Pertussis Immunization During Pregnancy: Assessment of the Role of Maternal Antibodies on Immune Responses in Term and Preterm-Born Infants.

BACKGROUND: Limited data exist on the impact of maternal tetanus, diphtheria, acellular pertussis (Tdap) vaccination for preterm born infants. We report its effect at birth and on antibody-mediated immune responses to a DTaP-IPV-HB-PRP~T vaccine in preterm compared with term infants. METHODS: Women delivering at term or prematurely were either vaccinated with a Tdap vaccine (Boostrix; GSK) during pregnancy or not vaccinated in the last 5 years. Cord and maternal blood were collected at delivery. Infants were vaccinated with DTaP-IPV-HB-PRP~T vaccine (Hexyon; Sanofi Pasteur) and blood collected before and 1 month after primary (8-12-16 weeks) and before and 1 month after booster vaccination (13 or 15 months for preterm and term, respectively). Immunoglobulin G antibodies against all antigens included in DTaP-IPV-HB-PRP~T vaccine were measured (NCT02511327). RESULTS: Cord blood geometric mean concentrations (GMCs) in preterm infants from Tdap-vaccinated women were significantly higher than in term and preterm infants from unvaccinated women. A longer time interval between maternal vaccination and delivery resulted in higher cord blood GMCs in preterm infants. Equal GMCs in term and preterm infants from Tdap-vaccinated women were observed after primary vaccination. After boosting, significantly lower GMCs were seen for pertussis toxin, filamentous hemagglutinin, and tetanus toxoid in preterm compared with term infants from Tdap-vaccinated women, yet still comparable to GMCs in both term and preterm infants from unvaccinated women. CONCLUSIONS: Preterm infants profit from maternal Tdap vaccination. Prematurity did not influence primary immune responses in the presence of maternal antibodies but was associated with a lower booster immune response.

Breast Milk Antibody Levels in Tdap-Vaccinated Women After Preterm Delivery.

BACKGROUND: Enrichment of breast milk (BM) with immunoglobulin (Ig) A and IgG through maternal vaccination could help infants combat targeted pathogens. However, evidence on this effect after preterm delivery is lacking. In this study, we investigated the total and anti-pertussis toxin (anti-PT)-specific IgA and IgG production in BM after term and preterm delivery in the presence of maternal Tdap (tetanus, diphtheria, acellular pertussis) vaccination. METHODS: Serum and BM samples of lactating women who delivered at term or prematurely and did or did not receive Tdap vaccine (Boostrix, GSK Biologicals) during pregnancy were collected as part of a clinical study (N = 234). Anti-PT IgA/IgG (IBL assay; Meso Scale Discovery assay) and total IgA/IgG (Thermofisher, on BM samples only) immunosorbent assays were performed on all samples collected at 72 hours and 4, 8, and 12 weeks postpartum. RESULTS: BM after preterm delivery contained anti-PT IgA and IgG geometric mean concentrations (GMCs) comparable to those after term delivery (eg, colostrum anti-PT IgA, 5.39 IU/mL vs 6.69 IU/mL, respectively). Maternal Tdap vaccination induced significantly higher anti-PT IgG GMCs in colostrum of vaccinated compared with unvaccinated women who delivered at term (0.110 IU/mL vs 0.027 IU/mL, P = .009). Anti-PT antibodies persisted up to 12 weeks postpartum. CONCLUSIONS: This study provides evidence that maternal Tdap vaccination induces high Ig levels in BM after both term and preterm delivery and that these antibodies remain abundantly present throughout lactation, possibly offering additional mucosal protection during the most vulnerable period in early life. CLINICAL TRIAL REGISTRATION: NCT02511327.

Number of sites of perinatal Candida colonization and neutropenia are associated with nosocomial candidemia in the neonatal intensive care unit patient.

OBJECTIVES: To determine the role of perinatally acquired Candida colonization to invasive Candida infection (candidemia) and to assess risk factors associated with Candida colonization and candidemia in neonatal intensive care unit patients. DESIGN: Retrospective case-control study. SETTING: Neonatal intensive care unit of a teaching hospital. PATIENTS: A total of 39 of 3219 (1.2%) who were positive for Candida colonization at birth were compared with 117 noncolonized controls. INTERVENTIONS: Routine surveillance cultures for Candida of skin and meconium were performed at admission. All neonates with Candida colonization at birth during a 10-yr period were identified. Each case was matched to place of birth and date of admission with three noncolonized controls. MEASUREMENTS AND MAIN RESULTS: Perinatal and neonatal variables were collected. Blood or skin culture was obtained when signs of sepsis or dermatitis were present. Patients with Candida colonization were compared with their noncolonized controls, whereas in this cohort, patients with candidemia were compared with those without by multivariate analysis. Vaginal candidiasis (odds ratio [OR] 15.8, 95% confidence interval [CI] 2.63, 94.77), birth weight below 1000 g (OR 8.1, 95% CI 1.22, 52.26), and vaginal delivery (OR 7.08, 95% CI 1.17, 42.70) were associated with Candida colonization. An increased risk for nosocomial candidemia was independently associated with the number of sites of Candida colonization (OR 24.02, 95% CI 1.89, 304), early neonatal neutropenia (OR 7.15, 95% CI 0.98, 80.95) and illness severity (clinical risk index for babies [CRIB]) score at day 1 (OR 1.38, 95%CI 1.065, 1.811). CONCLUSIONS: Maternal vaginal candidiasis and vaginal birth are risk factors for neonatal colonization. When controlling for illness severity, the number of sites colonized with Candida at birth contributes to neonatal nosocomial candidemia. Early neutropenia increases the risk further. These findings offer opportunities for prevention of Candida infection in neonatal intensive care unit patients.

Increased levels of tumor necrosis factor-alpha and decreased levels of interleukin-12 p 70 in tracheal aspirates, within 2 hrs after birth, are associated with mortality among ventilated preterm infants.

OBJECTIVE: To determine the association of antibacterial interleukin (IL)-12 p 70 levels as well as the pathogen-induced proinflammatory cytokine response in tracheal aspirate (TA) to respiratory failure and mortality among ventilated preterm infants. DESIGN: A prospective observational clinical cohort study with measurements of cytokine levels and microbial cultures of TA from ventilated preterm neonates. Interleukin (IL)-1 beta, IL-8, IL-6, IL-10, IL-12 p 70, and tumor necrosis factor (TNF)-alpha were measured in TA within 2 hrs of birth, and comorbidity characteristics were recorded prospectively. The association between cytokine levels in TA and neonatal mortality was determined, with correction for comorbidity factors by means of multivariate stepwise logistic regression. SETTING: A single tertiary neonatal intensive care unit at the University Hospital of Antwerp, Belgium. PATIENTS: One hundred forty-one neonates born before a gestational age of 31 wks and who required ventilation were enrolled in the study; 31 (22%) died and 37 (26%) had airway colonization. MEASUREMENTS AND MAIN RESULTS: The airway colonization rate was significantly greater among deceased neonates (45% vs. 21%; chi-square, 7.4; p=.007). Neonates who died had a significantly lower IL-12 p 70 cytokine level (6 pg/mL vs. 11 pg/mL; p<.05) in their TA. Neonates with a low IL-12 p 70 cytokine level had more pronounced respiratory failure (significantly higher oxygenation index, higher degree of radiologic respiratory distress syndrome, higher critical index for babies score, and more surfactant use). Multivariate analysis revealed that, after correction for severity of disease by critical index for babies score, the degree of intraventricular hemorrhage (odds ratio, 5.0 [95% confidence interval, 2.6-9.7]), low IL-12 p 70 levels (odds ratio, 4.9 [95% confidence interval, 2.1-11.7]), and high TNF-alpha levels in TA (odds ratio, 3.5 [95% confidence interval, 1.6-7.5]) were significantly associated with neonatal mortality. CONCLUSIONS: Pathogen-induced excessive production of the proinflammatory cytokine TNF-alpha and lack of antibacterial IL-12 p 70 response in the TA are associated with increased neonatal mortality among ventilated preterm infants.

Time to positivity of neonatal blood cultures: fast and furious?

The aim of this study was to determine the time to positivity (TTP) of neonatal blood cultures, to investigate differences between early onset versus late-onset sepsis, and non-proven versus proven sepsis, and to examine differences in TTP by organism type using a retrospective observational study at the Neonatal Intensive Care Unit, Antwerp University Hospital, Belgium. The subjects were 1828 neonates with suspected sepsis who were treated with antimicrobials for at least 3 days. The TTP was recorded for all episodes of suspected sepsis in an approximately 6.5 year period. A total of 2916 blood cultures were collected, of which 437 (15%) became positive. The overall TTP was 21.33 h (Q1-Q3 13.17-32.46). The difference between the median TTP in early onset versus late-onset sepsis was 0.83 h (22.00 versus 21.17 h, P=0.75). The median TTP for Gram-negative organisms was 11.17 h (Q1-Q3 8.84-15.67), whereas the median TTP for Gram-positive organisms was 23.59 h (Q1-Q3 15.29-34.58, P<0.001). In Gram-positive isolates, the median TTP for coagulase-negative staphylococci (CNS) was 26.67 h (Q1-Q3 19.00-38.17), whereas the median TTP for non-CNS was 12.83 h (Q1-Q3 10.50-18.17, P<0.001). The median TTP in proven sepsis was 20.17 h (Q1-Q3 13.00-30.37), whereas it was 29.67 h (Q1-Q3 21.17-50.63, P<0.001) in non-proven sepsis. TTP of neonatal blood cultures was significantly shorter for Gram-negative organisms. We suggest shortening the total incubation time of neonatal blood cultures to a maximum of 3 days. However, blood cultures collected in infants<72 h of age might require a longer incubation time. According to our results, it may be safe to narrow the antimicrobial spectrum to solely target Gram-positive bacteria when the culture is still negative after 48 h, and to cease antimicrobial therapy when the culture is still negative after 72 h in clinically well infants.

Decreasing incidence of neonatal nosocomial bloodstream infections in a neonatal intensive care unit: antenatal corticosteroid treatment an innocent bystander?

UNLABELLED: We studied the effect of the use of antenatal steroid treatment on the incidence of nosocomial bloodstream infections (NBSI). All episodes of culture proven NBSI occurring after 96 h of hospitalisation were identified retrospectively during a 10-year period (1991-2001). Throughout the study period, the use of antenatal steroids, demographic characteristics and morbidity of the patients were recorded prospectively. Since 1996 more efforts were made to use antenatal steroids to decrease neonatal morbidity and mortality. The incidence rates of NBSI were compared between period 1 (1991-1995) and period 2 (1996-2001). The overall incidence rate of NBSI dropped significantly from 7.4% (6.1%-8.9%) in period 1 to 5.0% (4.0%-6.2%) in period 2 and was most pronounced in the birth weight category 1000 g-1500 g (11.7%, 7.9%-15.0% to 6.9%, 4.3%-10.5%) and 1500 g-2500 g (3.6%, 2.2%-5.6% to 1.4%, 0.6%-2.8%). Antenatal use of steroids increased overall from 19% in 1991 to 51% in 2001 ( P<0.001). Since 1996 there was a decreasing number of ventilation days ( P=0.011) and decreasing incidence of patent ductus arteriosus ( P=0.001), while the incidence of neonatal surgery, chronic lung disease and duration of hospitalisation remained constant over time. CONCLUSION: increased use of antenatal steroids is associated with a decreasing incidence rate of nosocomial bloodstream infections in neonates with birth weights between 1000 g and 2500 g, probably by decreasing the incidence of patent ductus arteriosus and/or due to improved respiratory outcome. This finding needs to be confirmed by randomised control trials or by a large prospective cohort study in similar population groups.

Internal and external validation of the NOSEP prediction score for nosocomial sepsis in neonates.

OBJECTIVE: To evaluate the performance of a scoring system (NOSEP) to predict nosocomial sepsis in neonates at the hospital where the score was developed (internal validation) and in an independent data set from other centers (external validation). DESIGN: Multiple center prospective cohort study. SETTING: Six neonatal intensive care units from the Flanders in Belgium. PATIENTS: We analyzed two groups of patients: 62 episodes of presumed nosocomial sepsis in the internal validation cohort and 93 episodes of presumed nosocomial sepsis in a multiple center external validation cohort. INTERVENTIONS: Assessment of the predictive power of the NOSEP score 24 hrs preceding sepsis workup and the patients' basic demographic characteristics and co-morbidity was performed. Diagnosis of nosocomial sepsis and the microbiology results were registered. MAIN RESULTS: The NOSEP score's discriminative capability was very good in the internal validation (area under receiver operating characteristic curve = 0.73 +/- 0.08 [sem]). The NOSEP score performed satisfactory in the external validation (area under receiver operating characteristic curve = 0.66 +/- 0.06). The calibration capability in both validation sets as measured by goodness-of-fit tests (internal validation, p =.56; external validation, p =.48) was good. An improvement of the NOSEP score was obtained for the external centers by redefining the cut-off of the items of the NOSEP score (area under receiver operating characteristic curve for NOSEP-NEW-I = 0.71 +/- 0.05) or adding co-morbidity factors (area under receiver operating characteristic curve for NOSEP-NEW-II = 0.82 +/- 0.04), with good calibration performance (goodness-of-fit test, p >.50). Finally, the fit of the NOSEP score demonstrated no significant variation across subgroups of patients. CONCLUSIONS: The predictive power of the original NOSEP score is very good in neonates at the original neonatal intensive care unit. In other neonatal intensive care units, its discriminatory performance is satisfactory but could be improved after modification of the variables in the model or adding additional variables. To use such a NOSEP score in other neonatal intensive care units, its accuracy has to be validated and adjusted if necessary.