Preschool impulse oscillometry predicts active asthma and impaired lung function at school age.

BACKGROUND: Asthmatic symptoms often start during early childhood. Impulse oscillometry (IOS) is feasible in preschool children who may be unable to reliably perform spirometry measurements. OBJECTIVE: We sought to evaluate the use of IOS in a multicenter, multiethnic high-risk asthma cohort titled the Vitamin D Antenatal Asthma Reduction Trial. METHODS: The trial recruited pregnant women whose children were followed from birth to age 8 years. Lung function was assessed with IOS at ages 4, 5, and 6 years and spirometry at ages 5, 6, 7, and 8 years. Asthma status, respiratory symptoms, and medication use were assessed with repeated questionnaires from birth to age 8 years. RESULTS: In total, 220 children were included in this secondary analysis. Recent respiratory symptoms and short-acting ß2-agonist use were associated with increased respiratory resistance at 5 Hz at age 4 years (ß = 2.6; 95% CI, 1.0 to 4.4; P = .002 and ß = 3.4; 95% CI, 0.7 to 6.2; P = .015, respectively). Increased respiratory resistance at 5 Hz at age 4 years was also associated with decreased lung function from ages 5 to 8 years (ß = -0.3; 95% CI, -0.5 to -0.1; P < .001 for FEV1 at 8 years) and active asthma at age 8 years (ß = 2.0; 95% CI, 0.2 to 3.8; P = .029). CONCLUSIONS: Increased respiratory resistance in preschool IOS is associated with frequent respiratory symptoms as well as school-age asthma and lung function impairment. Our findings suggest that IOS may serve as a potential objective measure for early identification of children who are at high risk of respiratory morbidity.

Cord blood DNA methylation signatures associated with preeclampsia are enriched for cardiovascular pathways: insights from the VDAART trial.

BACKGROUND: Preeclampsia has been associated with maternal epigenetic changes, in particular DNA methylation changes in the placenta. It has been suggested that preeclampsia could also cause DNA methylation changes in the neonate. We examined DNA methylation in relation to gene expression in the cord blood of offspring born to mothers with preeclampsia. METHODS: This study included 128 mother-child pairs who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), where assessment of preeclampsia served as secondary outcome. We performed an epigenome-wide association study of preeclampsia and cord blood DNA methylation (Illumina 450 K chip). We then examined gene expression of the same subjects for validation and replicated the gene signatures in independent DNA methylation datasets. Lastly, we applied functional enrichment and network analyses to identify biological pathways that could potentially be involved in preeclampsia. FINDINGS: In the cord blood samples (n = 128), 263 CpGs were differentially methylated (FDR <0.10) in preeclampsia (n = 16), of which 217 were annotated. Top pathways in the functional enrichment analysis included apelin signaling pathway and other endothelial and cardiovascular pathways. Of the 217 genes, 13 showed differential expression (p's < 0.001) in preeclampsia and 11 had been previously related to preeclampsia (p's < 0.0001). These genes were linked to apelin, cGMP and Notch signaling pathways, all having a role in angiogenic process and cardiovascular function. INTERPRETATION: Preeclampsia is related to differential cord blood DNA methylation signatures of cardiovascular pathways, including the apelin signaling pathway. The association of these cord blood DNA methylation signatures with offspring's long-term morbidities due to preeclampsia should be further investigated. FUNDING: VDAART is funded by National Heart, Lung, and Blood Institute grants of R01HL091528 and UH3OD023268. HMK is supported by Jane and Aatos Erkko Foundation, Paulo Foundation, and the Pediatric Research Foundation. HM is supported by K01 award from NHLBI (1K01HL146977-01A1). PK is supported by K99HL159234 from NIH/NHLBI.

Maternal vitamin D status modifies the effects of early life tobacco exposure on child lung function.

BACKGROUND: Prior studies suggest that vitamin D may modify the effects of environmental exposures; however, none have investigated gestational vitamin D and cumulative tobacco smoke exposure (TSE) throughout pregnancy and early life. OBJECTIVES: This study investigated the effects of early life TSE on child lung function and the modulatory effects of gestational vitamin D on this association. METHODS: The VDAART (Vitamin D Antenatal Asthma Reduction Trial) recruited nonsmoking pregnant women and followed the mother-child pairs to age 6 years. TSE was assessed with questionnaires and plasma cotinine measurements in the mothers (10-18 and 32-38 gestational weeks) and children (1, 3, and 6 years). Cumulative TSE was calculated from the repeated cotinine measurements. 25-hydroxyvitamin D (25[OH]D) levels were measured at 10-18 and 32-38 gestational weeks. Lung function was assessed at 6 years with spirometry and impulse oscillometry. RESULTS: Of the 476 mother-child pairs, 205 (43%) had increased cotinine levels at ≥1 time point. Cumulative TSE was associated with decreased FEV1 (ß = -0.043 L, P = .018) and increased respiratory resistance at 5 Hz (R5; ß = 0.060 kPa/L/s, P = .002). This association persisted in subjects with insufficient (<30 ng/mL) 25(OH)D levels throughout pregnancy (ß = 0.077 kPa/L/s, P = .016 for R5) but not among those with sufficient levels throughout pregnancy. CONCLUSIONS: Cumulative TSE from pregnancy to childhood is associated with dose- and duration-dependent decreases in child lung function at 6 years even in the absence of reported maternal smoking. Gestational vitamin D may modulate this effect and have therapeutic potential for minimizing the adverse effect of TSE on lung throughout early life. RANDOMIZED TRIAL: Maternal Vitamin D Supplementation to Prevent Childhood Asthma (VDAART); clinicaltrials.gov identifier: NCT00920621.

The Association of Prenatal C-Reactive Protein Levels With Childhood Asthma and Atopy.

BACKGROUND: The pathogenesis of childhood asthma is complex, and determinants of risk may begin in utero. OBJECTIVE: To describe the association of systemic prenatal inflammation, measured by plasma C-reactive protein (CRP), with childhood asthma, eczema, and allergic rhinitis. METHODS: A total of 522 maternal-offspring pairs from the Vitamin D Antenatal Asthma Reduction Trial were included. Prenatal plasma CRP level was measured between 10 and 18 weeks of gestation and between 32 and 38 weeks of gestation. Offspring asthma, eczema, and allergic rhinitis were assessed quarterly between birth and age 6 years. We performed mediation analyses of prenatal CRP on the association between several maternal characteristics and offspring asthma. RESULTS: Elevated early and late prenatal CRP and an increase in CRP from early to late pregnancy were associated with asthma by age 6 years (early: adjusted odds ratio [aOR], 1.76, 95% CI, 1.12-2.82, P = .02; late: aOR, 2.45, 95% CI, 1.47-4.18, P < .001; CRP increase: aOR, 2.06, 95% CI, 1.26-3.39, P < .004). Prenatal CRP and childhood asthma associations were strengthened among offspring with atopic asthma (early: aOR, 3.78, 95% CI, 1.49-10.64, P = .008; late: aOR, 4.84, 95% CI, 1.68-15.50, P = .005; CRP increase: aOR, 3.01, 95% CI, 1.06-9.16, P = .04). Early and late prenatal CRP mediated 96% and 86% of the association between maternal prepregnancy body mass index and offspring asthma, respectively. CONCLUSIONS: Higher prenatal CRP and an increase in CRP from early to late pregnancy are associated with childhood asthma. Systemic inflammation during pregnancy associated with modifiable maternal characteristics may be an important determinant of childhood asthma risk.

Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma.

The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.

Metabolomic differences in lung function metrics: evidence from two cohorts.

RATIONALE: The biochemical mechanisms underlying lung function are incompletely understood. OBJECTIVES: To identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery-the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk, n=10 460) and validation-the VA Normative Aging Study (NAS) metabolomic cohort (n=437). METHODS: We ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05. MEASUREMENTS AND MAIN RESULTS: Of 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC. CONCLUSIONS: The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze.

BACKGROUND: Prenatal vitamin D3 supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze. METHODS: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D3 supplementation versus placebo. RESULTS: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC2010), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC2010). CONCLUSION: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Low gestational vitamin D level and childhood asthma are related to impaired lung function in high-risk children.

BACKGROUND: Lung function impairment in early life often persists into adulthood. Therefore, identifying risk factors for low childhood lung function is crucial. OBJECTIVE: We examined the effect of 25-hydroxyvitamin D (25[OH]D) level and childhood asthma phenotype on childhood lung function in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). METHODS: The 25(OH)D level was measured at set time points in mothers during pregnancy and in children during early life. On the basis of parental reports, children were categorized into 3 clinical phenotypes: asymptomatic/infrequent wheeze, early transient wheeze, and asthma at age 6 years. Lung function was assessed with impulse oscillometry at ages 4, 5, and 6 years and with spirometry at ages 5 and 6 years. RESULTS: A total of 570 mother-child pairs were included in this post hoc analysis. Mean gestational 25(OH)D-level quartiles were negatively associated with child respiratory resistance at 5 Hz (R5) from age 4 to 6 years (ß, -0.021 kPa/L/s; 95% CI, -0.035 to -0.007; P = .003) and positively associated with FEV1 (ß, 0.018 L; 95% CI, 0.005-0.031; P = .008) and forced vital capacity (ß, 0.022 L; 95% CI, 0.009-0.036; P = .002) from age 5 to 6 years. Children with asthma at age 6 years had lower lung function from age 4 to 6 years than the asymptomatic/infrequent wheeze group (ß, 0.065 kPa/L/s; 95% CI, 0.028 to 0.102; P < .001 for R5 and ß, -0.063 L; 95% CI, -0.099 to -0.028; P < .001 for FEV1). CONCLUSIONS: Low gestational 25(OH)D level and childhood asthma are important risk factors for decreased lung function in early childhood.

The effect of sildenafil on pleural and peritoneal effusions after the TCPC operation.

BACKGROUND: We evaluated whether the administration of sildenafil in children undergoing the TCPC operation shortened the interval from the operation to the removal of the pleural and peritoneal drains. METHODS: We retrospectively reviewed the data of 122 patients who had undergone the TCPC operation between 2004 and 2014. Patients were divided into two groups on the basis of their treatments. Sildenafil was orally administered pre-operatively in the morning of the procedure or within 24 hours after the TCPC operation to the sildenafil group (n = 48), which was compared to a control group (n = 60). Fourteen patients were excluded from the study. RESULTS: The primary outcome measure was the time from the operation to the removal of the drains. The study groups had similar demographics. The median [interquartile range] time for the removal of drains (sildenafil group 11 [8-19] vs control group 11 [7-16] d, P = .532) was comparable between the groups. The median [interquartile range] fluid balance on the first post-operative day was significantly higher (P = .001) in the sildenafil group compared with controls (47 [12-103] vs 7 [-6-67] mL kg-1 ). The first post-operative day fluid balance was a significant predictor for a prolonged need for drains in the multivariate analysis. CONCLUSIONS: Sildenafil administration, pre-operatively or within 24 hours after the TCPC operation, did not reduce the required time for pleural and peritoneal drains but was associated with a significantly higher positive fluid balance.