Michiel L. Houben

Cord Blood Vitamin D Deficiency is Associated With Respiratory Syncytial Virus Bronchiolitis

BACKGROUND: Respiratory syncytial virus (RSV) is the most important pathogen causing severe lower respiratory tract infection (LRTI) in infants. Epidemiologic and basic studies suggest that vitamin D may protect against RSV LRTI. OBJECTIVE: To determine the association between plasma vitamin D concentrations at birth and the subsequent risk of RSV LRTI. DESIGN: A prospective birth cohort study was performed in healthy term neonates. Concentrations of 25-hydroxyvitamin D (25-OHD) in cord blood plasma were related to RSV LRTI in the first year of life, defined as parent-reported LRTI symptoms in a daily log and simultaneous presence of RSV RNA in a nose-throat specimen. RESULTS: The study population included 156 neonates. Eighteen (12%) developed RSV LRTI. The mean plasma 25-OHD concentration was 82 nmol/L. Overall, 27% of neonates had 25-OHD concentrations <50 nmol/L, 27% had 50-74 nmol/L and only 46% had 25-OHD 75 nmol/L. Cord blood 25-OHD concentrations were strongly associated with maternal vitamin D3 supplementation during pregnancy. Concentrations of 25-OHD were lower in neonates who subsequently developed RSV LRTI compared with those who did not (65 nmol/L versus 84 nmol/L, P = .009). Neonates born with 25-OHD concentrations <50 nmol/L had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥75 nmol/L. CONCLUSIONS: Vitamin D deficiency in healthy neonates is associated with increased risk of RSV LRTI in the first year of life. Intensified routine vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI during infancy.

Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, with remarkable variability in disease severity. Factors determining severity of disease in previously healthy infants are still unclear. It was hypothesized that disease severity is correlated with viral load in primary RSV infection. Infants of a healthy birth cohort were included at signs of their first respiratory tract infection. Nasopharyngeal aspirate was obtained within 48–96 hr and disease severity was assessed with a previously published severity scoring model. PCR was applied to test the aspirates in a semi‐quantitative way for the presence of 10 respiratory pathogens. In case of multiple infection, the pathogen with the highest load was defined as the primary pathogen. The correlation between disease severity and viral load was analyzed. A total of 82 infants were included over a period of 2 years. Median age at first respiratory tract infection was 3 months. Pathogens were detected in 77 (94%) infants; more than one pathogen was detected in 35 (43%) infants. RSV was present in aspirates of 30 infants; in 16 aspirates RSV was the primary pathogen. A negative correlation between RSV CT‐value and disease severity was found in all RSV cases (ρ = −0.52, P = 0.003) and in cases with RSV as the primary pathogen (ρ = −0.54, P = 0.03). In conclusion, this is the first report on viral loads in previously healthy infants with RSV infection in the community. Disease severity correlated positively with viral load during primary RSV infection. J. Med. Virol. 82: 1266–1271, 2010.

The Association between Intrauterine Inflammation and Spontaneous Vaginal Delivery at Term: A Cross-Sectional Study

Background Different factors contribute to the onset of labor at term. In animal models onset of labor is characterized by an inflammatory response. The role of intrauterine inflammation, although implicated in preterm birth, is not yet established in human term labor. We hypothesized that intrauterine inflammation at term is associated with spontaneous onset of labor. Methods/Results In two large urban hospitals in the Netherlands, a cross-sectional study of spontaneous onset term vaginal deliveries and elective caesarean sections (CS), without signs of labor, was carried out. Placentas and amniotic fluid samples were collected during labor and/or at delivery. Histological signs of placenta inflammation were determined. Amniotic fluid proinflammatory cytokine concentrations were measured using ELISA. A total of 375 women were included. In term vaginal deliveries, more signs of intrauterine inflammation were found than in elective CS: the prevalence of chorioamnionitis was higher (18 vs 4%, p = 0.02) and amniotic fluid concentration of IL-6 was higher (3.1 vs 0.37 ng/mL, p<0.001). Similar results were obtained for IL-8 (10.93 vs 0.96 ng/mL, p<0.001) and percentage of detectable TNF-α (50 vs 4%, p<0.001). Conclusions This large cross-sectional study shows that spontaneous term delivery is characterized by histopathological signs of placenta inflammation and increased amniotic fluid proinflammatory cytokines.

Breastfeeding modulates neonatal innate immune responses: a prospective birth cohort study

To cite this article: Belderbos ME, Houben ML, van Bleek GM, Schuijff L, van Uden NOP, Bloemen‐Carlier EM, Kimpen JLL, Eijkemans MJC, Rovers M, Bont LJ. Breastfeeding modulates neonatal innate immune responses: a prospective birth cohort study. Pediatric Allergy Immunology 2012: 23: 65–74.

Clinical Prediction Rule for RSV Bronchiolitis in Healthy Newborns: Prognostic Birth Cohort Study

OBJECTIVE: Our goal was to determine predictors of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) among healthy newborns. METHODS: In this prospective birth cohort study, 298 healthy term newborns born in 2 large hospitals in the Netherlands were monitored throughout the first year of life. Parents kept daily logs and collected nose/throat swabs during respiratory tract infections. The primary outcome was RSV LRTI, which was defined on the basis of the combination of positive RSV polymerase chain reaction results and acute wheeze or moderate/severe cough. RESULTS: Of the 298 children, 42 (14%) developed RSV LRTI. Independent predictors for RSV LRTI were day care attendance and/or siblings, high parental education level, birth weight of >4 kg, and birth in April to September. The area under the receiver operating characteristic curve was 0.72 (95% confidence interval: 0.64–0.80). We derived a clinical prediction rule; possible scores ranged from 0 to 5 points. The absolute risk of RSV LRTI was 3% for children with scores of ≤2 (20% of all children) and 32% for children with all 4 factors (scores of 5; 8% of all children). Furthermore, 62% of the children with RSV LRTI experienced wheezing during the first year of life, compared with 36% of the children without RSV LRTI. CONCLUSIONS: A simple clinical prediction rule identifies healthy newborns at risk of RSV LRTI. Physicians can differentiate between children with high and low risks of RSV LRTI and subsequently can target preventive and monitoring strategies toward children at high risk.

Low neonatal Toll‐like receptor 4‐mediated interleukin‐10 production is associated with subsequent atopic dermatitis

Atopic dermatitis (AD) and respiratory syncytial virus lower respiratory tract infection (RSV LRTI) are common diseases during early life. Impaired Th1‐cell polarizing Toll‐like receptor (TLR) responses play an important role in the pathogenesis of both diseases. Neonatal TLR‐mediated production of Th1‐type cytokines is decreased at birth, but rapidly increases during the first month of life.

Porphyromonas gingivalis within placental villous mesenchyme and umbilical cord stroma is associated with adverse pregnancy outcome

Intrauterine presence of Porphyromonas gingivalis (Pg), a common oral pathobiont, is implicated in preterm birth. Our aim was to determine if the location of Pg within placental and/or umbilical cord sections was associated with a specific delivery diagnosis at preterm delivery (histologic chorioamnionitis, chorioamnionitis with funisitis, preeclampsia, and preeclampsia with HELLP-syndrome, small for gestational age). The prevalence and location of Pg within archived placental and umbilical cord specimens from preterm (25 to 32 weeks gestation) and term control cohorts were evaluated by immunofluorescent histology. Detection of Pg was performed blinded to pregnancy characteristics. Multivariate analyses were performed to evaluate independent effects of gestational age, being small for gestational age, specific preterm delivery diagnosis, antenatal steroids, and delivery mode, on the odds of having Pg in the preterm tissue. Within the preterm cohort, 49 of 97 (51%) placentas and 40 of 97 (41%) umbilical cord specimens were positive for Pg. Pg within the placenta was significantly associated with shorter gestation lengths (OR 0.63 (95%CI: 0.48–0.85; p = 0.002) per week) and delivery via caesarean section (OR 4.02 (95%CI: 1.15–14.04; p = 0.03), but not with histological chorioamnionitis or preeclampsia. However, the presence of Pg in the umbilical cord was significantly associated with preeclampsia: OR 6.73 (95%CI: 1.31–36.67; p = 0.02). In the term cohort, 2 of 35 (6%) placentas and no umbilical cord term specimens were positive for Pg. The location of Pg within the placenta was different between preterm and term groups in that Pg within the villous mesenchyme was only detected in the preterm cohort, whereas Pg associated with syncytiotrophoblasts was found in both preterm and term placentas. Taken together, our results suggest that the presence of Pg within the villous stroma or umbilical cord may be an important determinant in Pg-associated adverse pregnancy outcomes.

Placental characteristics in women with polycystic ovary syndrome

STUDY QUESTION Are macroscopic and microscopic placental characteristics in a heterogeneous group of women diagnosed with polycystic ovary syndrome (PCOS) different from those of a low-risk general population? SUMMARY ANSWER Women with PCOS have significantly different microscopic placental characteristics compared with control women, independently from pregnancy complications. WHAT IS KNOWN ALREADY Non-obese women with PCOS who conceived spontaneously have a significantly reduced placental volume and weight, with more chronic villitis and intervillositis compared with healthy controls. STUDY DESIGN, SIZE, DURATION A subset of a large prospective cohort study of pregnant women with PCOS was used. Healthy (low-risk) women who delivered at term after an uncomplicated pregnancy were used as the reference population. The placentas of 73 women with PCOS were analysed and compared with 209 placentas of healthy women. PARTICIPANTS/MATERIALS, SETTING, METHODS Placentas were collected after delivery from women with PCOS who were followed from prior to conception until delivery. The placentas were macroscopically and microscopically analysed and compared with placentas of healthy women with either a spontaneous start of labour who delivered at term or who had an elective Caesarean section. MAIN RESULTS AND THE ROLE OF CHANCE After adjusting for potential confounders, placentas from women with PCOS showed more chorioamnionitis (P < 0.001), funisitis (P = 0.019), villitis (P = 0.045), thrombosis (P = 0.018), infarction (P = 0.010), villous immaturity (P = 0.009) and nucleated fetal red blood cells (P < 0.001). In a subgroup analysis, among women with and without pregnancy complications within the PCOS group, only the occurrence of thrombosis was increased in pregnancies complicated by pregnancy-induced hypertension or pre-eclampsia (30%, versus 0% in gestational diabetes pregnancies and 13% in uncomplicated pregnancies; P = 0.008). LIMITATIONS, REASONS FOR CAUTION There might be a small proportion of women with PCOS in the reference group, since this group was not screened for PCOS. As a result, the observed difference may be an underestimation of the true difference. Placentas were stored for up to 72 h at 4°C, this is common practice but some degenerative changes cannot be ruled out absolutely. Also, there is possibility that baseline differences between the groups may in part explain some of the differences in placental pathology. WIDER IMPLICATIONS OF THE FINDINGS Our findings suggest that, in general, women with PCOS can have placental alterations associated with an increased hypoxic state, which seems not to be caused by the increased incidence of pregnancy complications.

Rhinovirus wheezing illness in infancy is associated with medically attended third year wheezing in low risk infants: results of a healthy birth cohort study

Rhinoviruses may be pathogens contributing to the development of childhood wheezing. However, their role in low risk infants without an asthmatic predisposition is unknown. Knowing which healthy, low risk children are at increased risk for childhood wheezing after rhinovirus wheezing illness (RV‐WI) in infancy, might help in developing prevention and treatment strategies for childhood wheezing. The aim of this study was to determine the association of medically attended wheezing at the age of three with RV‐WI in the first year of life in low risk children without parental asthma. In a low risk, prospective birth cohort study, we followed 181 healthy born children from birth through the third year of life. We considered children ‘low risk’ if neither parent had a doctors diagnosis of asthma. We determined infant RV‐WI by parent‐reported wheezing (based on daily logs) and simultaneous molecular rhinovirus detection in the first year of life. Respiratory function and blood eosinophil count were both measured in the first month of life. The primary outcome, third year wheezing, was defined as the use of prescribed inhaled asthma medications together with a doctors visit for respiratory symptoms in the third year of life. We calculated the association of RV‐WI with medically attended third year wheezing and other known possible risk factors for wheezing at the age of three. Among low risk children, third year wheezing was observed in 7 out of 18 (39%) children with versus 10 out of 163 (6%) children without infant RV‐WI (OR 9.7, 95% CI 3.1–33.5, P < 0.0001). The association between RV‐WI and third year wheezing was unchanged after adjustment for potential confounders such as eosinophilia and atopic eczema. RV‐WI is a robust and independent risk factor for third year wheezing in low risk children without parental asthma. Future research will identify and protect those children at increased risk for RV‐WI.

Commentary: why are young healthy term infants protected against respiratory syncytial virus bronchiolitis?

In this month’s edition of the journal, Simões et al report on the incidence of respiratory syncytial virus (RSV) lower respiratory illness (LRI) in children less than 5 years of age in a large rural and suburban population in Indonesia. The authors prospectively followed more than 2000 children for 28 months. They performed physical examinations during each LRI episode. Nasal washes were obtained for RSV testing by enzyme immunoassay or polymerase chain reaction. The authors characterized 802 episodes of LRI in 479 children. RSV LRI was observed in 149 children. In children 12 months of age, 42% of RSV LRI cases fulfilled WHO criteria of severe pneumonia, whereas among older children, this was only 18%. Hospitalization was required in 12% of cases with RSV LRI. The most remarkable finding in the study by Simões et al is the age distribution of patients with RSV LRI. The highest incidence of RSV LRI was found at the age of 6 to 24 months. The incidence of RSV LRI in children 6 months was low and virtually absent in children 3 months of age. This finding was in sharp contrast with existent literature suggesting that RSV LRI is most commonly observed during the first 3 to 6 months of life. However, most of these data are derived from cohorts of children hospitalized for RSV LRI. The results of the study by Simões et al resemble data from other population-based studies in which it becomes clear that RSV LRI is a relatively rare event in children 3 to 6 months of age. For example, the age distribution of RSV LRI cases in the study by Simões et al is remarkably similar to our recent healthy birth cohort study in the Netherlands. In this study, RSV LRI incidence was also low during the first 3 to 6 months of life. Age distribution of RSV LRI cases in the general community (Fig. 1A) was clearly different from other cohorts of RSV patients previously described by our group (Fig. 1B–D). We conclude that RSV LRI during the first 3 to 6 months of life is rare, but has a severe course of disease when it occurs. The explanation for the remarkable absence of RSV LRI during the first months of life in healthy term children is not obvious. The first and most likely explanation is protection by maternal antibodies. Indeed, high titers of RSV-neutralizing antibodies in cord blood are associated with reduced incidence of RSV bronchiolitis. Nevertheless, this explanation is not completely satisfactory, because protection provided by maternal antibodies is only partial. Second breast-feeding is associated with reduced risk of RSV LRI. Simões does not show detailed breast-feeding data. However, previous studies have only shown modest effects of breast-feeding on the incidence of RSV LRI. Third, low viral exposure during early infancy may explain low incidence of RSV LRI in children 3 to 6 months of age. Children 3 to 6 months of age often do not yet attend day care. However, the article by Simões et al clearly shows that low incidence of RSV LRI is also observed in families with large number of preschool and school-aged children. Could there be alternative explanations for the low incidence of RSV LRI during the first months of life? It appears unlikely, that a robust innate immune system protects against RSV infection. Instead, children are born with weak innate immune responses. In particular, they produce less cytokines required for antiviral immunity, such as type I interferons and interleukin-12 on Toll-like receptor activation. Could the airway epithelium of young infants be resistant to RSV infection? And if so, what would be the underlying mechanism? Information is required on age-specific functions of infant airway epithelium, such as expression of surface immune receptors and production of antiviral molecules. Taken together, RSV LRI is a rare disease during the first 3 to 6 months of life and we need new explanations to fully understand this phenomenon. Can we use the results of the study by Simões et al to prevent hospitalization for RSV LRI in healthy term infants? Although the highest incidence of hospitalization for RSV LRI is observed at 3 to 6 months of life, Simões shows that the highest incidence in the community is typically observed at a later age. We need to identify children at the highest risk of developing RSV LRI during the first months of life. Host factors, such as genetic polymorphisms, immunologic maturation, neonatal lung function, and also socioeconomic factors contribute to the risk of viral bronchiolitis. We now need to use this information to identify individual healthy term infants with the highest risk of RSV LRI before the age of 3 to 6 months.