Vitamin D in Early Childhood and the Effect on Immunity to Mycobacterium tuberculosis

A potential role for vitamin D as a therapeutic immunomodulator in tuberculosis (TB) has been recognised for over 150 years, but has only recently returned to the centre of the research arena due to the increasing awareness of the global vitamin D deficiency epidemic. As early as birth a child is often deficient in vitamin D, which may not only affect their bone metabolism but also modulate their immune function, contributing to the increased susceptibility to many infections seen early in life. Recent studies have begun to explain the mechanisms by which vitamin D affects immunity. Antimicrobial peptides are induced in conjunction with stimulation of innate pattern recognition receptors enhancing immunity to particular infections. In contrast the role of vitamin D within the adaptive immune response appears to be more regulatory in function, perhaps as a mechanism to reduce unwanted inflammation. In this paper we focus on the effect of vitamin D on immunity to TB. Where much of the attention has been paid by past reviews to the role of vitamin D in adult TB patients, this paper, where possible, focuses on research in paediatric populations

Modeling the impact of novel diagnostic tests on pediatric and extrapulmonary tuberculosis

BACKGROUND: Extrapulmonary tuberculosis (EPTB) and most pediatric TB cannot be diagnosed using sputum-based assays. The epidemiological impact of different strategies to diagnose EPTB and pediatric TB is unclear. METHODS: We developed a dynamic epidemic model of TB in a hypothetical population with epidemiological characteristics similar to India. We evaluated the impact of four alternative diagnostic test platforms on adult EPTB and pediatric TB mortality over 10 years: (1) Nucleic acid amplification test optimized for diagnosis of EPTB (“NAAT-EPTB”); (2) NAAT optimized for pediatric TB (“NAAT-Peds”); (3) more deployable NAAT for sputum-based diagnosis of adult pulmonary TB (“point-of-care (POC) sputum NAAT”); and (4) more deployable NAAT capable of diagnosing all forms of TB using non-invasive, non-sputum specimens (“POC non-sputum NAAT”). RESULTS: NAAT-EPTB lowered adult EPTB mortality by a projected 7.6% (95% uncertainty range [UR]: 6.5-8.8%). NAAT-Peds lowered pediatric TB mortality by 6.8% (UR: 4.9-8.4%). POC sputum NAAT, though only able to diagnose pulmonary TB, reduced projected pediatric TB deaths by 13.3% (UR: 4.6-15.7%) and adult EPTB deaths by 8.4% (UR 2.0-9.3%) simply by averting transmission of disease. POC non-sputum NAAT had the greatest effect, lowering pediatric TB mortality by 34.7% (UR: 26.8-38.7), and adult EPTB mortality by 38.5% (UR: 30.7-41.2). The relative impact of a POC sputum NAAT (i.e., enhanced deployability) versus NAAT-EPTB (i.e., enhanced ability to specifically diagnose TB-NSP) on adult EPTB mortality depends most strongly on factors that influence transmission, with settings of higher transmission (e.g., higher per-person transmission rate, lower diagnostic rate) favoring POC sputum NAAT. CONCLUSION: Although novel tests for pediatric TB and EPTB are likely to reduce TB mortality, major reductions in pediatric and EPTB incidence and mortality also require better diagnostic tests for adult pulmonary TB that reach a larger population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2334-14-477) contains supplementary material, which is available to authorized users

Influence of Enteric Infections on Response to Oral Poliovirus Vaccine: A Systematic Review and Meta-analysis

BACKGROUND: The impaired immunogenicity of oral poliovirus vaccine (OPV) in low-income countries has been apparent since the early field trials of this vaccine. Infection with enteropathogens at the time of vaccination may contribute to this phenomenon. However, the relative influence of these infections on OPV performance remains uncertain. METHODS: We conducted a systematic review to examine the impact of concurrent enteric infections on OPV response. Using random-effects models, we assessed the effects of nonpolio enteroviruses (NPEVs) and diarrhea on the odds of seroconversion and/or vaccine virus shedding. RESULTS: We identified 25 trials in which OPV outcomes were compared according to the presence or absence of enteric infections, the majority of which (n = 17) reported only on NPEVs. Concurrent NPEVs significantly reduced the odds of per-dose seroconversion for type 1 poliovirus (odds ratio [OR] 0.44, 95% confidence interval 0.23-0.84), but not type 2 (OR 0.53 [0.19-1.46]) or type 3 (OR 0.56 [0.27-1.12]). A similar reduction, significant for type 1 poliovirus (OR 0.50 [0.28-0.89]), was observed in the odds of vaccine virus shedding among NPEV-infected individuals. Concurrent diarrhea significantly inhibited per-dose seroconversion overall (OR 0.61 [0.38-0.87]). CONCLUSIONS: Our findings are consistent with an inhibitory effect of concurrent enteric infections on OPV response

Achieving comprehensive childhood immunization: an analysis of obstacles and opportunities in The Gambia

INTRODUCTION: Immunization is a vital component in the drive to decrease global childhood mortality, yet challenges remain in ensuring wide coverage of immunization and full immunization, particularly in low- and middle-income countries. This study assessed immunization coverage and the determinants of immunization in a semi-rural area in The Gambia. METHODS: Data were drawn from the Farafenni Health and Demographic Surveillance System. Children born within the surveillance area between January 2000 and December 2010 were included. Main outcomes assessed included measles, BCG and DTP vaccination status and full immunization by 12 months of age as reported on child healthcards. Predictor variables were evaluated based on a literature review and included gender, ethnicity, area of residence, household wealth and mother's age. RESULTS: Of the 7363 children included in the study, immunization coverage was 73% (CI 72-74) for measles, 86% (CI 86-87) for BCG, 79% (CI 78-80) for three doses of DTP and 52% (CI 51-53) for full immunization. Coverage was significantly associated with area of residence and ethnicity, with children in urban areas and of Mandinka ethnicity being least likely to be fully immunized. CONCLUSIONS: Despite high levels of coverage of many individual vaccines, delivery of vaccinations later in the schedule and achieving high coverage of full immunization remain challenges, even in a country with a committed childhood immunization programme, such as The Gambia. Our data indicate areas for targeted interventions by the national Expanded Programme of Immunization

Specific antibodies against vaccine-preventable infections: a mother-infant cohort study

OBJECTIVES: To determine maternal and neonatal specific antibody levels to selected vaccine-preventable infections (pertussis, Haemophilus influenzae type b (Hib), tetanus and pneumococcus). DESIGN: Prospective cohort study. SETTING: A UK secondary care maternity unit (March 2011-January 2012). PARTICIPANTS: Mothers and infants within 72 h of delivery were eligible. Unwell individuals, mothers less than 18 years of age, and infants born at less than 36 weeks gestation, or weighing less than 2500 g, were excluded. HIV-infected mothers were included. 112 mother-infant pairs were recruited. Samples from 111 mothers and 109 infants (108 pairs) were available for analysis. OUTCOME MEASURES: Specific antibody levels were determined using standard commercial ELISAs. Specific antibody to pertussis antigens (PT and FHA) of >50 IU/ml, defined as 'positive' by the test manufacturer, were interpreted as protective. Antitetanus antibody titres >0.1 IU/ml and anti-Hib antibody titres >1 mg/l were regarded as protective. RESULTS: Only 17% (19/111) of women exhibited a protective antibody response against pertussis. 50% (56/111) of women had levels of antibody protective against Hib and 79% (88/111) against tetanus. There was a strong positive correlation between maternal-specific and infant-specific antibodies' responses against pertussis (rs=0.71, p<0.001), Hib (rs=0.80, p<0.001), tetanus (rs=0.90, p<0.001) and pneumococcal capsular polysaccharide (rs=0.85, p<0.001). Only 30% (33/109) and 42% (46/109) of infants showed a protective antibody response to pertussis and Hib, respectively. Placental transfer (infant:mother ratio) of specific IgG to pertussis, Hib, pneumococcus and tetanus was significantly reduced from HIV-infected mothers to their HIV-exposed, uninfected infants (n=12 pairs) compared with HIV-uninfected mothers with HIV-unexposed infants (n=96 pairs) by 58% (<0.001), 61% (<0.001), 28% (p=0.034) and 32% (p=0.035), respectively. CONCLUSIONS: Low baseline antibody levels against pertussis in this cohort suggest the recently implemented UK maternal pertussis immunisation programme has potential to be effective

Defining operational strengths and gaps relevant to post licensure Group B Streptococcus vaccine effectiveness studies: an expert stakeholder evaluation of the United Kingdom and Uganda

A future Group B Streptococcal (GBS) vaccine for pregnant women to protect neonates is likely to be licensed based on evidence of vaccine induced protective antibody levels. Post licensure surveillance to monitor the impact of any future vaccine on GBS disease therefore needs to be clearly defined (in both high and low income settings). A priority research gap is understanding health system preparedness for a GBS vaccine evaluation This expert stakeholder evaluation aimed to describe the UK and Uganda's operational strengths and gaps relevant to post-licensure GBS vaccine studies

The influence of paediatric HIV infection on circulating B cell subsets and CXCR5+ T helper cells

Antiretroviral therapy (ART) only partially restores HIV-induced alterations in lymphocyte populations. We assessed B and T cell phenotypes in a cohort of children from a single centre in the United Kingdom with perinatally acquired HIV compared to healthy controls. The majority of HIV infected children (44 of 56) were on fully suppressive combination ART. Children with perinatally acquired HIV had significantly lower memory B and CD4(+) CD45RO(+) CXCR5(+) [follicular T helper cell (Tfh)-like] T cell percentages. Detectable viraemia was associated with higher CD21(-) (activated and exhausted/tissue-like memory) B cells. A greater proportion of life spent on suppressive ART was associated with higher memory B cell percentages. These results suggest that early and sustained suppressive ART may preserve B and T cell phenotypes in perinatally acquired HIV and limit deficits in humoral immunity. A lower proportion of circulating Tfh-like cells in HIV infected children appears to be independent of HIV treatment history and ongoing HIV viraemia and warrants further investigation

Effects of different leukocyte subpopulations and flow conditions on leukocyte accumulation during reperfusion

Background/Aims: The study examined the interdependent effects of shear stress and different leukocyte subpopulations on endothelial cell activation and cell interactions during low flow and reperfusion. Methods: Human umbilical venous endothelial cells were perfused with either neutrophils or monocytes at different shear stress (2-0.25 dyn/cm 2) and adhesion was quantified by microscopy. Effects of adherent neutrophils and monocytes on endothelial cell adhesion molecule expression were analyzed by flow cytometry after 4-hour static coincubation. After coincubation, the cocultures were reperfused with labeled neutrophils at 2 dyn/cm 2 and their adhesion was quantified selectively. For the control, endothelium monocultures with and without lipopolysaccharide activation were used. Results: At 2 dyn/cm 2, adhesion did not exceed baseline levels on nonactivated endothelium. Decreasing shear stress to 0.25 dyn/cm 2 largely increased the adhesion of both leukocyte subpopulations, similar to the effect of lipopolysaccharide at 2 dyn/cm 2. However, only adherent monocytes increased adhesion molecule expression, whereas neutrophils had no effect. As a functional consequence, adherent monocytes largely increased neutrophil adhesion during reperfusion, whereas adherent neutrophils did not. Conclusion: Compromised shear stress is an autonomous trigger of leukocyte adhesion even in the absence of additional activators. Exceeding this immediate effect, adherent monocytes induce further endothelial activation and enhance further neutrophil adhesion during reperfusion. Copyrigh

Serological response to 13-valent pneumococcal conjugate vaccine in children and adolescents with perinatally acquired HIV infection

BACKGROUND: Children with perinatally acquired HIV (paHIV) remain at an increased risk of pneumococcal infection despite highly active antiretroviral therapy (HAART). Beyond infancy, responses to pneumococcal conjugate vaccine (PCV) remain under-investigated. There are currently no published data on serological response to 13-valent PCV (PCV13) in the HIV-infected populations. METHODS: We measured pneumococcal serotype-specific IgG in 48 paHIV-infected child patients (CP), 27 young adult healthy controls (AHC) and 30 child healthy controls (CHC). Opsonophagocytic assay (OPA) titres for three PCV13-exclusive serotypes were measured in a subset of children. Serotype-specific IgG was repeated 1 and 6 months following PCV13 vaccination of CP and AHC groups. OPA titres for four serotypes were measured at the 1-month time-point. RESULTS: The majority of CP, CHC and AHC had serotype-specific IgG above 0.35 μg/ml at baseline, although OPA activity was undetectable for two of the three serotypes studied. Baseline IgG concentrations were significantly lower in CP than AHC for a proportion of serotypes and were strongly predictive of responses to vaccine. After adjusting for baseline, postvaccination IgG concentrations were comparable, although responses to some serotypes were impaired for CP. OPA correlated well with IgG after vaccination. Detectable HIV viral load was associated with significantly lower IgG concentration and OPA titre. CONCLUSION: Children with paHIV mount a robust serological response to PCV13 for most but not all vaccine serotypes. Viral load suppression with HAART and higher baseline IgG concentration are associated with higher postvaccination antibody levels. This has implications for HAART treatment and vaccination practices

Relative validity of a web-based food frequency questionnaire for Danish adolescents

Background: With increased focus on dietary intake among youth and risk of diseases later in life, it is of importance, prior to assessing diet-disease relationships, to examine the validity of the dietary assessment tool. This study’s objective was to evaluate the relative validity of a self-administered web-based FFQ among Danish children aged 12 to 15 years. Methods: From a nested sub-cohort within the Danish National Birth Cohort, 124 adolescents participated. Four weeks after completion of the FFQ, adolescents were invited to complete three telephone-based 24HRs; administered 4 weeks apart. Mean or median intakes of nutrients and food groups estimated from the FFQ were compared with the mean of 3x24HRs. To assess the level of ranking we calculated the proportion of correctly classified into the same quartile, and the proportion of misclassified (into the opposite quartile). Spearman’s correlation coefficients and de-attenuated coefficients were calculated to assess agreement between the FFQ and 24HRs. Results: The mean percentage of all food groups, for adolescents classified into the same and opposite quartile was 35 and 7.5%, respectively. Mean Spearman’s correlation was 0.28 for food groups and 0.35 for nutrients, respectively. Adjustment for energy and within-person variation in the 24HRs had little effect on the magnitude of the correlations for food groups and nutrients. We found overestimation by the FFQ compared with the 24HRs for fish, fruits, vegetables, oils and dressing and underestimation by the FFQ for meat/poultry and sweets. Median intake of beverages, dairy, bread, cereals, the mean total energy and carbohydrate intake did not differ significantly between the two methods. Conclusion: The relative validity of the FFQ compared with the 3x24HRs showed that the ranking ability differed across food groups and nutrients with best ranking for estimated intake of dairy, fruits, and oils and dressing. Larger variation was observed for fish, sweets and vegetables. For nutrients, the ranking ability was acceptable for fatty acids and iron. When evaluating estimates from the FFQ among Danish adolescents these findings should be considered.The study was supported by grants from The Danish Research Council 09–067124 (Center for Fetal Programming), 09–075611; and the Intramural Research Program of The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract # HHSN275201000020C). The funding bodies had no role in the design of the study, collection, analysis, interpretation of data or in writing the manuscript.Peer Reviewe