Childhood asthma: pathogenesis and phenotypes.

In the pathogenesis of asthma in children there is a pivotal role for a type 2 inflammatory response to early life exposures or events. Interactions between infections, atopy, genetic susceptibility and environmental exposures (such as farmyard environment, air pollution and tobacco smoke exposure) influence the development of wheezing illness and the risk of progression to asthma. The immune system, lung function and the microbiome in gut and airways develop in parallel, and dysbiosis of the microbiome may be a critical factor in asthma development. Increased infant weight gain and preterm birth are other risk factors for development of asthma and reduced lung function. The complex interplay between these factors explains the heterogeneity of asthma in children. Subgroups of patients can be identified as phenotypes, based on clinical parameters, or endotypes, based on a specific pathophysiological mechanism. Paediatric asthma phenotypes and endotypes may ultimately help to improve diagnosis of asthma, prediction of asthma development and treatment of individual children, based on clinical, temporal, developmental or inflammatory characteristics. Unbiased, data-driven clustering, using a multidimensional or systems biology approach may be needed to better define phenotypes. The present knowledge on inflammatory phenotypes of childhood asthma has now been successfully applied in the treatment with biologicals of children with severe therapy-resistant asthma, and it is to be expected that more personalised treatment options may become available.

Risk factors for intensive care admission in children with severe acute asthma in the Netherlands: a prospective multicentre study.

RATIONALE: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS). OBJECTIVES: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections. METHODS: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses. MEASUREMENTS AND MAIN RESULTS: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission. CONCLUSIONS: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors.

Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation.

INTRODUCTION: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation. AIMS AND METHODS: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward. RESULTS: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status. CONCLUSIONS: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose-response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here. IMPLICATIONS: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking.

The influence of Epstein-Barr virus and cytomegalovirus on childhood respiratory health: A population-based prospective cohort study.

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection are common in early childhood. CMV infection favours a T-helper-1 and EBV infection a T-helper-2 cell response, possibly leading to disbalanced T-helper cell response, and subsequent risk of asthma or atopy. OBJECTIVE: To study the associations of EBV and CMV with lung function, asthma and inhalant allergic sensitization at school age. METHODS: This study among 3546 children was embedded in a population-based prospective cohort. At age 6 years, serum IgG levels against EBV and CMV were measured by ELISA. At age 10 years, lung function was measured by spirometry, asthma by questionnaire and inhalant allergic sensitization by skin prick test. RESULTS: Unadjusted models showed that seropositivity for EBV was associated with a higher FEV1 and FEF75 (Z-score difference (95% CI): 0.09 (0.02, 0.16) and 0.09 (0.02, 0.15)), while seropositivity for CMV was not. Specific combinations of viruses showed that seropositivity for EBV was only associated with FEV1 and FEF75 in the presence of seropositivity for CMV (0.12 (0.04, 0.20)) and 0.08 (0.01, 0.15)). Seropositivity for CMV in the absence of seropositivity for EBV was associated with an increased risk of inhalant allergic sensitization (OR (95% CI): 1.31 (1.02, 1.68)). All effect estimates attenuated into non-significant mainly after adjustment for child's ethnicity. Seropositivity for EBV or CMV was not associated with asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Associations of EBV and CMV infections in early childhood with school-age lung function and inhalant allergic sensitization are explained by ethnicity, or sociodemographic and lifestyle-related factors.

Associations of Th2, Th17, Treg cells, and IgA+ memory B cells with atopic disease in children: The Generation R Study.

BACKGROUND: New insights into immune cells could contribute to treatment and monitoring of atopic disease. Because nongenetic factors shape the human immune system, we here studied these immune cells in a large cohort with atopic children with adjustment for prenatal and postnatal confounders. METHODS: Information on atopic dermatitis, inhalant- and food-allergic sensitization, asthma lung function scores was obtained from 855 10-year-old children within the Generation R cohort. 11-color flow cytometry was performed to determine CD27+ and CD27- IgG+ , IgE+ and IgA+ memory B cells, Th1, Th2, Th17, and Treg-memory cells from venous blood. Associations between any atopic disease, the individual atopic diseases, and immune cell numbers were determined. RESULTS: Children with any atopic disease had higher Th2, Treg, Treg-memory, and CD27+ IgA+ memory B-cell numbers compared to children without atopic disease. When studying the individual diseases compared to children without the individual diseases, children with atopic dermatitis, inhalant-, and food-allergic sensitization had higher memory Treg cell numbers 12.3% (95% CI 4.2; 21.0), (11.1% (95% CI 3.0; 19.8), (23.7% (95% CI 7.9; 41.8), respectively. Children with food-allergic sensitization had higher total B and CD27+ IgA+ memory B-cell numbers (15.2% [95% CI 3.2; 28.7], 22.5% [95% CI 3.9; 44.3], respectively). No associations were observed between asthma and B- or T-cell numbers. CONCLUSION: Children with any atopic disease and children with inhalant- and food-allergic sensitization or atopic dermatitis had higher circulating memory Treg cells, but not higher IgE+ B-cell numbers. The associations of higher Treg and CD27+ IgA+ B-cell numbers in children with food-allergic sensitization are suggestive of TGF-ß-mediated compensation for chronic inflammation.

Maternal blood pressure and hypertensive disorders during pregnancy and childhood respiratory morbidity: the Generation R Study.

Pre-eclampsia is associated with an increased risk of bronchopulmonary dysplasia, wheezing and asthma in later childhood. Currently, there are no studies available investigating maternal blood pressure measurements during multiple time-points in pregnancy and respiratory outcome measures in the child.We examined the associations of maternal blood pressure and hypertensive disorders with the risk of lower lung function, wheezing and asthma in children aged 10 years. This study among 4894 children was embedded in a population-based prospective cohort study. We used multivariate analyses, taking lifestyle and socioeconomic factors into account.We observed consistent associations per 5 mmHg higher maternal blood pressure in early pregnancy with a lower forced expiratory volume in 1 s/forced vital capacity ratio (z-score -0.03 (95% CI -0.05- -0.01)) and per 5 mmHg higher blood pressure in late pregnancy with a higher risk for current wheezing and current asthma (OR 1.07 (95% CI 1.02-1.12) and 1.06 (95% CI 1.00-1.11), respectively). We found no associations of maternal hypertensive disorders during pregnancy with child lung function, current wheezing or current asthma.Our results suggest that higher blood pressure in pregnant women is associated with lower lung function and increased risks of current wheezing and current asthma in children. The associations may be trimester specific.

Air pollution and airway resistance at age 8 years - the PIAMA birth cohort study.

BACKGROUND: Air pollution has been found to adversely affect children's lung function. Forced expiratory volume in 1 s and forced vital capacity from spirometry have been studied most frequently, but measurements of airway resistance may provide additional information. We assessed associations of long-term air pollution exposure with airway resistance. METHODS: We measured airway resistance at age 8 with the interrupter resistance technique (Rint) in participants of the Dutch PIAMA birth cohort study. We linked Rint with estimated annual average air pollution concentrations [nitrogen oxides (NO2, NOx), PM2.5 absorbance ("soot"), and particulate matter < 2.5 µm (PM2.5), < 10 µm (PM10) and 2.5-10 µm (PMcoarse)] at the birth address and current home address (n = 983). Associations between air pollution exposure and interrupter resistance (Rint) were assessed using multiple linear regression adjusting for potential confounders. RESULTS: We found that higher levels of NO2 at the current address were associated with higher Rint [adj. mean difference (95% confidence interval) per interquartile range increase in NO2: 0.018 (0.001, 0.035) kPa·s·L- 1]. Similar trends were observed for the other pollutants, except, PM10. No association was found between Rint and exposure at the birth address. CONCLUSIONS: Our results support the hypothesis that air pollution exposure is associated with a lower lung function in schoolchildren.

Influence of genetic variants on childhood lung function - The Generation R Study.

Genetic variants associated with adult lung function could already exert the effects on childhood lung function. We aimed to examine the associations of adult lung function-related genetic variants with childhood lung function and asthma, and whether these associations were modified by atopic predisposition, tobacco smoke exposure, or early growth characteristics. In a population-based prospective cohort study among 3347 children, we selected 7 and 20 single nucleotide polymorphisms (SNPs) associated with adult forced expiratory volume in 1 second (FEV1 ) and FEV1 /forced vital capacity (FEV1 /FVC), respectively. Weighted genetic risk scores (GRSs) for FEV1 and FEV1 /FVC were constructed. At age 10, FEV1 , FVC, FEV1 /FVC, forced expiratory flow between 25% and 75% (FEF25-75 ), and forced expiratory flow at 75% (FEF75 ) of FVC were measured, and information on asthma was obtained by parental-reported questionnaires. The FEV1 -GRS was associated with lower childhood FEV1 , FEV1 /FVC, and FEF75 (Z-score (95% CI): -0.03 (-0.05, -0.01), -0.03 (-0.05, -0.01), and -0.04 (-0.05, -0.01), respectively, per additional risk allele). The FEV1 /FVC-GRS was associated with lower childhood FEV1 /FVC and FEF75 (Z-score (95% CI): -0.04 (-0.05, -0.03) and -0.03 (-0.05, -0.02), respectively, per additional risk allele). Effect estimates of FEV1 -GRS with FEF25-75 , FEV1 , FEF75 , and FVC, and of FEV1 /FVC-GRS with FEV1 /FVC and FEF25-75 were stronger among children exposed to non-atopic mothers, smoking during pregnancy or in childhood, or those born with a lower birthweight, respectively (P-values for interaction < .05). Genetic risk scores were not associated with asthma. Adult lung function-related genetic variants were associated with childhood lung function. Maternal atopy, smoking during pregnancy or in childhood, and birthweight modified the observed effects.

Ceramides in tracheal aspirates of preterm infants: Marker for bronchopulmonary dysplasia.

BACKGROUND: In an experimental mouse model we showed that ceramides play a role in the pathogenesis of bronchopulmonary dysplasia (BPD) and are a potential target for therapeutic intervention. We investigated whether ceramides are detectable in tracheal aspirates (TAs) of preterm infants and differ between infants with or without BPD. METHODS: Infants born ≤ 32 weeks of gestational age in need of mechanical ventilation in the first week of life were included. TAs were obtained directly after intubation and at day 1, 3, 5, 7, and 14. Ceramide concentrations were measured by tandem mass spectrometry. At 36 weeks postmenstrual age BPD was defined as having had ≥ 28 days supplemental oxygen. RESULTS: 122 infants were included, of which 14 died and 41 developed BPD. All infants showed an increase in ceramides after the first day of intubation. The ceramide profile differed significantly between preterm infants who did and did not develop BPD. However, the ceramide profile had no additional predictive value for BPD development over GA at birth, birth weight and total days of mechanical ventilation. CONCLUSIONS: Ceramides are measurable in TAs of preterm born infants and may be an early marker for BPD development.

Structural and functional ventilatory impairment in infants with severe bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most frequent serious complication in preterm infants. We aimed to describe lung structure and ventilatory function of preterm infants with severe BPD and explored the association between early postnatal growth and these outcomes. METHODS: We included preterm infants born ≤32 weeks gestational age (GA) with severe BPD. Lung structure was assessed on chest CT with the PRAGMA-BPD scoring system and ventilatory function by polysomnography (PSG) at 6 months corrected age. Postnatal growth was assessed by weight measured at birth, and at 2 and 6 months corrected age. RESULTS: We included 49 infants (median [IQR] GA of 25.7 [24.6-26.3] weeks and mean [SD] birth weight of 760 [210] g). A 95.5% of the chest CT scans showed architectural distortion of the lung, and an oxygen desaturation index (ODI) >5 was found in 74% of the infants. An increase in GA of 1 week was associated with higher total and normal lung volume (ß coefficient [95% CI]: 1.86 [0.15, 3.57] and 2.03 [0.41, 3.65]), less hypoattenuation (-4.3 [-7.70, -0.90]%) and lower ODI (-36.7 [-64.2, -9.10]%). Higher weight at 6 months was independently associated with higher total and normal lung volume, and with less severe desaturations. Increased weight gain between 2 and 6 months of corrected age was associated with less severe desaturations during sleep (ß coefficient [95% CI]: 2.09 [0.49, 3.70]). CONCLUSION: Most preterm infants with severe BPD have structural lung abnormalities and impaired ventilatory function early in life, partly explained by birth characteristics and infant growth.