Neonatal BCG vaccination and atopic dermatitis before 13 months of age: A randomized clinical trial.

BACKGROUND: Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. METHODS: The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational age <32 weeks, birth weight <1000 g, known immunodeficiency or no Danish-speaking parent. Data were collected through telephone interviews and clinical examinations until 13 months. RESULTS: Clinical atopic dermatitis was diagnosed in 466/2,052 (22.7%) children in the BCG group and 495/1,952 (25.4%) children in the control group (RR = 0.90 [95% confidence intervals 0.80-1.00]). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74-0.95)) and children without atopic predisposition (RR 1.09 [0.88-1.37]) (test of no interaction, P = .04). CONCLUSION: Among children with atopic predisposition, the number-needed-to-treat with BCG to prevent one case of atopic dermatitis was 21 (12-76).

Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1ß, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

Risk factors for respiratory syncytial virus hospitalisation in children with heart disease.

OBJECTIVE: To assess the risk and risk factors for respiratory syncytial virus (RSV) hospitalisation and determinants of the severity of RSV disease in children with heart disease. METHODS: By using a database on RSV tests in Denmark all children with RSV diagnosed with heart disease in Denmark from January 1996 to April 2003 were identified. For each case child one control child matched for age and centre was drawn from the population of children with heart disease. Clinical information was obtained through a review of all records. RESULTS: Data were obtained on 313 pairs. Median age at admission was 280 days (range 15-2379). In the multivariate analysis predictors of RSV hospitalisation were Down syndrome (odds ratio (OR) 3.24, 95% CI 1.80 to 5.80), cardiomyopathy (OR 5.84, 95% CI 1.26 to 27.16) and haemodynamically significant heart disease (OR 1.53, 95% CI 1.04 to 2.26). During RSV hospitalisation predictors of the need for respiratory support (supplemental oxygen, nasal continuous positive airway pressure or mechanical ventilation) were young age (relative risk (RR) 0.47, 95% CI 0.32 to 0.67 per additional year of age) and cardiac decompensation (RR 1.81, 95% CI 1.02 to 3.23). The incidence rate of RSV hospitalisation among children with any heart disease aged 0-23 months was 5.65 per 100 child-years. CONCLUSION: In children with heart disease risk factors for RSV admission are Down syndrome, cardiomyopathy and haemodynamically significant heart disease. Young age and cardiac decompensation are associated with a more severe course of RSV disease.

Beneficial non-targeted effects of BCG--ethical implications for the coming introduction of new TB vaccines.

Non-targeted effect of BCG: Several recent studies suggest that BCG has beneficial non-targeted effects on general child survival in low-income countries. Studies of the effect of BCG on morbidity in humans are scarce; some found a positive effect of BCG and others show no effect. Non-targeted effects of vaccines-possible bias and confounding: The major argument against comparing vaccinated and unvaccinated groups is that there is a beneficial social selection bias for vaccinated children-the "Healthy vaccinee effect". However, controlling for various social and health-related background factors in the survival analyses had no effect on the estimates, making this source of bias less likely. A more powerful argument that the findings are not due to the healthy vaccinee effect is that differential non-targeted effects of other vaccines have been observed; diphteria-tetanus-pertussiss vaccination has marked negative effects on child survival, whereas measles vaccine has a positive effect in several studies. Several studies have shown better survival for children reacting to their BCG vaccination with a BCG scar or tuberculin skin test reaction (TST). It could be argued that the reacting children were immunologically stronger and therefore more likely to survive-the "Healthy reactor effect". However, recent findings show that a BCG scar and a TST reaction depend to a large extent on the vaccination technique. Hence, the BCG responses may reflect a true vaccine effect and not merely the health status of the children. Since HIV-1 has been shown to suppress both TST and BCG scar reaction in response to BCG, it is an obvious contributor to the healthy reactor effect, but excluding deaths of children with HIV-1 infection from analysis did not affect the beneficial effect of having a positive TST. Excluding children exposed to tuberculosis (TB) in the household did not affect the estimates either. Furthermore, there are strong sex-differential effects of BCG in both mortality and morbidity data, BCG being more beneficial for girls. These observations cannot consistently be explained by the healthy vaccinee or healthy reactor effects. Ethical implications: For future TB-vaccine studies, these findings imply that: These recommendations might be considered to delay or to be a too large obstacle for the development and trials of new TB vaccines. However, most of the non-targeted beneficial effects of BCG have been observed in children below 2 years of age, which is not a long follow-up time in a TB-vaccine trial. Furthermore, considering the difficulty in setting the TB diagnose in children and the lack of reliable TB-protection markers, it does not seem unreasonable to argue for monitoring of general morbidity and survival in future TB-vaccine trials.

Comparison of nasopharyngeal aspirate and nasal swab specimens for detection of respiratory syncytial virus in different settings in a developing country.

OBJECTIVE: To compare detection of respiratory syncytial virus (RSV) for diagnostic purposes using nasopharyngeal aspirate (NPA) and nasal swabs (NS) in different clinical settings in a community study in Guinea-Bissau. METHOD: During 1996-98 paired specimens were obtained from 635 children under 5 years of age (median: 274 days; interquartile range: 144-453 days) with symptoms of lower respiratory infections (LRI). The specimens were analysed by an enzyme-linked immunosorbent assay for RSV antigen in Guinea-Bissau and re-analysed in Denmark using the same assay. The gold standard for RSV antigen detection was defined as any test being positive. RESULTS: RSV antigen was detected in 84 (13%) children, the prevalence being 19% (41/219) among infants aged < 6 months, 12% (22/184) in infants aged 6-11 months, and 9% (21/230) in older children. Sensitivity of antigen detection was higher in NPA (92% in analyses in Guinea-Bissau and 98% in Denmark) than in NS (63% in analyses in Guinea-Bissau, 71% in Denmark). Specificity of RSV antigen detection was equally high in NPA and NS (99-100%). Time since onset of symptoms was significantly shorter in RSV antigen positive than negative samples. Sensitivity did not depend on clinical setting or age of the child. CONCLUSION: Using NS samples was associated with a 27-31% reduction in sensitivity compared with NPA specimens. As NPAs are costly and considered a nuisance by the population, it might be cost-effective in larger epidemiological studies to lose 25-30% in sensitivity but be able to collect samples from a much larger population.

Duration of secretory IgM and IgA antibodies to respiratory syncytial virus in a community study in Guinea-Bissau.

Respiratory syncytial virus (RSV) is probably the single major cause of lower respiratory infection (LRI) among infants worldwide. Its relative importance may be underestimated, as the diagnosis is based on antigen detection and antigen may only be detectable in the early phase of infection. We have therefore assessed the duration of secretory IgM and IgA antibody responses and whether assays for these antibodies can be used to improve the diagnosing of RSV-associated infections. During two RSV epidemics in Guinea-Bissau, 32 RSV antigen-positive children with LRI were followed with sequential nasopharyngeal suction on days 7, 14, 30, 60 and 120 in the first epidemic and every fortnight for 6 mo after the second epidemic to measure the duration of secretory IgM and IgA responses. Nearly all of the children had an IgM response during the first month after infection. The response ratio was highest on days 7 and 14, being 84% and 71%, respectively. After 30 d the IgM response decreased rapidly. Among 27 age- and sex-matched controls, only 1 child was positive for IgM. During the second epidemic, when the children were followed more intensively, half of the children were IgM-positive after the acute phase of infection. A secondary response may be more likely in children with low IgM responses in the acute phase (RR = 2.08 (95% confidence interval (CI) 0.92-4.70)). The IgA response was highest on days 28 and 42 after antigen detection, 72% having a detectable IgA response within the first 1.5 mo. Among 27 controls, only 2 were IgA-positive (7%). In the second epidemic with more intensive follow-up, 62% (8/13) of the IgA-positive children had a response that lasted 10 wk. Of the children with no persistent IgA response, half (5/10) had a subsequent IgA-positive response after the first 42 d. All of these children had a simultaneous IgM-positive response. When 29 of the children were tested after an epidemic when they were 1-3-y-old, >80% again had high IgM (24/29, 82%) and IgA (28/29, 94%) levels. Among samples collected over a 1-y period from infants with LRI in a community morbidity surveillance conducted at the local health centre and via paediatric outpatient consultation, 17% (110/659) were antigen-positive, 26% (171/659) IgM-positive and 38% (248/659) either antigen- or IgM-positive. IgM responses are short-lived among infants and may therefore be used as an indication of recent RSV infection among children with LRI. Using both antigen and IgM detection may significantly improve our detection of RSV infections.