Elevated serum 25-hydroxy (OH) vitamin D levels are associated with risk of TB progression in Gambian adults

SummaryBackgroundVitamin D is essential in the host defence against tuberculosis (TB) as an immune modulator. The aim of this study was to determine the level of 25-hydroxyvitamin D (25 (OH) D) from adult TB index cases before and after treatment and their exposed household contacts (HHC) in The Gambia.MethodsSerum from adult index TB cases and their TB-exposed household contacts (HHC) was analysed for 25(OH) D and Vitamin D binding protein (VDBP) concentrations. Tuberculin skin test (TST) status was used as a measure of Mycobacterium tuberculosis (Mtb) infectivity in the HHC. In addition, HHC who later progressed to active TB (incident cases) were assessed alongside non-progressors to determine the influence of 25 (OH) D levels on TB risk.ResultsEighty-three TB cases, 46 TST+ and 52 TST− HHC were analysed. Generally levels of 25(OH) D were considered insufficient in all subjects. However, median levels of 25(OH) D and VDBP were significantly higher in TB cases compared to both TST+ and TST− HHC at recruitment and were significantly reduced after TB therapy (p < 0.0001 for all). In addition, levels of serum 25(OH) D at recruitment were significantly higher in TB progressors compared to non-progressors (median (IQR): 25.0(20.8–29.2) in progressors and 20.3 (16.3–24.6) ng/ml in non-progressors; p = 0.007).ConclusionIn The Gambia, an equatorial country, 25(OH) D levels are higher in serum of TB progressors and those with active disease compared to latently infected and uninfected subjects. These results contrast to findings in non-equatorial countries

Characteristics of neonatal near-miss in hospitals in Benin, Burkina Faso and Morocco in 2012-2013.

: The objective of this study is to explore the usefulness of neonatal near miss in low- and middle-income countries by examining the incidence of neonatal near miss and pre-discharge neonatal deaths across various obstetric risk categories in 17 hospitals in Benin, Burkina Faso and Morocco. : Data were collected on all maternal deaths, maternal near miss, neonatal near miss (based on organ-dysfunction markers), Caesarean sections, stillbirths, neonatal deaths before discharge and non-cephalic presentations, and on a sample of births not falling in any of the above categories. : The burden of stillbirth, pre-discharge neonatal death or neonatal near miss ranged from 23 to 129 per 1000 births in Moroccan and Beninese hospitals, respectively. Perinatal deaths (range 17-89 per 1000 births) were more common than neonatal near miss (range 6-43 per 1000 live births), and between a fifth and a third of women who had suffered a maternal near miss lost their baby. Pre-discharge neonatal deaths and neonatal near miss had a similar distribution of markers of organ dysfunction, but unlike pre-discharge neonatal deaths most neonatal near miss (63%, 81% and 71% in Benin, Burkina Faso and Morocco, respectively) occurred among babies who were not considered premature, low birthweight or with a low 5-min Apgar score as defined by WHO's pragmatic markers of severe neonatal morbidity. : Whether the measurement of neonatal near miss adds useful insights into the quality of perinatal or newborn care in settings where facility-based intrapartum and early newborn mortality is very high is uncertain. Perhaps the greatest advantage of adding near miss is the shift in focus from failure to success so that lessons can be learned on how to save lives even when clinical conditions are life-threatening.<br/

Kinetics of antibodies against pneumococcal proteins and their relationship to nasopharyngeal carriage in the first two months of life.

INTRODUCTION: The currently used Streptococcus pneumoniae vaccines have had a significant impact on the pneumococcal diseases caused by the serotypes they cover. Their limitations have stimulated a search for alternate vaccines that will cover all serotypes, be affordable and effective in young children. Pneumococcal protein antigens are potential vaccine candidates that may meet some of the shortfalls of the current vaccines. Thus, this study aimed to determine the relationship between antibodies against pneumococcal protein antigens and nasopharyngeal carriage in infants. METHODS: One hundred and twenty mother-infant pairs were enrolled into the study. They had nasopharyngeal swabs(NPS) taken at birth and every two weeks for the first eight weeks after delivery, and blood samples were obtained at birth and every four weeks for the first eight weeks after delivery. Nasopharyngeal carriage of S. pneumoniae was determined from the NPS and antibodies against the pneumococcal proteins CbpA, PspA and rPly were measured in the blood samples. RESULTS: The S. pneumoniae carriage rate in infants increased to that of mothers by eight weeks of age. The odds of carriage in infants was 6.2 times (95% CI: 2.0-18.9) higher when their mothers were also carriers. Bacterial density in infants was lower at birth compared to their mothers (p = 0.004), but increased with age and became higher than that of their mothers at weeks 4 (p = 0.009), 6 (p = 0.002) and 8 (p<0.0001). At birth, the infants' antibodies against CbpA, and rPly pneumococcal protein antigens were similar, but that of PspA was lower (p<0.0001), compared to their mothers. Higher antibody concentrations to CbpA [OR (95% CI): 0.49 (0.26-0.92, p = 0.03)], but not PspA and rPly, were associated with protection against carriage in the infants. CONCLUSION: Naturally induced antibodies against the three pneumococcal protein antigens were transferred from mother to child. The proportion of infants with nasopharyngeal carriage and the bacterial density of S. pneumoniae increased with age within the first eight weeks of life. Higher concentrations of antibodies against CbpA, but not PspA and rPly, were associated with reduced risk of nasopharyngeal carriage of S. pneumoniae in infants

Evaluation of Dried Blood and Cerebrospinal Fluid Filter Paper Spots for Storing and Transporting Clinical Material for the Molecular Diagnosis of Invasive Meningococcal Disease.

To improve the storage and transport of clinical specimens for the diagnosis of Neisseria meningitidis (Nm) infections in resource-limited settings, we have evaluated the performance of dried blood spot (DBS) and dried cerebrospinal fluid spot (DCS) assays. DBS and DCS were prepared on filter paper from liquid specimens previously tested for Nm in the United Kingdom. Nm was detected and genogrouped by real-time PCR performed on crude genomic DNA extracted from the DBS (n = 226) and DCS (n = 226) specimens. Targeted whole-genome sequencing was performed on a subset of specimens, DBS (n = 4) and DCS (n = 6). The overall agreement between the analysis of liquid and dried specimens was (94.2%; 95% CI 90.8–96.7) for blood and (96.4%; 95% CI 93.5–98.0) for cerebrospinal fluid. Relative to liquid specimens as the reference, the DBS and DCS assays had sensitivities of (89.1%; 95% CI 82.7–93.8) and (94.2%; 95% CI 88.9–97.5), respectively, and both assays had specificities above 98%. A genogroup was identified by dried specimen analysis for 81.9% of the confirmed meningococcal infections. Near full-length Nm genome sequences (>86%) were obtained for all ten specimens tested which allowed determination of the sequence type, clonal complex, presence of antimicrobial resistance and other meningococcal genotyping. Dried blood and CSF filter spot assays offer a practical alternative to liquid specimens for the molecular and genomic characterisation of invasive meningococcal diseases in low-resource settings

Interactions between fecal gut microbiome, enteric pathogens, and energy regulating hormones among acutely malnourished rural Gambian children.

BACKGROUND: The specific roles that gut microbiota, known pathogens, and host energy-regulating hormones play in the pathogenesis of non-edematous severe acute malnutrition (marasmus SAM) and moderate acute malnutrition (MAM) during outpatient nutritional rehabilitation are yet to be explored. METHODS: We applied an ensemble of sample-specific (intra- and inter-modality) association networks to gain deeper insights into the pathogenesis of acute malnutrition and its severity among children under 5 years of age in rural Gambia, where marasmus SAM is most prevalent. FINDINGS: Children with marasmus SAM have distinct microbiome characteristics and biologically-relevant multimodal biomarkers not observed among children with moderate acute malnutrition. Marasmus SAM was characterized by lower microbial richness and biomass, significant enrichments in Enterobacteriaceae, altered interactions between specific Enterobacteriaceae and key energy regulating hormones and their receptors. INTERPRETATION: Our findings suggest that marasmus SAM is characterized by the collapse of a complex system with nested interactions and key associations between the gut microbiome, enteric pathogens, and energy regulating hormones.  Further exploration of these systems will help inform innovative preventive and therapeutic interventions. FUNDING: The work was supported by the UK Medical Research Council (MRC; MC-A760-5QX00) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement; Bill and Melinda Gates Foundation (OPP 1066932) and the National Institute of Medical Research (NIMR), UK. This network analysis was supported by NIH U54GH009824 [CLD] and NSF OCE-1558453 [CLD]

Rapid growth is a dominant predictor Of hepcidin suppression and declining ferritin in Gambian infants

Iron deficiency and iron deficiency anemia are highly prevalent in low-income countries, especially among young children. Hepcidin is the major regulator of systemic iron homeostasis. It controls dietary iron absorption, dictates whether absorbed iron is made available in circulation for erythropoiesis and other iron-demanding processes, and predicts response to oral iron supplementation. Understanding how hepcidin is itself regulated is therefore important, especially in young children. We investigated how changes in iron-related parameters, inflammation and infection status, season and growth influenced plasma hepcidin and ferritin concentrations during infancy using longitudinal data from two birth-cohorts of rural Gambian infants (N=114 and N=193). This setting is characterized by extreme seasonality, prevalent childhood anemia, undernutrition and frequent infection. Plasma was collected from infants at birth and at regular intervals, up to 12 months of age. Hepcidin, ferritin and plasma iron concentrations declined markedly during infancy, with reciprocal increases in sTfR and transferrin concentrations, indicating declining iron stores and increasing tissue iron demand. In cross-sectional analyses at 5 and 12 months of age, we identified expected relationships of hepcidin with iron and inflammatory markers, but additionally observed significant negative associations between hepcidin and antecedent weight gain. Correspondingly, longitudinal fixed effects modelling demonstrated weight gain to be the most notable dynamic predictor of decreasing hepcidin and ferritin through infancy across both cohorts. Infants who grow rapidly in this setting are at particular risk of depletion of iron stores but since hepcidin concentrations decrease with weight gain, they may also be most responsive to oral iron interventions

Kinetics of antibodies against pneumococcal proteins and their relationship to nasopharyngeal carriage in the first two months of life

<div><p>Introduction</p><p>The currently used <i>Streptococcus pneumoniae</i> vaccines have had a significant impact on the pneumococcal diseases caused by the serotypes they cover. Their limitations have stimulated a search for alternate vaccines that will cover all serotypes, be affordable and effective in young children. Pneumococcal protein antigens are potential vaccine candidates that may meet some of the shortfalls of the current vaccines. Thus, this study aimed to determine the relationship between antibodies against pneumococcal protein antigens and nasopharyngeal carriage in infants.</p><p>Methods</p><p>One hundred and twenty mother-infant pairs were enrolled into the study. They had nasopharyngeal swabs(NPS) taken at birth and every two weeks for the first eight weeks after delivery, and blood samples were obtained at birth and every four weeks for the first eight weeks after delivery. Nasopharyngeal carriage of <i>S</i>. <i>pneumoniae</i> was determined from the NPS and antibodies against the pneumococcal proteins CbpA, PspA and rPly were measured in the blood samples.</p><p>Results</p><p>The <i>S</i>. <i>pneumoniae</i> carriage rate in infants increased to that of mothers by eight weeks of age. The odds of carriage in infants was 6.2 times (95% CI: 2.0–18.9) higher when their mothers were also carriers. Bacterial density in infants was lower at birth compared to their mothers (p = 0.004), but increased with age and became higher than that of their mothers at weeks 4 (p = 0.009), 6 (p = 0.002) and 8 (p<0.0001). At birth, the infants’ antibodies against <i>CbpA</i>, and <i>rPly</i> pneumococcal protein antigens were similar, but that of <i>PspA</i> was lower (p<0.0001), compared to their mothers. Higher antibody concentrations to <i>CbpA</i> [OR (95% CI): 0.49 (0.26–0.92, p = 0.03)], but not <i>PspA</i> and <i>rPly</i>, were associated with protection against carriage in the infants.</p><p>Conclusion</p><p>Naturally induced antibodies against the three pneumococcal protein antigens were transferred from mother to child. The proportion of infants with nasopharyngeal carriage and the bacterial density of <i>S</i>. <i>pneumoniae</i> increased with age within the first eight weeks of life. Higher concentrations of antibodies against <i>CbpA</i>, but not <i>PspA</i> and <i>rPly</i>, were associated with reduced risk of nasopharyngeal carriage of <i>S</i>. <i>pneumoniae</i> in infants.</p></div

Effects of mother’s log-antibody concentrations against <i>CbpA</i>, <i>PspA</i> and <i>rPly</i> at delivery on infant’s log-antibody concentrations and difference in infant’s antibody concentrations between carriers and non-carriers at birth, 4 and 8 weeks.

<p>Effects of mother’s log-antibody concentrations against <i>CbpA</i>, <i>PspA</i> and <i>rPly</i> at delivery on infant’s log-antibody concentrations and difference in infant’s antibody concentrations between carriers and non-carriers at birth, 4 and 8 weeks.</p