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.Peer reviewe

Small airway function in children with mild to moderate asthmatic symptoms

Background: Clinical significance of small airway obstruction in mild pediatric asthma is unclear. Objective: To evaluate small airway properties in children with mild to moderate asthmatic symptoms and the association of small airway function with asthma control and exercise-induced bronchoconstriction (EIB). Methods: Children (5-10 years old) with recurrent wheezing (n = 42) or persistent troublesome cough (n = 16) and healthy controls (n = 19) performed impulse oscillometry (IOS), spirometry, and a multiple-breath nitrogen washout (MBNW) test. Exhaled nitric oxide (NO) was measured at multiple flow rates to determine alveolar NO concentration (CAIN). Asthma control was evaluated with the Childhood Asthma Control Test (C-ACT), short-acting beta(2)-agonist (SABA) use within the past month, and asthma exacerbations within the past year. Results: IOS, spirometry, and exhaled NO indexes that are related to small airway function differed between children with recurrent wheezing and healthy controls, whereas only forced expiratory flow at 25% to 75% of the forced vital capacity was associated with persistent cough. The MBNW indexes showed no difference between the groups. Among symptomatic children, conducting airway ventilation inhomogeneity and CALV were associated with asthma exacerbations (P = .03 and P = .002, respectively), and lung clearance index and CALV were associated with EIB (P = .04 and P = .004, respectively). None of the proposed small airway indexes was associated with the C-ACT score or SABA use. Conclusion: Subtle changes were observed in the proposed small airway indexes of IOS, spirometry, and exhaled NO among children with mild to moderate recurrent wheezing. Small airway dysfunction, expressed as ventilation inhomogeneity indexes and CALV, was also associated with asthma exacerbations and EIB. (C) 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.Peer reviewe

Assessment of Small Airway Function : Application of Impulse Oscillometry in Young Children with Asthmatic Symptoms

Small airway dysfunction has been associated with different clinical features of asthma, such as symptom severity, exacerbations, and airway hyperresponsiveness (AHR). However, the diagnosis and monitoring of asthma focus on indices that reflect mainly large airway function, and no gold standard measure for small airways exists. Especially in children, the clinical significance of small airway dysfunction in asthma is poorly understood. This thesis investigates small airway dysfunction in children with symptoms suggestive of asthma, with a special interest in the clinical utility of impulse oscillometry (IOS) indices postulated to reflect small airway function in these children. First, IOS results of 103 healthy Finnish children (aged 2-7 years) were used to establish reference values for IOS indices postulated to reflect small airway properties (R5-20, R5-20%, and AX). The ability of these indices to distinguish different phenotypes of early respiratory morbidity was evaluated in 65 symptomatic children (aged 3-8 years). Second, the cut-off values for normal bronchodilator responses (BDR) and between-visit repeatability were determined for these indices. Third, the presence of small airway dysfunction in 58 children (aged 5-10 years) with mild to moderate respiratory symptoms suggestive of asthma was evaluated by comparing their IOS, spirometry, multiple breath nitrogen washout, and alveolar nitric oxide concentration (CALV) results with those of 19 healthy controls (aged 5-10 years). The associations of small airway dysfunction with asthma control and AHR were also evaluated. Fourth, the longitudinal association between preschool (2-7 years) IOS and spirometry in adolescence (12-18 years) was evaluated in 154 subjects with asthma. Height- and sex-adjusted reference equations were created for R5-20, R5-20%, and AX. When using the established reference equations, these indices were superior to conventional IOS parameters (R5 and X5) in distinguishing all patient groups from healthy controls. In the healthy reference sample, these indices showed marked BDRs. Although these indices showed larger variability relative to R5, their between-visit agreement remained good in symptomatic children. The proposed small airway indices of IOS, spirometry, and CALV differed between children with mild to moderate recurrent wheezing and healthy controls. Furthermore, ventilation inhomogeneity indices and CALV were associated with frequent asthma exacerbations and AHR. In the longitudinal study, preschool IOS parameters, especially those related to small airway function, were associated with lung function in adolescence. Children with respiratory symptoms suggestive of asthma may present with early changes related to small airway dysfunction and IOS seems to be useful in detecting these children. Furthermore, the proposed small airway IOS indices appear to be associated with later lung function. Although these indices show greater variability than conventional IOS parameters, their between-visit agreement remains good. Therefore, these IOS indices provide a potential tool for evaluating early disease changes and the effects of interventions in young children with symptoms suggestive of asthma.Pienten hengitysteiden toimintahäiriö on liitetty astman kliinisiin piirteisiin, kuten oireiden vaikeusasteeseen ja hengitysteiden hyperreaktiviteettiin (AHR). Tavanomaiset keuhkojen toiminnan mittausmenetelmät kuitenkin kuvastavat lähinnä suurempien hengitysteiden toimintaa, ja erityisesti lasten astmassa pienten hengitysteiden merkityksestä on hyvin vähän tutkimustietoa. Väitöskirjatutkimuksen tarkoituksena oli selvittää pienten hengitysteiden toimintahäiriön merkitystä lasten astmaan viittaavissa oireissa ja erityisesti impulssioskillometrian (IOS) käyttökelpoisuutta näiden muutosten arvioinnissa. Ensimmäisessä osatyössä määritettiin terveille lapsille (ikä 2-7 vuotta, n=103) viitearvot pienten hengitysteiden toimintaan liitetyille IOS-parametreille (R5-20, R5-20% ja AX). Poikkeavien tulosten yleisyyttä tutkittiin lapsilla (ikä 3-8 vuotta, n=65), joilla oli astmaan viittaavia oireita tai bronkopulmonaalinen dysplasia. Toisessa osatyössä määritettiin raja-arvot keuhkoputkia avaavan lääkeaineen aiheuttamille muutoksille näissä parametreissa terveillä lapsilla. Lisäksi arvioitiin IOS:n toistettavuutta astmaoireisilla lapsilla (n=43). Kolmannessa osatyössä tutkittiin pienten hengitysteiden toimintaan liitettyjen IOS-, spirometria-, monihengitysnitrografia- (MBNW) ja uloshengitysilman typpioksidiparametrien (CALV) kykyä tunnistaa astmaoireiset lapset (ikä 5-10 vuotta, n=58) terveistä verrokeista (ikä 5-10 vuotta, n=19). Neljännessä osatyössä selvitettiin leikki-iän (2-7 vuotta) IOS:n ja teini-iän (12-18 vuotta) spirometriatulosten yhteyttä astmapotilailla (n=154). Uusien viitearvojen mukaiset IOS-parametrit R5-20, R5-20% ja AX erottelivat perinteisiä IOS-parametreja (R5 ja X5) paremmin oireiset lapset terveistä verrokeista. Näissä parametreissa nähtiin merkittävät vasteet keuhkoputkia avaavalle lääkeaineelle, joiden normaalina pidettäville muutoksille määritettiin raja-arvot. Parametrien vaihtelu oli oireisilla lapsilla suurempaa kuin perinteisillä IOS-parametreilla, mutta tulosten 7-14 päivän yhteneväisyys säilyi hyvänä. Pienten hengitysteiden toimintaan liitetyt IOS- ja spirometriaparametrit sekä CALV erosivat merkittävästi toistuvasta uloshengityksen vinkunasta kärsivien lasten ja terveiden verrokkien välillä. Hengitysteiden heterogeenista toimintaa kuvaavat MBNW-parametrit ja CALV olivat myös yhteydessä astman pahenemisvaiheiden määrään sekä poikkeavaan AHR-tulokseen. Pitkittäistutkimuksessa leikki-iän IOS-mittaustulos oli astmapotilailla erityisesti pienten hengitysteiden toimintaan liitettyjen parametrien osalta myös yhteydessä keuhkojen toimintaan teini-iässä. Astmaoireisten lasten pienten hengitysteiden toiminnassa voidaan havaita eroja terveisiin kontrolleihin verrattuna ja IOS vaikuttaa käyttökelpoiselta näiden muutosten arvioinnissa. Astmapotilailla pienten hengitysteiden toimintahäiriö voi myös olla yhteydessä myöhempään keuhkojen toimintaan. Perinteisiä parametreja suuremmasta vaihtelusta huolimatta pienten hengitysteiden toimintaan liitettyjen IOS-parametrien 7-14 päivän yhteneväisyys säilyy hyvänä. IOS tarjoaa potentiaalisen menetelmän astmaoireisten lasten pienten hengitysteiden toiminnan arviointiin sekä pieniin hengitysteihin suunnattujen hoitointerventioiden seurantaan

Small Airway Indices of Impulse Oscillometry in Healthy and Symptomatic Preschool Children

Background: Early origins of chronic obstructive pulmonary disease have been recognized. Impulse oscillometry (IOS) is postulated to enable assessment of small airways function but limited data exist on the determinants of these proposed small airway indices, and on their sensitivity to detect lung function deficits in young children. Methods: IOS measurements of 103 healthy Finnish preschool children were evaluated to establish reference equations for the difference between respiratory resistance at 5 and 20 Hz (R5-20), the relative difference of R5-20 (R5-20%), and area under the reactance curve (AX). Thereafter, IOS results of young children with current troublesome lung symptoms (n=20), history of early wheeze (n=38), or bronchopulmonary dysplasia (BPD) (n=8) were compared to those of healthy children. Results: Height was the best independent determinant for reference equations of R5-20 (r=-0.417), R5-20% (r=-0.236), and AX (r=-0.678). R5-20 and R5-20% also showed variability with gender (p<0.05). Z-scores of R5-20, R5-20%, and AX appeared significantly higher in symptomatic than in healthy children (p<0.001), whereas respiratory resistance and reactance at 5 Hz (R5 and X5) differed from healthy only in children with history of BPD. Conclusions: R5-20, R5-20%, and AX are superior to conventional IOS parameters in distinguishing symptomatic children from the healthy ones. These parameters may prove valuable for screening early lung function deficits

Serum chitinase-like protein YKL-40 is linked to small airway function in children with asthmatic symptoms

Background Lung function impairment among asthmatic children begins in early life, and biomarkers for identifying this impairment are needed. The chitinase-like protein YKL-40 has been associated with asthma and lung function in adults, but studies in children have yielded conflicting results. We evaluated the potential of YKL-40 and other systemic biomarkers for identifying lung function deficits in children with asthmatic symptoms. Methods We determined the levels of serum YKL-40, periostin, and high-sensitivity C-reactive protein (hs-CRP) from the blood samples of 49 children with asthmatic symptoms. Lung function was assessed with impulse oscillometry (IOS) and spirometry, combined with an exercise challenge and a bronchodilator test. Fractional exhaled nitric oxide was measured at multiple flow rates. Results Serum levels of YKL-40 showed significant correlations with most IOS indices at baseline (P = .008-.039), but there was no association between YKL-40 and spirometry parameters. Neither periostin nor hs-CRP were associated with baseline lung function. Children with a significant response in either the exercise challenge or the bronchodilator test had increased serum levels of YKL-40 (P = .003) and periostin (P = .035). YKL-40 correlated significantly with the blood neutrophil count (r(s) = .397, P = .005) but was not associated with biomarkers of eosinophilic inflammation. Conclusion Serum YKL-40 is a potential biomarker for lung function deficits in children with asthmatic symptoms. These deficits appear to be focused on small airways and may remain undetected with spirometry.Peer reviewe

Pets, furry animal allergen components, and asthma in childhood

Abstract Background The use of component‐resolved allergy diagnostics has provided a clearer understanding of the species‐specific sensitization and severity of potential allergic reactions. This cross‐sectional study aimed to determine whether sensitization to allergen components in furry animals is indicative of blood eosinophilia, a positive fractional exhaled nitric oxide (FeNO) test, abnormal lung function, and asthma symptoms in children. Additionally, we investigated whether having pets during childhood affects the development of asthma or allergic sensitization to furry animals. Methods We recruited 203 children aged 4–17 years with asthma diagnosis based on abnormal lung function and 33 controls. IgE‐sensitization to allergen components for dogs, cats, and horses was analyzed using a multiplex microarray. Children were tested with FeNO, impulse oscillometry, spirometry, methacholine challenge, and skin prick test. A questionnaire was used to investigate pet ownership and symptom profile. Results FeNO results and blood eosinophilia revealed a correlation with sensitization to all furry animal allergens, particularly lipocalins (r = 0.203–0.560 and 0.206–0.560, respectively). Can f 3 was found to correlate with baseline R5 (r = 0.298). No association between methacholine challenge results and sensitization to furry animal allergens was found. Children with asthma who were sensitized to Can f 1, Can f 6, or both frequently reported asthma symptoms. Dog ownership was associated with a lower level of IgE‐sensitization to lipocalins, fewer asthma symptoms, and less blood eosinophilia. Conclusion Furry animal allergen component IgE‐sensitization is a risk factor for type 2‐inflammation and asthma symptoms

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

BACKGROUND: Prenatal vitamin D(3) 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 SNP rs12936231 of the child, which regulates the expression of ORMDL3, 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 D(3) supplementation against offspring asthma/recurrent wheeze. METHODS: We determined the rs12936231 genotype of mother-child pairs from two randomized-controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC(2010), 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 D(3) supplementation versus placebo. RESULTS: Offspring of mothers with low-risk GG-genotype or GC-genotype who received high-dose vitamin D(3) supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared to the placebo group (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.37–0.77; P<0.001 for VDAART and HR, 0.56; 95% CI, 0.35–0.92; P=0.021 for COPSAC(2010)), whereas no difference was observed among the offspring of mothers with 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 COPSAC(2010)). CONCLUSION: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D(3) supplementation against offspring asthma/recurrent wheeze

Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated. Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data. Methods: We used untargeted liquid chromatography–mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC(2010) (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort. Measurements and Main Results: Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05. Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme

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.Effort from PK, JALS and STW is supported by P01HL132825 from the National Heart, Lung and Blood Institute, National Institutes of Health (NIH/NHLBI), USA. IDS is funded by the Medical Research Council (MC_UU_00006/1 - Etiology and Mechanisms). Effort for RK, DIS, MC, KM, MS and JALS is supported by R01HL123915 from the NIH/NHLBI and W81XWH-17-1-0533 from the U.S.A Department of Defense. Effort for RSK is supported by K01HL146980 from the NIH/NHLBI. Effort for SHC is supported by K01HL153941 from the NIH/NHLBI. Effort for MH and JALS is supported by R01HL141826 from the NIH/NHLBI. Effort for AD is supported by K01HL130629 from the NIH/NHLBI. Effort for AD and JALS is supported by 1R01HL152244 from the NIH/NHLBI. Effort for MM and JALS is supported by R01HL155742 from the NIH/NHLBI. Effort for HK is supported by the Jane and Aatos Erkko Foundation, the Paulo Foundation, and the Pediatric Research Foundation. Effort for KLS is supported by K08HL148178 from the NIH/NHLBI. Effort for MM is supported by R01HL139634 from the NIH/NHLBI. Effort for AW is supported by K23HL151819 from the NIH/NHLBI and Thrasher Research Fund Award (15115). Effort for ACW is supported by 1R01HD085993 from the NICHD. Effort for YV is supported by K23AI130408 from the NIAID. Effort for JALS, STW, EWK is supported by the NIH U01HG008685. Effort for PZ and CEW was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant (JP19K21239), the Japanese Environment Research and Technology Development Fund (No. 5-1752), the Gunma University Initiative for Advanced Research (GIAR), the Japan-Sweden Research Cooperative Program between JSPS and STINT (grant no. JPJSBP-1201854), the Swedish Heart Lung Foundation (HLF 20180290, HLF 20200693), and the Swedish Research Council (2016-02798). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 MC-UU_12015/1 and MC_UU_00006/1) and Cancer Research UK (C864/A14136). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372