BCG-vaccinated Children Research Articles

Comparison of Mantoux and Tine Tuberculin Skin Tests in BCG-Vaccinated Children Investigated for Tuberculosis

BackgroundTuberculin skin tests (TSTs) are long-established screening methods for tuberculosis (TB). We aimed to compare agreement between the intradermal Mantoux and multipuncture percutaneous Tine methods and to quantify risk factors for a positive test result.Methodology/Principal Findings1512 South African children younger than 5 years of age who were investigated for tuberculosis (TB) during a Bacille Calmette Guerin (BCG) trial were included in this analysis. Children underwent both Mantoux and Tine tests. A positive test was defined as Mantoux ≥15 mm or Tine ≥ Grade 3 for the binary comparison. Agreement was evaluated using kappa (binary) and weighted kappa (hierarchical). Multivariate regression models identified independent risk factors for TST positivity. The Mantoux test was positive in 430 children (28.4%) and the Tine test in 496 children (32.8%, p<0.0001), with observed binary agreement 87.3% (kappa 0.70) and hierarchical agreement 85.0% (weighted kappa 0.66). Among 173 children culture-positive for Mycobacterium tuberculosis, Mantoux was positive in 49.1% and Tine in 54.9%, p<0.0001 (kappa 0.70). Evidence of digit preference was noted for Mantoux readings at 5 mm threshold intervals. After adjustment for confounders, a positive culture, suggestive chest radiograph, and proximity of TB contact were risk factors for a positive test using both TST methods. There were no independent associations between ethnicity, gender, age, or over-crowding, and TST result.Conclusions/SignificanceThe Tine test demonstrated a higher positive test rate than the Mantoux, with substantial agreement between TST methods among young BCG-vaccinated children. TB disease and exposure factors, but not demographic variables, were independent risk factors for a positive result using either test method. These findings suggest that the Tine might be a useful screening tool for childhood TB in resource-limited countries.

Prevalence of Mantoux test positivity among apparently healthy children in Maiduguri, Nigeria

Background: The impact of TB is highest in the developing countries of Asia and Africa especially among children in whom the diagnosis is challenging. Periodic skin testing by Mantoux method is recommended in children residing in high TB prevalence regions. Objective: To determine the prevalence of Mantoux test positivity among BCG-vaccinated and non-vaccinated under-five children in Maiduguri, Nigeria. Method: The study was descriptive and cross-sectional, conducted in Maiduguri, Nigeria, among apparently healthy 3-59 months old children who attended the child welfare clinics of the University of Maiduguri Teaching Hospital and two Primary Health Care centres from May to August 2008. All children who fulfilled the inclusion criteria were evaluated for history of BCG vaccination and Mantoux tested. Results: The study included 390 children, comprising 201 (51.5%) males and 189(48.5%) females; the male to female ratio was 1.1:1. Thirty one out of the 390 (7.9%) children had a positive Mantoux reaction, 27(87 %) of whom had induration of 10-14mm, while the remaining 4 (13 %) had induration of 15-20mm. The prevalence of Mantoux positivity among the vaccinated children was 10.1% and among the non-vaccinated children was1.1%, (p= 0.0034). No significant statistical difference for Mantoux positivity was observed between the sexes, (p= 0.087), and the different age groups, (p= 0.159). Conclusion: Although, positive Mantoux response is usually attributed to TB infection, the effect of previous BCG on Mantoux test reactivity especially in children should be taken into consideration in the interpretation of Mantoux test responses.

Purified Protein Derivative Response in Juvenile Idiopathic Arthritis

To examine the purified protein derivative (PPD) response that develops depending upon Th1 immune response in children with juvenile idiopathic arthritis (JIA). PPD skin test was performed in 115 children with JIA who were vaccinated with bacillus Calmette-Guerin (BCG), and then they were compared to the PPD response of 45 healthy children of the same age who were vaccinated with BCG. Children with a PPD induration > or = 5 mm were accepted as PPD-positive. PPD induration > or = 10 mm was accepted as a limit for suspecting tuberculosis. PPD induration size and PPD positivity rates (PPD > or = 5 mm) of children with JIA were significantly lower than those of healthy children. The mean of PPD induration size was significantly lower (p < 0.0001) in patients with either 1 BCG vaccine (3.7 +/- 3.6) or more than 1 BCG vaccine than controls with either 1 BCG vaccine (7.10 +/- 3.2) or more than 1 BCG vaccine (10.05 +/- 4.1). PPD was positive in 35.9% of patients with JIA vaccinated once (n = 32), in 50% of patients with JIA vaccinated more than once (n = 13), in 82.1% of controls vaccinated once (n = 23), and in 88.2% of controls vaccinated more than once. This result was statistically significant (patients, p = 0.03; controls, p = 0.039). It was determined that neither the activity of the disease nor the use of corticosteroid and methotrexate affected the PPD response. The response to PPD, which is one of the Th1 cell-type responses, was significantly lower in BCG-vaccinated children with JIA compared to healthy children.

Primary tubercular osteomyelitis of the sternum

Primary tuberculous osteomyelitis of the sternum is a rare clinical entity. Sternal tuberculosis can result from direct extension of the disease from hilar lymph nodes, hematogenous or lymphatic dissemination from other sites, and following BCG vaccination in children. An unusual case of primary tuberculous osteomyelitis of the sternum that presented with a swelling and pain over the manubrium sterni is reported. Diagnosis was confirmed by demonstration of epithelioid granulomas and acid-fast bacilli and a positive M. tuberculosis culture from the aspirate taken from the sternal swelling. Extensive diagnostic work-up did not reveal any other focus of tuberculosis in this case. The patient was successfully managed with anti-tubercular treatment.

Use of T Cell–Based Diagnosis of Tuberculosis Infection to Optimize Interpretation of Tuberculin Skin Testing for Child Tuberculosis Contacts

Treatment of recent tuberculosis infection in children aged <2 years is essential, because of high risk of progression to disease, but diagnosis is hindered by the inaccuracy of the tuberculin skin test (TST). More-accurate T cell-based tests of infection could enhance diagnosis by optimizing interpretation of the TST results. A total of 979 child tuberculosis contacts in Istanbul underwent the TST and enzyme-linked immunospot assay. Using enzyme-linked immunospot test results as a reference standard, we assessed the effect of age and bacille Calmette-Guérin (BCG) vaccination on the sensitivity and specificity of the TST, and we computed the optimal TST cutoff points, using receiver operating characteristic curves. With a TST cutoff point of >or=10 mm, the sensitivity of the TST was 66% for children aged <2 years, which was lower than that for older children (P= .006). Specificity was 75% for BCG-vaccinated children, compared with 92% for unvaccinated children (P= .001). Optimal cutoff points improved TST specificity for children with 1 BCG scar, with little loss of sensitivity. Despite the use of optimal cutoff points, TST sensitivity remained <70% for children aged <2 years, specificity remained <87% for BCG-vaccinated children aged >or=2 years, and overall accuracy was low for children with >1 BCG scar. Negative results of the TST cannot exclude tuberculosis infection for child tuberculosis contacts aged <2 years, which supports the use of preventive therapy regardless of the TST results for this age group. In children aged >or=2 years, the accuracy of the TST can be improved by adjustment of cutoff points for BCG-vaccinated children but remains poor for children with >1 BCG scar. This methodology can define optimal TST cutoff points for diagnosis of tuberculosis infection tailored to target populations.

Using of T-Spot.TB and Mantoux tests in diagnosis of M. tuberculosis infection in BCG vaccinated children aged five and younger

Using of T-Spot.TB and Mantoux tests in diagnosis of M. tuberculosis infection in BCG vaccinated children aged five and younger Infection with M. tuberculosis (MT) is difficult to diagnose in young BCG (Bacillus Calmette-Guérin) vaccinated children using Mantoux test alone, as a positive test result may be due to infection with MT and previous BCG vaccination. We aimed to test the T-SPOT. TB test for BCG-vaccinated children aged five and younger in two groups — with or without contact with an active tuberculosis (ATB) patient. Prospectively a study group of 121 children (having contact with ATB patient) and a control group of 64 children (without known contact with ATB patient) were examined using Mantoux and T-SPOT. TB tests. The T-SPOT. TB test was positive in 66 (54.5%) study group children and in 2 (3.1%) control group children (P &lt; 0.01). Induration in the Mantoux test ≥ 10 mm was observed in 62 (91.0%) of 68 T-SPOT. TB positive children, and 34 (29.1%) of 117 T-SPOT. TB negative children (P &lt; 0.01). In the group with a negative T-SPOT. TB result boosting of the Mantoux test was observed in 21 (66%) of 32 children who had received repeated Mantoux testing before being included in the study. According to the results, the application of the T-SPOT. TB test is reasonable for primary contact children evaluation and follow-up contact children for whom primary tests did not confirm infection with MT.

The role of a whole blood interferon-γ assay for the detection of latent tuberculosis infection in Bacille Calmette–Guérin vaccinated children

The tuberculin skin test (TST) has limitations in children who are under the Bacille Calmette–Guérin (BCG) effect. Our aim was to evaluate the QuantiFERON®-TB Gold In-Tube (QFT-G IT) blood test for Mycobacterium tuberculosis infection in children and to compare results with those of the TST. QFT-G IT and TST data were collected from 227 children between 0 and 15 years of age, split into 4 risk groups. Forty-two children were close contacts, 29 were casual contacts, and 65 were controls. The QFT-G IT positivity rates were 19% (8/42), 6.9% (2/29), and 1.5% (1/65), with a significantly higher rate for the close contacts over the controls ( P < 0.05). The high specificity of the QFT-G IT assay and the association of positive results with increasing risk of infection in our study suggest it has major benefits over the TST as a screening test for latent infection with M. tuberculosis in BCG-vaccinated children.

Interpretation of repeat tuberculin skin testing in international adoptees: conversions or boosting.

Internationally-adopted children are a unique group of Bacille Calmette-Guérin (BCG)-vaccinated children with high rates of latent tuberculosis infection (LTBI) in whom serial tuberculin skin tests (TST) are recommended. No study has measured the incidence of TST conversion in these children. Internationally-adopted children completed baseline and follow-up TST to measure the incidence of Mycobacterium tuberculosis infection and factors associated with TST conversion. Data were collected regarding age, gender, birth country, vaccination history, history of tuberculosis (TB) exposure, previous TB screening, and preadoptive environment. All children completed physical examinations including a standardized evaluation for TB, anthropometric assessment, and documentation of BCG scar. Fourteen percent of children (N = 390) had evidence of LTBI at baseline. Children were more likely to have LTBI if they were older, BCG vaccinated, or had been in the United States longer. An additional 13% of children had TST indurations > or = 10 mm at follow-up testing. Regardless of BCG vaccination status or nutritional status, children who were younger at baseline were more likely to have a TST induration > or = 10 mm at follow-up. International adoptees have significant risk of LTBI. Although our findings suggest that recent infection with M. tuberculosis led to TST conversion in some children, the increase in follow-up TST induration could also be attributed to TST boosting resulting from prior BCG vaccination. When serial TST testing is completed in young, BCG-vaccinated children, interpretation of the follow-up TST should consider baseline TST results.

Reduced rate of adverse reactions to the BCG vaccine in children exposed to the vertical transmission of HIV infection and in HIV-infected children from an endemic setting in Brazil

We report on the adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in BCG-vaccinated children. We examined children exposed to the vertical transmission of human immunodeficiency virus (HIV) (n = 141), who participated in a prevention program of vertical transmission, and HIV-infected children (n = 66) in a setting endemic for HIV and tuberculosis (TB) in Brazil from August 2000 to February 2008. No cases of disseminated BCG disease occurred in either group of children. While no cases of regional BCG disease were noted in exposed/uninfected children, the rate of regional BCG disease in HIV-infected children was 4.5% (3/66); the three events occurred in <1-year-old children (3/17; 17.6%). One case was associated with severe immunodepression before highly active antiretroviral therapy (HAART). Two cases were manifestations of immune reconstitution inflammatory syndrome (IRIS). Among the HIV-infected children, the accrued benefits of potentially preventing severe TB outweighed the risks associated with the use of the BCG vaccine.

Comparison of Positive Tuberculin Skin Test with an Interferon-γ-Based Assay in Unexposed Children

A false-positive tuberculin skin test (TST) may be a result of T-cell sensitivity due to Bacille Calmette-Guérin (BCG) vaccination or exposure to non-tuberculous mycobacteria, thus leading to unnecessary isoniazid preventive therapy, especially in low-risk populations. Unlike TST, T-SPOT.TB is not confounded by BCG vaccination or exposure to most of the other non-tuberculous mycobacteria, because this assay is based on enumeration of interferon-γ-secreting T cells in response to Mycobacterium tuberculosis-specific antigens. We compared the TST with T-SPOT.TB with respect to different TST cut-off points in healthy unexposed BCG-vaccinated schoolchildren. A total of 209 children between 6 and 10 years of age with a TST induration of 0 (n = 50), 10 - 14 (n = 45), 15 - 19 (n = 95) and ≥20 mm (n = 19) were enrolled. Among TST-positive subjects, only 26 (23%) were positive with T-SPOT.TB, and T-SPOT.TB was positive in 4, 7, 20 and 42% of children with TST indurations of 0, 10 - 14, 15 - 19 and ≥20 mm, respectively. We suggest that confirmation of a positive TST by the interferon-γ-based test would reduce unnecessary preventive therapy significantly in healthy unexposed BCG-vaccinated children.

Immunogenicity of Neonatal BCG Vaccination in Children Entering Primary School

This study has been designed to evaluate the immunogenicity of neonatal BCG-vaccination in children at the age of 7 to 8 years, by skin test using Purified Protein Derivative (PPD), as BCG vaccination at birth is a part of routine program of immunization in our country, Iran; we decided to study its efficacy and also tried to determine if there is any correlation between PPD-test results and BCG scar size. This is a comparative study on 150 children (94 males and 56 females) at the age of 7 to 8 years, who possess neonatal-BCG scar. They were chosen from several primary schools in Tabriz-Iran, by simple random sampling and tested with 0.1 mL of 5-unit-PPD solution (a product of Iran Institute of Razi); then observations recorded. The average diameter of BCG scars were 7.03 mm in girls, 5.45 mm in boys and 6.05 for all. The diameter of induration area resulted from PPD-test after 72 h was less than 5 mm in 95.33% and 5-9 mm in 4.66% of studied children; there was no case with induration area of 10 mm or more at all. Every child who developed an induration area of 5 mm or more by PPD test, had a BCG scar with the diameter of 5 mm or more. There was a statistically meaningful direct correlation between sizes of neonatal-BCG scar and diameter of induration area after PPD-test (r = 0.21 and p = 0.008). This study shows that reactivity to PPD test (and probably immunity against tuberculosis) decreases as age increases; therefore it seems to be necessary to repeat BCG-vaccination in children at the age of entering primary school.

Prevalence of Tuberculosis Infection in BCG-Vaccinated and Unvaccinated Mediterranean Schoolchildren

To determine the prevalence of tuberculous infection in schoolchildren in the province of Malaga, Spain, and to evaluate its relation to sociodemographic variables. Tuberculin skin tests were used to screen 6-year-olds in their first year of primary school in this cross-sectional study of the prevalence of infection, with calculation of 95% confidence interval (CI). Children who had not been vaccinated against tuberculosis at birth were considered to have a positive test result if they had an induration of >or=5 mm. Those who had received bacillus Calmette-Guerin (BCG) vaccination at birth were considered to have a positive test result if they had an induration size of >10 mm or >15 mm, depending on whether they came from a country with a high or low prevalence of tuberculosis, respectively. The prevalence of infection in the group of unvaccinated children was 1.16% (95% CI, 0.69%-1.63%). No statistically significant differences were found for any of the sociodemographic variables analyzed. The prevalence of infection in the BCG-vaccinated children was 6.66% (95% CI, 5.55%-7.77%). The prevalence of tuberculosis infection in our area is slightly higher than that reported after other studies conducted in Spain. This could indicate that tuberculosis continues to be a public health problem in the province of Malaga. Infection in the subgroup of BCG-vaccinated children, however, was lower than that observed in studies of immigrants in Spain who had been immunized at birth. This is probably because the majority of immigrants in our area come from countries with a low incidence of tuberculosis.

Prevalence of BCG Scar Formation Among BCGVaccinated Apparently Healthy U-5 Children and its Correlation with Mantoux Skin Test Induration in Maiduguri, Nigeria

Background: Tuberculosis (TB) is still a major public health problem world-wide. BCG scar is often used as an indicator of previous vaccination in clinical settings as well as in Immunization Surveys, although not allBCG-vaccinated children formscar. Objective: This study was under-taken to determine the BCG scar rate formation among BCG-vaccinated children and the pattern of Mantoux test reactions among the children with and without BCG-scar inMaiduguri, Nigeria. Methods: The study was descriptive and cross-sectional, conducted in Maiduguri, Nigeria, among 296 BCG-vaccinated apparently healthy 3-59 months old children who attended the child welfare clinics of the University of Maiduguri Teaching Hospital and two Primary Health Care centres from May to August 2008. Children who fulfilled the inclusion criteria were examined for BCG-scar andMantoux tested. Results: Out of 296 BCG-vaccinated children studied, 165 (55.7%) had BCGscar, while the remaining 131 (44.3%) had no scar. No significant statistical difference in relation to age at vaccination and BCGscar formationwas noted, (p =0.376). The mean Mantoux reactions between those vaccinated in the neonatal and post-neonatal period, (p =0.258), was also not statistically significant. The vaccinated children with scar had a significant negative Mantoux test correlation with age; (r = - 0.39, p Conclusion: BCG scar formation among vaccinated children in Maiduguri is low. In spite of the difference inMantoux readings between the childrenwith and withoutBCG-scar,we recommend continued immunization with BCG at birth of all children in Maiduguri, as recommended by the Nigerian, National Programme on Immunization. Niger Med J. Vol. 49, No.4, Oct – Dec, 2008: 84 – 87. Keywords: BCG,Mantouxtest,Correlation,Apparentlyhealthy,U-5.

Tuberculin reactivity and allergic disorders in schoolchildren, Okinawa, Japan

Bacillus Calmette-Guérin (BCG) vaccination triggers a T-helper type 1 response. Whether BCG vaccination and positive tuberculin reactivity are preventive against allergic disorders remains controversial. The current cross-sectional study investigated the relationship of BCG vaccination and tuberculin reactivity with the prevalence of allergic disorders using data from the Ryukyus Child Health Study (RYUCHS). Subjects were 5717 schoolchildren aged 8-11 years in Okinawa, Japan. The RYUCHS collected information on symptoms of allergic disorders and potential confounding factors. The outcomes were based on diagnostic criteria from the International Study of Asthma and Allergies in Childhood. Data on BCG vaccination and tuberculin tests were obtained from school records. Allowance was made for grade, sex, sibship size, smoking in the household, paternal and maternal history of asthma, atopic eczema, and allergic rhinitis, and paternal and maternal educational level. No measurable relationship was found between BCG vaccination in infants and the prevalence of allergic disorders. Among 5567 BCG-vaccinated children, positive tuberculin reactivity (induration >/=10 mm) in the first grade was independently associated with a decreased prevalence of wheeze, asthma, and atopic eczema: the multivariate odds ratios for wheeze, asthma, and atopic eczema were 0.80 (95% confidence interval [CI], 0.67-0.94), 0.78 (95% CI, 0.64-0.95), and 0.77 (95% CI, 0.62-0.95), respectively. The inverse associations were more pronounced in children with a negative parental allergic history than in those with a positive parental allergic history. There was no significant relationship between tuberculin reactivity and allergic rhinoconjunctivitis. The findings suggest that positive tuberculin reactivity may be inversely associated with the prevalence of wheeze, asthma, and atopic eczema, but not allergic rhinoconjunctivitis, especially among Japanese children without a parental allergic history.

Non-specific effects of diphtheria tetanus pertussis vaccination on child mortality in Cebu, The Philippines

To determine the non-specific effects of diphtheria, tetanus and pertussis (DTP) vaccination and sex on mortality before 30 months of age among those who received Bacille Calmette Guerin (BCG) vaccine in a high mortality area. This analysis used a longitudinal study of child survival monitoring the use of primary care services, morbidity and mortality in Metro Cebu, The Philippines. Participants included 14 537 children under 30 months of age who received a BCG vaccination from July 1988 to January 1991. The main outcome measure was all-cause mortality. Mortality before 30 months of age was 57% lower among BCG-vaccinated children who received DTP vaccination than BCG-vaccinated children who did not receive DTP vaccination {hazard ratio (HR) for vaccinated vs unvaccinated 0.43 [95% confidence interval (CI) 0.21-0.88]}. Females had lower mortality rates [HR = 0.19 (0.04-0.86), P = 0.03] than males among DTP-unvaccinated children. The protective effect of DTP vaccination was more pronounced in males [HR 0.32 (0.14-0.73)] than in females [HR 0.86 (0.18-4.23)]. DTP vaccination increased (interaction term P = 0.08) the female-to-male mortality ratio to 0.76 (0.52-1.12). Among BCG-vaccinated children under 30 months of age, DTP vaccination is associated with improved survival. The increased female-male mortality ratio is associated with reduced mortality among males following DTP vaccination rather than increased mortality among female children.

Is the prevalence of wheeze in children altered by neonatal BCG vaccination?

The prevalence of asthma and atopic disease has increased in recent decades, but precise reasons for this increase are unknown. BCG vaccination is thought to be among a group of vaccines capable of manipulating the immune system toward T(H)1 dominance and therefore reducing the likelihood of atopic disease. The aim of this study was to determine the influence of neonatal BCG vaccination on the prevalence of wheeze in a large community population of children. In a historical cohort study, a parent-completed questionnaire was used to identify the prevalence of wheeze in BCG-vaccinated and nonvaccinated children in Manchester, England. There were 2414 participants aged between 6 and 11 years. In a univariate analysis neonatal BCG vaccination was associated with a significantly lower prevalence of wheeze (odds ratio, 0.69; 95% CI, 0.55-0.86), and statistical significance was retained when the analysis was adjusted for potential confounders (odds ratio, 0.68; 95% CI, 0.53-0.87). These results demonstrate an association between asthma symptom prevalence and neonatal BCG vaccination, relating to a possible 27% reduction in prevalence, and are therefore of considerable public health importance. The capacity of neonatal BCG vaccination to reduce the prevalence of respiratory symptoms in children warrants further investigation.

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

Safety and immunogenicity of a candidate vaccine for visceral leishmaniasis (Alum-precipitated autoclavedLeishmania major+ BCG) in children: an extended phase II study

Untreated visceral leishmaniasis (VL) is an inevitably fatal childhood disease. First-generation candidate vaccines for VL [autoclaved Leishmania major (ALM) + BCG] have been found to be safe and immunogenic but not superior to BCG alone. Modulation of ALM by adsorption to Alum significantly increases the immunogenicity. The Alum-adsorbed ALM vaccine was found to be safe and strongly immunogenic in healthy adult volunteers in a non-VL-endemic area. This study aimed at establishing the safety and immunogenicity of Alum-precipitated autoclaved L. major + BCG vaccine in children under field conditions. A total of 544 healthy, leishmanin non-reactive children (<15 y) were randomly allocated to receive either a single intradermal injection of Alum/ALM + BCG or vaccine diluent (placebo). Volunteers were closely followed for 2 years at 6-month intervals for vaccine safety and immunogenicity. The vaccine was well tolerated with minimal side-effects. Leishmanin skin test conversion (>or=5 mm) was seen in 56%, 50%, 25% and 31% at 6, 12, 18 and 24 months post-vaccination, respectively; conversion in the placebo group was 4%, 12%, 3% and 13% at the same follow-up visits. There was no significant increase in anti-leishmanial antibodies in either study arm at any of the follow-up visits. During the study, four patients in the placebo arm developed parasitologically confirmed VL. Alum/ALM + BCG vaccine is safe and immunogenic in children under field conditions. Multiple injections might be needed to obtain results similar to those obtained in healthy volunteers.

Is tuberculin skin testing useful to diagnose latent tuberculosis in BCG-vaccinated children?

The tuberculin skin test (TST) is the most commonly used tool to detect infection with Mycobacterium tuberculosis. We sought to determine whether tuberculin skin testing is useful to detect latent infection by M. tuberculosis in a population that was vaccinated with the Bacille Calmette Guérin (BCG) vaccine. We performed a cross-sectional study during October 2000-February 2001, enrolling first and sixth graders from a random, stratified sample of public elementary schools in Orizaba, Veracruz, Mexico. We assessed the relationship between sociodemographic and epidemiological information, BCG scars, and TST reactivity. There were 858 children enrolled in the study with a completed questionnaire and TST result. The prevalence of a positive TST result (> or =10 mm) was 12.4%. Controlling for BCG scar, age, and other characteristics, close contact with pulmonary tuberculosis patients (odds ratio 6.56, 95% confidence interval 2.05-21.07, P = 0.001) was independently associated with TST reactivity. TST results helped identify children in a BCG-vaccinated population who had recent exposure to persons with pulmonary tuberculosis, were probably infected with M. tuberculosis, and could benefit from treatment for their latent tuberculosis infection.

Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART

Recent epidemiological studies in adults suggest that HAART can prevent the development of tuberculosis in HIV-infected individuals, but the mechanisms are incompletely understood and no data exist in children. We investigated whether changes in mycobacterial-specific immune responses can be demonstrated in children after commencing antiretroviral therapy. We measured mycobacterial growth in vitro using a novel whole-blood assay employing reporter-gene tagged bacillus Calmette-Guérin (BCG) in a prospective cohort study in the tuberculosis-endemic environment of South Africa. Key cytokines were measured in supernatants collected from the whole-blood assay using cytometric bead array. A cohort of 15 BCG-vaccinated HIV-infected children was evaluated prospectively for in-vitro antimycobacterial immune responses before and during the first year of HAART. All children had advanced HIV disease. Nine children completed all study timepoints. Before HAART, blood from children showed limited ability to restrict the growth of mycobacteria in the functional whole-blood assay. The introduction of HAART was followed by rapid and sustained reconstitution of specific antimycobacterial immune responses, measured as the decreased growth of mycobacteria. IFN-gamma levels in culture supernatants did not reflect this response; however, a decline in TNF-alpha was observed. This is the first study using a functional in-vitro assay to assess the effect of HAART on immune responses to mycobacteria in HIV-infected children. Our in-vitro data mirror the in-vivo observation of decreased susceptibility to tuberculosis in HIV-infected adults receiving antiretroviral agents. This model may be useful for further characterizing immune reconstitution after HAART.