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1.
Pediatr Pulmonol ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31651095

RESUMO

BACKGROUND: Adrenal suppression is a side effect of long-term use of inhaled corticosteroids (ICS). Hair cortisol concentration (HCC) measurement is a noninvasive tool for measuring adrenal function that may be useful for asthmatic patients who are on long-term ICS treatment. The aim of this study was to compare HCC between children with and without asthma and to explore the association between HCC and ICS dose in asthmatic children. METHODS: A cross-sectional observational study in subjects with or without asthma (n = 72 and 226, respectively, age 6-21 years). Hair samples were obtained from the posterior vertex for each subject and data on medication use were collected using questionnaires. HCC was analyzed by liquid chromatography-mass spectrometry in the most proximal 3 cm of hair. RESULTS: Median HCC was significantly lower in subjects with asthma than in subjects without asthma: 1.83 pg/mg and 2.39 pg/mg, respectively (P value after adjustment for age, sex, and body mass index: .036). Median HCC was 1.98 pg/mg in asthmatics using no ICS, 1.84 pg/mg in those using a low dose, 1.75 pg/mg in those on a medium dose, and 1.46 in those using a high ICS dose (P = .54). CONCLUSION: We observed a significantly lower HCC in asthmatics than in healthy controls and a nonsignificant trend of lower HCC with increasing ICS dose. Whether HCC measurement may be used to detect individuals at risk for hypocortisolism and may be useful to monitor adrenal function in asthmatic children using ICS needs to be further investigated.

2.
Drug Saf ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31617080

RESUMO

INTRODUCTION: As asthma medications are frequently prescribed for children, knowledge of the safety of these drugs in the paediatric population is important. Although spontaneous reports cannot be used to prove causality of adverse events, they are important in the detection of safety signals. OBJECTIVE: Our objective was to provide an overview of adverse drug events associated with asthma medications in children from a spontaneous reports database and to identify new signals. METHODS: Spontaneous reports concerning asthma drugs were obtained from EudraVigilance, the European Medicine Agency's database for suspected adverse drug reactions. For each drug-event combination, we calculated the proportional reporting ratio (PRR) in the study period 2011-2017. Signals in children (aged 0-17 years) were compared with signals in the whole population. Analyses were repeated for different age categories, by sex and by therapeutic area. RESULTS: In total, 372,345 reports in children resulted in 385 different signals concerning asthma therapy. The largest group consisted of psychiatric events (65 signals). Only 30 signals were new, with seven, including herpes viral infections, associated with omalizumab. Stratification by age, sex and therapeutic area provided additional new signals, such as hypertrichoses with budesonide and encephalopathies with theophylline. Of all signals in children, 60 (16%) did not appear in the whole population. CONCLUSIONS: The majority of signals regarding asthma therapy in children were already known, but we also identified new signals. We showed that signals can be masked if age stratification is not conducted. Further exploration is needed to investigate the risk and causality of the newly found signals.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31597047

RESUMO

Background Obesity has been implicated as a pathogenic factor in asthma, but the underlying role of general and organ fat is unclear. We hypothesized that organ fat, rather than the total fat mass, increases the risk of asthma. Methods In a population-based prospective cohort study among 5,421 children aged 10 years we measured general fat including body mass index (BMI) and fat mass index by dual-energy X-ray absorptiometry, and organ fat including subcutaneous fat index, visceral fat index, pericardial fat index and liver fat fraction by magnetic resonance imaging. Lung function was measured by spirometry. Current asthma was assessed by questionnaire. Results A higher BMI and fat mass index were associated with a higher FEV1 (Z-score difference (95% CI): 0.16 (0.14, 0.19) and 0.06 (0.03, 0.09) per standard deviation score increase, respectively), a higher FVC (0.19 (0.17, 0.22) and 0.07 (0.04, 0.10)), a lower FEV1/FVC ratio ((-0.07 (-0.10, -0.05) and -0.03 (-0.06, -0.00)), but not with FEF75 or asthma. A higher visceral fat index, independent of fat mass index, was associated with a higher FVC (0.07 (0.03, 0.10)), a lower FEV1/FVC (-0.05 (-0.09, -0.01)), and a higher risk of asthma (Odds Ratio (95%CI): 1.20 (1.01, 1.43) per standard deviation score increase). No other organ fat measures were independently associated with lung function or asthma. Conclusion The obesity-asthma link is mainly driven by visceral fat, independent of total fat mass. Hence, abdominal fat might contribute to asthma development.

4.
Eur J Pediatr ; 178(10): 1507-1517, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31414213

RESUMO

The prevalence of allergic diseases in children is markedly increasing to epidemic proportions. The aim of this study is to describe the presence and examine associated parental and child characteristics of allergic sensitization and physician-diagnosed allergy in Dutch children at age 10 years. This study among 5471 children was performed in a population-based prospective cohort from fetal life onwards. Allergic sensitization was measured by skin prick tests. Physician-diagnosed allergy and parental and child characteristics were collected by questionnaires. In children aged 10 years, inhalant and food allergic sensitization was present in 32.2% and 7.1%, and physician-diagnosed inhalant and food allergy in 12.4% and 2.3%. Maternal and paternal history of allergy, eczema or asthma was associated with increased risks of physician-diagnosed inhalant allergy (aOR (95% CI) 1.44 (1.23-1.70) and 1.59 (1.30-1.94), respectively), but not with food allergy. Asthma and eczema ever at age 10 years were associated with increased risks of physician-diagnosed inhalant allergy (4.60 (3.55-5.96) and 2.42 (1.94-3.03), respectively). Eczema ever at age 10 years was associated with an increased risk of physician-diagnosed food allergy (5.78, 3.04-9.52), with the highest risk of cashew (7.36, 3.20-16.94) and peanut (5.58, 3.08-10.10) food allergy.Conclusions: We found strong effects of parental history of allergy, eczema or asthma on the presence of physician-diagnosed inhalant allergy in children at age 10 years. Eczema ever at age 10 years was a strong risk factor for the development of physician-diagnosed inhalant and food allergy. What is Known: • The prevalence of allergic diseases in children has markedly increased. • Early-life influences are critically important in the development of allergic diseases. What is New: • Maternal and paternal history of allergy, eczema or asthma is associated with increased risks of physician-diagnosed inhalant allergy but not with food allergy. • Eczema ever at age 10 years is associated with an increased risk of physician-diagnosed food allergy, with the highest risk for cashew and peanut food allergy.

5.
Allergy ; 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31385614

RESUMO

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.

7.
Pediatr Pulmonol ; 54(9): 1439-1446, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31211525

RESUMO

OBJECTIVES: To evaluate whether episodic viral wheeze (EVW) and multiple-trigger wheeze (MTW) are clinically distinguishable and stable preschool wheezing phenotypes. METHODS: Children of age 1 to 4 year with recurrent, pediatrician-confirmed wheeze were recruited from secondary care; 189 were included. Respiratory and viral upper respiratory tract infection (URTI) symptoms were recorded weekly by parents in an electronic diary during 12 months. Every 3 months, diary-based symptoms were classified as EVW or MTW and compared to phenotypes assigned by pediatricians based on clinical history. We collected nasal samples for respiratory virus PCR during URTI, respiratory symptoms and in absence of symptoms. RESULTS: Of 660 3-month periods, the diary-based phenotype was EVW in 11%, MTW in 54% and 35% were free from respiratory episodes. Pediatrician-based classification showed 59% EVW and 26% MTW. The Kappa measure of agreement between diary-based and pediatrician-assigned phenotypes was very low (0.12, 95%CI, 0.07-0.17). Phenotypic instability was observed in 32% of cases. PCR was positive in 71% during URTI symptoms, 66% during respiratory symptoms and 38% in the absence of symptoms. CONCLUSION: This study shows that EVW and MTW are variable over time within patients. Pediatrician classification of these phenotypes based on clinical history does not correspond to prospectively recorded symptom patterns. The applicability of these phenotypes as a basis for therapeutic decisions and prognosis should be questioned.

8.
Clin Exp Allergy ; 49(6): 900-910, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30866115

RESUMO

BACKGROUND: Vitamin D deficiency in early life might affect the developing lung and immune system, and subsequently influence the risk of asthma and allergy in later life. OBJECTIVE: We examined the associations of 25-hydroxyvitamin D concentrations in mid-gestation and at birth with lung function, asthma, inhalant allergic sensitization and inhalant allergy at school-age. METHODS: This study among 4951 children and their mothers was embedded in a population-based prospective cohort in Rotterdam, the Netherlands. Maternal venous blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D concentrations. At age 10 years, lung function was measured by spirometry, current asthma and physician-diagnosed inhalant allergy by questionnaire, and inhalant allergic sensitization by skin prick tests. We used multivariable regression models to examine associations. RESULTS: Higher 25-hydroxyvitamin D concentrations in mid-gestation were associated with a higher forced vital capacity (FVC), but a lower forced expiratory volume in 1 second/FVC (FEV1 /FVC) and a lower forced expiratory flow after exhaling 75% of FVC (FEF75 ) (Z-score differences [95% CI] 0.02 [0.00, 0.03], -0.02 [-0.03, -0.01] and -0.01 [-0.03, -0.00], respectively, per 10 nmol/L 25-hydroxyvitamin D), but not with asthma. Furthermore, higher 25-hydroxyvitamin D concentrations in mid-gestation were associated with an increased risk of inhalant allergy (Odds Ratio [95% CI] 1.07 [1.02, 1.12]), but not with inhalant allergic sensitization. After additional adjustment for child's 25-hydroxyvitamin D concentrations at the age of 6 years, only the associations of 25-hydroxyvitamin D concentrations in mid-gestation with FEV1 /FVC and FEF75 remained. We did not find consistent associations of 25-hydroxyvitamin D concentrations at birth with respiratory or allergy outcomes. CONCLUSION AND CLINICAL RELEVANCE: Our results suggest that maternal 25-hydroxyvitamin D concentrations in mid-gestation may influence lung development. The clinical implications of the observed associations remain unclear.

9.
Eur Respir J ; 53(4)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30765504

RESUMO

RATIONALE: We aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course. METHODS: We meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7-13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes. RESULTS: We identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways. INTERPRETATION: Our findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

10.
Pediatr Pulmonol ; 54(5): 628-636, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30741484

RESUMO

OBJECTIVE: Children with congenital diaphragmatic hernia (CDH) suffer from long-term pulmonary morbidity. Longitudinal data of exercise capacity in these children are lacking. We hypothesized that exercise capacity would be impaired in children with CDH and deteriorates over time. We evaluated exercise capacity and its determinants in CDH patients longitudinally until 12 years of age. DESIGN: Prospective longitudinal follow-up study in tertiary university hospital. PATIENTS: One hundred and fourteen children with CDH born between 1999 and 2012. METHODS: Exercise capacity was evaluated using the Bruce treadmill-protocol at the ages of 5, 8, and 12 years. Primary outcome parameter was standard deviation score (SDS) of maximal endurance time. Data were analyzed by using linear mixed models. RESULTS: A total of 107 children (30 treated with extracorporeal membrane oxygenation [ECMO]) performed 191 reliable exercise tests. At ages 5, 8, and 12 years, the mean (95%CI) SDS endurance time was -0.44 (-0.65 to -0.24); -1.01 (-1.23 to -0.78); -1.10 (-1.40 to -0.80), respectively, all less than zero (P < 0.001). Exercise capacity declined significantly over time irrespective of ECMO-treatment (5-12 years: non-ECMO P = 0.015; ECMO P = 0.006). Duration of initial hospital stay and diffusion capacity corrected for alveolar volume were associated with SDS endurance time (P < 0.001 and P = 0.039). CONCLUSIONS: In CDH patients exercise capacity deteriorates between 5 and 12 years of age, irrespective of ECMO-treatment. CDH patients may benefit from long-term assessments of exercise capacity with timely intervention.

11.
Pediatr Allergy Immunol ; 30(4): 443-450, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30801809

RESUMO

BACKGROUND: Fetal growth restriction is associated with higher risks of childhood respiratory morbidity. Fetal blood flow adaptations might contribute to these associations. We examined the associations of fetal umbilical, cerebral, and pulmonary blood flow with wheezing patterns, lung function, and asthma in childhood. METHODS: In a population-based prospective cohort study among 903 children, we measured fetal umbilical, cerebral, and pulmonary blood flow by pulsed-wave Doppler at a median gestational age of 30.3 (95% range 28.8-32.3) weeks. We obtained information about wheezing patterns until the age of 6 years by questionnaires. Lung function was measured by spirometry and information about current asthma was obtained by questionnaire at the age of 10 years. RESULTS: Results showed a non-significant relationship between a higher umbilical artery pulsatility index (PI) and umbilical artery PI/cerebral artery PI ratio, indicating fetal blood flow redistribution at the expense of the trunk, with higher risks of early wheezing (OR [95% CI]: 2.07 (0.70-6.10) and 2.74 (0.60, 12.62) per unit increase, respectively). A higher pulmonary artery time velocity integral, indicating higher pulmonary vascular resistance, was associated with a higher risk of late/persistent wheezing (Z-score 1.14 [1.01-1.29]). A higher middle cerebral artery PI was associated with a higher FEV1 /FVC (Z-score [95% CI]: 0.21 [0.01-0.42]). Results did not materially change after additional adjustment for birth and growth characteristics. CONCLUSION: Third-trimester fetal blood flow patterns might be related to childhood respiratory health. These findings should be considered as hypothesis generating and need further replication.

12.
BMJ Open ; 8(11): e022979, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30498039

RESUMO

OBJECTIVES: To compare the rate, indications and type of antibiotic prescriptions in children with and without asthma. DESIGN: A retrospective cohort study. SETTING: Two population-based primary care databases: Integrated Primary Care Information database (IPCI; the Netherlands) and The Health Improvement Network (THIN; the UK). PARTICIPANTS: Children aged 5-18 years were included from January 2000 to December 2014. A child was categorised as having asthma if there were ≥2 prescriptions of respiratory drugs in the year following a code for asthma. Children were labelled as non-asthmatic if no asthma code was recorded in the patient file. MAIN OUTCOME MEASURES: Rate of antibiotic prescriptions, related indications and type of antibiotic drugs. RESULTS: The cohorts in IPCI and THIN consisted of 946 143 and 7 241 271 person years (PY), respectively. In both cohorts, antibiotic use was significantly higher in asthmatic children (IPCI: 197vs126 users/1000 PY, THIN: 374vs250 users/1000 PY). In children with asthma, part of antibiotic prescriptions were for an asthma exacerbation only (IPCI: 14%, THIN: 4%) and prescriptions were more often due to lower respiratory tract infections then in non-asthmatic children (IPCI: 18%vs13%, THIN: 21%vs12%). Drug type and quality indicators depended more on age, gender and database than on asthma status. CONCLUSIONS: Use of antibiotics was higher in asthmatic children compared with non-asthmatic children. This was mostly due to diseases for which antibiotics are normally not indicated according to guidelines. Further awareness among physicians and patients is needed to minimise antibiotic overuse and limit antibiotic resistance.

13.
Chest ; 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30359613

RESUMO

BACKGROUND: Repeated measurements of spirometry and fractional exhaled nitric oxide (Feno) are recommended as part of the management of childhood asthma, but the evidence base for such recommendations is small. We tested the hypothesis that reducing spirometric indices or increasing Feno will predict poor future asthma outcomes. METHODS: A one-stage individual patient data meta-analysis used data from seven randomized controlled trials in which Feno was used to guide asthma treatment; spirometric indices were also measured. Change in %FEV1 and % change in Feno between baseline and 3 months were related to having poor asthma control and to having an asthma exacerbation between 3 and 6 months after baseline. RESULTS: Data were available from 1,112 children (mean age, 12.6 years; mean %FEV1, 94%). A 10% reduction in %FEV1 between baseline and 3 months was associated with 28% increased odds for asthma exacerbation (95% CI, 3-58) and with 21% increased odds for having poor asthma control (95% CI, 1-45) 6 months after baseline. A 50% increase in Feno between baseline and 3 months was associated with 11% increase in odds for poor asthma control 6 months after baseline (95% CI, 0-16). Baseline Feno and %FEV1 were not related to asthma outcomes at 3 months. CONCLUSIONS: Repeated measurements of %FEV1 that are typically within the "normal" range add to clinical risk assessment of future asthma outcomes in children. The role of repeated Feno measurements is less certain because large changes were associated with small changes in outcome risk.

14.
Eur Respir J ; 52(5)2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30309974

RESUMO

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.

15.
Thorax ; 73(12): 1137-1145, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30064992

RESUMO

BACKGROUND: Infant weight gain is associated with lower lung function and a higher risk of childhood asthma. Detailed individual childhood growth patterns might be better predictors of childhood respiratory morbidity than the difference between two weight and height measurements. We assessed the associations of early childhood growth patterns with lung function and asthma at the age of 10 years and whether the child's current body mass index (BMI) influenced any association. METHODS: We derived peak height and weight growth velocity, BMI at adiposity peak, and age at adiposity peak from longitudinally measured weight and height data in the first 3 years of life of 4435 children enrolled in a population-based prospective cohort study. At 10 years of age, spirometry was performed and current asthma was assessed by questionnaire. Spirometry outcomes included forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, and forced expiratory flow after exhaling 75% of vital capacity (FEF75). RESULTS: Greater peak weight velocity was associated with higher FVC but lower FEV1/FVC and FEF75. Greater BMI at adiposity peak was associated with higher FVC and FEV1 but lower FEV1/FVC and FEF75. Greater age at adiposity peak was associated with higher FVC, FEV1, FEV1/FVC and FEF75, particularly in children with a small size at birth, and lower odds of current asthma in boys. The child's current BMI only explained the associations of peak weight velocity and BMI at adiposity peak with FVC and FEV1. Peak height velocity was not consistently associated with impaired lung function or asthma. CONCLUSION: Peak weight velocity and BMI at adiposity peak were associated with reduced airway patency in relation to lung volume, whereas age at adiposity peak was associated with higher lung function parameters and lower risk of asthma at 10 years, particularly in boys.

16.
Environ Health ; 17(1): 61, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30016982

RESUMO

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.

17.
Pediatr Allergy Immunol ; 29(6): 589-595, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29882296

RESUMO

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.

18.
Pediatr Pulmonol ; 53(7): 857-865, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29635844

RESUMO

The number of children requiring pediatric intensive care unit (PICU) admission for severe acute asthma (SAA) around the world has increased. OBJECTIVES: We investigated whether this trend in SAA PICU admissions is present in the Netherlands. METHODS: A multicenter retrospective cohort study across all tertiary care PICUs in the Netherlands. Inclusion criteria were children (2-18 years) hospitalized for SAA between 2003 and 2013. Data included demographic data, asthma diagnosis, treatment, and mortality. RESULTS: In the 11-year study period 590 children (660 admissions) were admitted to a PICU with a threefold increase in the number of admissions per year over time. The severity of SAA seemed unchanged, based on the first blood gas, length of stay and mortality rate (0.6%). More children received highflow nasal cannula (P < 0.001) and fewer children needed invasive ventilation (P < 0.001). In 58% of the patients the maximal intravenous (IV) salbutamol infusion rate during PICU admission was 1 mcg/kg/min. However, the number of patients treated with IV salbutamol in the referring hospitals increased significantly over time (P = 0.005). The proportion of steroid-naïve patients increased from 35% to 54% (P = 0.004), with a significant increase in both age groups (2-4 years [P = 0.026] and 5-17 years [P = 0.036]). CONCLUSIONS: The number of children requiring PICU admission for SAA in the Netherlands has increased. We speculate that this threefold increase is explained by an increasing number of steroid-naïve children, in conjunction with a lowered threshold for PICU admission, possibly caused by earlier use of salbutamol IV in the referring hospitals.

19.
Eur Respir J ; 51(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29519908

RESUMO

Interleukin-1 receptor-like 1 (IL1RL1) is an important asthma gene. (Epi)genetic regulation of IL1RL1 protein expression has not been established. We assessed the association between IL1RL1 single nucleotide polymorphisms (SNPs), IL1RL1 methylation and serum IL1RL1-a protein levels, and aimed to identify causal pathways in asthma.Associations of IL1RL1 SNPs with asthma were determined in the Dutch Asthma Genome-wide Association Study cohort and three European birth cohorts, BAMSE (Children/Barn, Allergy, Milieu, Stockholm, an Epidemiological survey), INMA (Infancia y Medio Ambiente) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy), participating in the Mechanisms of the Development of Allergy study. We performed blood DNA IL1RL1 methylation quantitative trait locus (QTL) analysis (n=496) and (epi)genome-wide protein QTL analysis on serum IL1RL1-a levels (n=1462). We investigated the association of IL1RL1 CpG methylation with asthma (n=632) and IL1RL1-a levels (n=548), with subsequent causal inference testing. Finally, we determined the association of IL1RL1-a levels with asthma and its clinical characteristics (n=1101).IL1RL1 asthma-risk SNPs strongly associated with IL1RL1 methylation (rs1420101; p=3.7×10-16) and serum IL1RL1-a levels (p=2.8×10-56). IL1RL1 methylation was not associated with asthma or IL1RL1-a levels. IL1RL1-a levels negatively correlated with blood eosinophil counts, whereas there was no association between IL1RL1-a levels and asthma.In conclusion, asthma-associated IL1RL1 SNPs strongly regulate IL1RL1 methylation and serum IL1RL1-a levels, yet neither these IL1RL1-methylation CpG sites nor IL1RL1-a levels are associated with asthma.

20.
Lancet Respir Med ; 6(5): 379-388, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29496485

RESUMO

BACKGROUND: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10-7) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. INTERPRETATION: Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context. FUNDING: EU and the Seventh Framework Programme (the MeDALL project).


Assuntos
Asma/genética , Ilhas de CpG , Metilação de DNA , Eosinófilos/imunologia , Epigênese Genética , Asma/sangue , Criança , Pré-Escolar , DNA/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Linfócitos T Citotóxicos
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