Hamburg, Germany.ResultsDuring a 6-month period, 309 contacts (mean age 28.5 ± 10.5 years) from a total of 15 source cases underwent both TST and QFT-G testing. Of those, 157 (50.8%) had received BCG vaccination and 84 (27.2%) had migrated to Germany from a total of 25 different high prevalence countries (i.e. >20 cases/100,000). For the TST, the positive response rate was 44.3% (137/309), whilst only 31 (10%) showed a positive QFT-G result. The overall agreement between the TST and the QFT-G was low (κ = 0.2, with 95% CI 0.14.-0.23), and positive TST reactions were closely associated with prior BCG vaccination (OR 24.7; 95% CI 11.7–52.5). In contrast, there was good agreement between TST and QFT-G in non-vaccinated persons (κ = 0.58, with 95% CI 0.4–0.68), increasing to 0.68 (95% CI 0.46–0.81), if a 10-mm cut off for the TST was used instead of the standard 5 mm recommended in Germany.ConclusionThe QFT-G assay was unaffected by BCG vaccination status, unlike the TST. In close contacts who were BCG-vaccinated, the QFT-G assay appeared to be a more specific indicator of latent tuberculosis infection than the TST, and similarly sensitive in unvaccinated contacts. In BCG-vaccinated close contacts, measurement of IFN-gamma responses of lymphocytes stimulated with M. tuberculosis-specific antigen should be recommended as a basis for the decision on whether to perform subsequent chest X-ray examinations or to start treatment for latent tuberculosis infection.

Discrepancy Between the Tuberculin Skin Test and the Whole-Blood Interferon γ Assay for the Diagnosis of Latent Tuberculosis Infection in an Intermediate Tuberculosis-Burden Country

A recently developed whole-blood interferon gamma (IFN-gamma) assay based on stimulation with the Mycobacterium tuberculosis-specific antigens early secreted antigenic target 6 and culture filtrate protein 10 shows promise for the diagnosis of latent tuberculosis (TB) infection. To compare the tuberculin skin test (TST) and the whole-blood IFN-gamma assay in the diagnosis of latent TB infection according to the intensity of exposure. A prospective comparison between the whole-blood IFN-gamma assay and the TST using a 2-TU dose of purified protein derivative RT23 in a population with intermediate TB burden was conducted sequentially between February 1, 2004, and February 28, 2005, in a Korean tertiary referral hospital. Of 273 participants, 220 (95.7%) had received BCG vaccine. Participants were grouped according to their risk of infection: group 1, no identifiable risk of M tuberculosis infection (n = 99); group 2, recent casual contacts (n = 72); group 3, recent close contacts (n = 48); group 4, bacteriologically or pathologically confirmed TB patients (n = 54). Levels of agreement between the TST and the IFN-gamma assay and the likelihood of infection in the various groups. For the TST with a 10-mm induration cutoff, the positive response rate in group 1 was 51%; group 2, 60%; group 3, 71%, and group 4, 78%. For the IFN-gamma assay, the positive response rate in group 1 was 4%; group 2, 10%; group 3, 44%; and group 4, 81%. The overall agreement between the TST and the IFN-gamma assay in healthy volunteers was kappa = 0.16. The odds of a positive test result per unit increase in exposure across the 4 groups increased by a factor of 5.31 (95% confidence interval [CI], 3.62-7.79) for the IFN-gamma assay and by a factor of 1.52 (95% CI, 1.20-1.91) for the TST (P<.001). Using a 15-mm induration cutoff for the TST did not make a substantial difference to the test results. The IFN-gamma assay is a better indicator of the risk of M tuberculosis infection than TST in a BCG-vaccinated population.

Lichen scrofulosorum: A prospective study of 39 patients

Lichen scrofulosorum is considered a rare form of cutaneous tuberculosis. Current information is based on case reports and case series with a small number of patients. Thirty-nine patients with Lichen scrofulosorum were followed during the period January 1996 to December 2002. Clinical details (age, sex, duration of disease, associated tubercular lesions, extent and distribution of skin lesions), laboratory parameters (hemoglobin, total leucocytic counts, erythrocyte sedimentation rate, Mantoux test, presence of BCG scar), and response to antitubercular treatment were recorded and analyzed. 7.6% patients of all (511) patients with cutaneous tuberculosis had LS. 22 (56.4%) were males and 32 (84%) were below 15 years of age. Twenty-eight (72%) had an associated focus of tuberculosis elsewhere in the body; 13 (33%) had tubercular lymphadenopathy, while 11 (28%), three (8%) and six (15%) had pulmonary tuberculosis, intracranial tuberculosis and other forms of cutaneous tuberculosis, respectively. Six (15%) had tubercular focus at multiple sites. Eleven (28%) had no other identifiable focus of tuberculosis. Twenty-eight (72%) had evidence of receiving BCG vaccination. Trunk was the commonest (100%) affected site. The two groups with and without associated tubercular focus were not different with respect to age, sex, duration of disease, hemoglobin, total leukocyte count, erythrocyte sedimentation rate, Mantoux test positivity, and presence of BCG scar. Mycobacteria tuberculosis could not be detected either on acid fast bacilli (AFB) staining or on culture from biopsies of LS lesions. All patients (including those without evidence of tubercular focus) responded to antitubercular treatment, signifying an underlying occult tubercular focus as etiology. Lichen scrofulosorum is an uncommon but not rare cutaneous manifestation of tuberculosis. A high index of suspicion and awareness is required for diagnosis. Systemic tuberculosis is often associated with LS and a prior BCG inoculation does not protect against development of LS. Response to antitubercular treatment is good irrespective of the presence or absence of associated tubercular focus.

Effects of BCG vaccination on evolution of leprosy

Background: BCG vaccine is considered to have immunoprophylactic potential in leprosy. However controversy exists about the extent of prophylaxis it provides. In view of this, a study was undertaken to see the evolution of disease in established cases of leprosy who were already vaccinated with BCG and to compare it with the cases of leprosy who were not vaccinated with BCG. Methods: 114 newly diagnosed cases of leprosy were studied. Patients were divided into two groups-BCG vaccinated and non-vaccinated. Clinical diagnosis of leprosy was confirmed by bacteriological and histopathological studies in each case. All patients were given standard anti leprosy treatment and were evaluated monthly for a minimum period of one year. Results: All the cases were males in the age group of 20 to 50 years. 25.4% of cases had received BCG vaccine and 74.6% were not vaccinated for the same. No significant difference was observed in the incidence of different types of leprosy in vaccinated and non-vaccinated groups. 25.9% cases in non-vaccinated group developed lepra reaction as compared to 13.8% in vaccinated group. The incidence of deformities and disabilities in vaccinated group was only 10.3% as against 18.8% in non-vaccinated group. The rate of bacillary clearance appeared faster in vaccinated group. Conclusions: Although there is no significant difference in the pattern of different types of leprosy in BCG vaccinated and non-vaccinated cases, there is reduction in the incidence of reactions as well as deformities and disabilities in BCG vaccinated cases as compared to non-vaccinated cases.

Localized Hypertrichosis following BCG Vaccination: Case Report

An eight-month-old Turkish boy presented at the Fatih University Pursaklar outpatient clinic with excessive hair on his left shoulder. The history was that 15 days after receiving BCG vaccination at the age of two months, new hairs were noticed at the site. Examination revealed an aggregation of dark hairs on an area measuring 4x3cm at the site of the vaccination with the scar of BCG vaccine at the base. We would like to draw attention to this hitherto unreported localized hypertrichosis complicating BCG vaccination. Key Words: BCG vaccine, hypertrichosis, side effect Nigerian Journal of Paediatrics 30(3) 2003: 93-95

Chronic facial crusts

A 13-year-old girl came to our clinic in rural southwest Uganda in October, 2000, with a 7-year history of a painless, crusted, skin lesion involving her upper lip and nasal vestibule (figure, top). The lesion had started as a sore in her right nostril and spread to the extent that it made her a social outcast and she had stopped going to school. Her HIV serostatus was unknown, but she denied any sexual contact or blood transfusion. She had always lived locally, had not received BCG vaccination, and had no known active tuberculosis or leprosy contact.

A meta-analysis of the effect of Bacille Calmette Guérin vaccination on tuberculin skin test measurements

Background: The accurate diagnosis of latent tuberculosis infection (LTBI) is an important component of any tuberculosis control programme and depends largely on tuberculin skin testing. The appropriate interpretation of skin...

Asthma, atopy and tuberculin responses in Chinese schoolchildren in Hong Kong

BACKGROUNDThe prevalence rates of asthma and other atopic disorders have increased steadily in many developed countries over the past few decades. Recent epidemiological and animal studies have suggested that BCG...

Risk factors for positive mantoux tuberculin skin tests in children in San Diego, California: evidence for boosting and possible foodborne transmission.

Source case finding in San Diego, California, rarely detects the source for children with tuberculosis (TB) infection or disease. One third of all pediatric TB isolates in San Diego are Mycobacterium bovis, a strain associated with raw dairy products. This study was conducted to determine risk factors for TB infection in San Diego. Case-control study of children </=5 years old screened for TB as part of routine health care visit. Asymptomatic children with a positive (>/=10 mm) Mantoux skin test (TST) were matched by age to 1 to 2 children with negative TST from the same clinic. We assessed risk factors for TB infection through parental interview and chart review. A total of 62 cases and 97 controls were enrolled. Eleven cases and 25 controls were excluded from analysis because of previous positive skin tests. Compared with controls, cases were more likely to have received BCG vaccine (73% vs 7%, odds ratio [OR] 44), to be foreign born (35% vs 11%, OR 4.3), and to have eaten raw milk or cheese (21% vs 8%, OR 3.76). The median time between the most recent previous TST and the current test was 12 months for cases and 25 months for controls. Other factors associated with a positive TST included foreign travel, staying in a home while out of the country, and having a relative with a positive TST. There was no association between contact with a known TB case. In a multivariable model, receipt of BCG, contact with a relative with a positive TST, and having a previous TST within the past year were independently associated with TB infection. We identified several new or reemerging associations with positive TST including cross border travel, staying in a foreign home, and eating raw dairy products. The strong associations with BCG receipt and more recent previous TST may represent falsely positive reactions, booster phenomena, or may be markers for a population that is truly at greater risk for TB infection. Unlike studies conducted in nonborder areas, we found no association between positive TB skin tests and contact with a TB case or a foreign visitor. Efforts to control pediatric TB in San Diego need to address local risk factors including consumption of unpasteurized dairy products and cross-border travel. The interpretation of a positive TST in a young child in San Diego who has received BCG is problematic.

Results of two-step tuberculin skin test against medical and nursing school students and treatment according to the results of the test

To assess the risk of tuberculosis infection in medical and nursing school students, tuberculin skin tests were carried out in the two-step manner. The second tuberculin skin test was repeated two weeks later excluding those who were strongly positive in the first test. BCG vaccination was done with the consent of students who showed negative reaction twice. Medical interview and revaluation of prior routine chest radiogram were made on students who were strongly positive. Prophylactic INH medication was considered to those who are at high risk of tuberculosis. Eight hundred thirty eight students underwent the two-step tuberculin skin test, and among them, 771 students showed the positive reaction on the first test (92.0%) which included 58 weakly positive (6.9%), 347 intermediately positive (41.4%) and 366 strongly positive (43.7%) and 2 not-measurable (0.2%), and 65 students were negative (7.8%). The average size of the erythema was 30.9 +/- 18.8 mm on the first test and 37.9 +/- 20.6 mm on the second test. Twenty one students were negative on the second tuberculin skin test, and among them, 15 received BCG vaccination. Out of eight students who were vaccinated with BCG in 1999 and were followed up in the next year, 6 (75.0%) converted to positive. Strongly positive reaction was seen in 28 students (3.3%) and one of them underwent prophylactic medication of INH according to her family history of exposure to tuberculosis.

Early BCG vaccination and reduction in atopy in Guinea-Bissau.

It has been proposed that certain viral and bacterial infections in early childhood may prevent allergic sensitization, by inducing Th1-type immune responses. This has led to speculation that mycobacterial vaccines might, through their Th1-stimulating properties, also protect against atopy. To investigate whether the prevalence of atopy is lower in children who have been vaccinated with BCG in infancy than in children who have not been vaccinated. We measured skin test reactivity to three allergens (Dermatophagoides pteronyssinus, D. farinae and cockroach) in 400 children, aged 3-14 years, as part of a follow-up study to examine the immune sequelae of measles in an urban area of Bissau, the capital of Guinea-Bissau in west Africa. Information on childhood vaccinations, including BCG in infancy, was available from child records. Of these children, 271 had been vaccinated with BCG (according to records) and 53 had not been vaccinated (no record and no BCG scar). Atopy was defined in two ways, according to the presence of any allergen reaction > or = 2 mm and any reaction > or = 3 mm. Of the children who had received BCG vaccine, 57 (21%) were atopic (any reaction > or = 2 mm), compared with 21 (40%) of the unvaccinated children [odds ratio, after controlling for potential confounding factors, 0.19 (95% CI 0.06-0.59)]. When atopy was defined using the 3-mm criterion, the reduction in atopy associated with BCG was greater the earlier the age at vaccination, and the largest reduction was seen in children vaccinated in the first week of life. BCG vaccination given early in infancy may prevent the development of atopy in African children.

Why there were few isolations of tubercle bacilli in young children with pulmonary tuberculosis?

We retrospectively evaluated the factors influencing the isolation of tubercle bacilli in 51 children under 14 years of age with pulmonary tuberculosis who were admitted to Yokohama City University Hospital from 1975 to 1998. Young children (0-6 years of age) with pulmonary tuberculosis were significantly less positive by smear and culture than elder children (7-14 years of age) with pulmonary tuberculosis. According to the Japanese Society for Tuberculosis classification of finding on chest X-ray film for pulmonary tuberculosis, the culture-positive patients with type II (cavitary lesions) were found in all, the culture-positive patients with type III (non-cavitary lesions) in 39.3%, and the culture-positive patients with type H (hilar and mediastinal lymphadenopathys) in 35.3%. Patients with cavitary lesions (type II) were significantly more positive by smear and culture than patients with non-cavitary lesions (type III + type H). Only 15.8% of the young children with pulmonary tuberculosis had received BCG vaccine and all had non-cavitary lesions (type III and type H). But, 84.6% out of the older children had received BCG vaccine and half had cavitary lesions. Taken together, the result was that there were few isolation of tubercle bacilli in young children with pulmonary tuberculosis because they had non-cavitary tuberculosis without delayed-type hypersensitivity to tubercle bacilli.

Tuberculous meningitis in children: clinical features and outcome in 40 cases.

In order to assess the epidemiology, clinical features and outcome of tuberculous meningitis, a retrospective review of patients was conducted between January 1989 and December 1995. Forty cases (representing 10%, of all paediatric patients with tuberculosis) were included. Mean age was 46 months (range 1-165 months). Eighteen (45%) children were classified as stage I (non-specific febrile illness without neurological signs), 16 (40%) as stage II (neurological signs without marked changes in sensorium) and 6 (15%) as stage III (major neurological signs with sensorial changes and/or coma). Twenty-seven (67%) patients had received BCG vaccination and 14 (35%) displayed an induration zone higher than 10 mm after a 2-TU PPD test. Mycobacterium tuberculosis was recovered from 24 (61%) patients. Hydrocephalus was demonstrated by cranial computed tomography in 31 (78%) children. Overall, 18 (45%) children had a full recovery. Mild, moderate and severe neurological sequelae were shown by 7 (18%), 3 (8%) and 9 (22%) of the patients, respectively. Three fatal cases (7%) were observed. The presence of seizures (RR 15.6, 2.02-119.1) and absence of extrameningeal foci (RR 4.95, 1.10-22.1) were identified as risk factors by multivariate analysis. These findings emphasize the need quickly to diagnose tuberculosis in children in order to give appropriate and early treatment.

Administration of the BCG vaccination using the multipuncture method in schoolchildren: a comparison with the intradermal method

BACKGROUNDBCG vaccination using the multipuncture device (the Heaf gun) is recommended in the UK for infants and very small children only. The aim of this study was to investigate the...

Miliary tuberculosis in children: a clinical review.

Miliary tuberculosis infection in childhood remains a significant health problem in developing countries. To characterize the clinical features of the disease, symptoms, signs and laboratory findings, associated infections and outcomes of the 23 children (14M, 9F) with miliary tuberculosis admitted to the Dicle University Hospital, Diyarbakir, Turkey from 1990 to 1997 were analysed. Mean age of the patients was 3.7 y ranging between 6 months and 11 y. All but 3 patients were below 6 y of age, and 5 of the patients were under 1 y of age. All of the children had not received BCG vaccination except for 1 who was immunized after the age of 5 y. Only 6 children had a positive reaction to 5 TU tuberculin test at admission to hospital. Eight of the 23 subjects were infected in the family, and all were nonHIV infected cases. All of the children were diagnosed clinically and by a miliary infiltrate visible on chest roentgenogram. Five cases had positive culture results for Mycobacterium tuberculosis. Duration of onset of symptoms prior to admission ranged between 15 d and 8 months with a mean of 58 d. The most frequently seen symptoms and clinical findings were fever in 17 cases, rales in 14, loss of appetite and weight in 10 and hepatosplenomegaly in 9 cases. Two cases had prior measles infection and 1 of the patients presented facial paralysis. Seven cases had also tuberculous meningitis. The outcome in general was good, with mortality in 2 cases.

Early BCG vaccination and development of atopy

The increase in atopic diseases may be partly explicable by a decline of certain infectious diseases, or changes in childhood vaccination programmes, or both. We investigated whether BCG vaccination against tuberculosis influences the development of atopy. We did a retrospective cohort study of 216 children with atopic heredity, born in Stockholm between 1989 and 1992, who received BCG vaccination when they were younger than 6 months, and 358 age-matched controls who had not been vaccinated. Both groups attended Sachs' Children's Hospital, Stockholm, Sweden, during 1995-96 for assessment of atopic history and clinical signs of atopic disease. All children also underwent skin-prick testing (SPT) and serum was analysed for allergen-specific IgE antibodies. Serum from parents was also analysed for IgE antibodies. 77 (36%) children in the BCG group and 145 (41%) in the control group had a positive history or clinical signs of atopic disease. In the vaccinated group, 26 (12%) children had one or more positive SPT, and 61 (31%) had circulating allergen-specific IgE antibodies, whereas in the control group, the numbers were 35 (10%) and 84 (27%) respectively. Atopy was confirmed by serology in parents of almost two-thirds of the children in each group. Other risk factors for atopic disease were evenly distributed between the two groups. Early BCG vaccination in children with atopic heredity does not seem to affect the development of atopic disease before school age.

Analysis of children with tuberculosis in the past 20 years

To characterize the clinical features of childhood tuberculosis, we analyzed the symptoms, signs, and laboratory findings of the 89 children with tuberculosis admitted to the Yokohama City University Hospital from 1975 to 1994. Compared with the numbers of patients admitted from 1975 to 1979, those of patients of the past 5 years (from 1990 to 1994) were reduced by half. Of the 89 subjects, 56.2% were below 3 years of age and 24.7% were under 1 year of age. 51.7% had primary complex and 20.2% had serious tuberculosis (tuberculous meningitis 14.6%, miliary tuberculosis 3.4%, and bone and joint tuberculosis 2.2%). Tuberculous children below 3 years of age consisted of primary complex (60.0%) and serious tuberculosis (32.0%). The majority (86.0%) of tuberculous children below 3 years of age had not received BCG vaccination. In 55 (61.8%) of 89 subjects, the sources of tuberculosis were clarified. Of these subjects, 83.6% were infected in the family. The rate of BCG inocluation tended to decrease with decreasing age, especially that of children below 3 years of age was 14.0%. Of the 89 subjects, only 16.9% proved to be smear-positive. Taken together, in order to eliminate tuberculous children below 3 years of age, the following is necessary; (1) BCG inoculation in early infancy, (2) early diagnosis of index cases with adult tuberculosis, and (3) prompt and appropriate family contact examination.