Hanna Maria Knihtila

All Publications

• Preschool Impulse Oscillometry Predicts Active Asthma and Impaired Lung Function at School Age. The Journal of allergy and clinical immunology Knihtilä, H. M., Stubbs, B. J., Carey, V. J., Laranjo, N., Zeiger, R. S., Bacharier, L. B., O'Connor, G. T., Weiss, S. T., Litonjua, A. A. 2024

  Abstract

  Asthmatic symptoms often start during early childhood. Impulse oscillometry (IOS) is feasible in preschool children who may be unable to reliably perform spirometry measurements.We evaluated the utility of IOS in a multicenter multiethnic high-risk asthma cohort entitled the Vitamin D Antenatal Asthma Reduction Trial (VDAART).The VDAART 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.In total 220 children were included in this secondary analysis. Recent respiratory symptoms and short-acting β2-agonist (SABA) use were associated with increased respiratory resistance at 5 Hz (R5) at age 4 years (β 2.6; 95% CI 1.0, 4.4; P=0.002 and β 3.4; 95% CI 0.7, 6.2; P=0.015, respectively). Increased R5 at age 4 years was also associated with decreased lung function from ages 5 to 8 years (β -0.3; 95% CI -0.5, -0.1; P<0.001 for FEV1 at 8 years) and active asthma at age 8 years (β 2.0; 95% CI 0.2, 3.8; P=0.029).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.

  View details for DOI 10.1016/j.jaci.2023.12.025

  View details for PubMedID 38244724

• Maternal vitamin D status modifies the effects of early life tobacco exposure on child lung function. The Journal of allergy and clinical immunology Knihtila, H. M., Huang, M., Prince, N., Stubbs, B. J., Carey, V. J., Laranjo, N., Mirzakhani, H., Zeiger, R. S., Bacharier, L. B., O'Connor, G. T., Litonjua, A. A., Weiss, S. T., Lasky-Su, J. 2022

  Abstract

  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.OBJECTIVE: We investigated the effects of early life TSE on child lung function and the modulatory effects of gestational vitamin D on this association.METHODS: The 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 (beta -0.043 L, P=0.018) and increased respiratory resistance (R5; beta 0.060 kPa/L/s, P=0.002). This association persisted in subjects with insufficient (<30 ng/ml) 25(OH)D levels throughout pregnancy (beta 0.077 kPa/L/s, P=0.016 for R5) but not among those with sufficient levels throughout pregnancy.CONCLUSION: 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.

  View details for DOI 10.1016/j.jaci.2022.10.030

  View details for PubMedID 36400177

• Author Correction: Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nature medicine Kachroo, P., Stewart, I. D., Kelly, R. S., Stav, M., Mendez, K., Dahlin, A., Soeteman, D. I., Chu, S. H., Huang, M., Cote, M., Knihtilä, H. M., Lee-Sarwar, K., McGeachie, M., Wang, A., Wu, A. C., Virkud, Y., Zhang, P., Wareham, N. J., Karlson, E. W., Wheelock, C. E., Clish, C., Weiss, S. T., Langenberg, C., Lasky-Su, J. A. 2022

  View details for DOI 10.1038/s41591-022-01949-2

  View details for PubMedID 35859205

• Low gestational vitamin D level and childhood asthma are related to impaired lung function in high-risk children. The Journal of allergy and clinical immunology Knihtilä, H. M., Stubbs, B. J., Carey, V. J., Laranjo, N., Chu, S. H., Kelly, R. S., Zeiger, R. S., Bacharier, L. B., O'Connor, G. T., Lasky-Su, J., Weiss, S. T., Litonjua, A. A. 2021; 148 (1): 110-119.e9

  Abstract

  Lung function impairment in early life often persists into adulthood. Therefore, identifying risk factors for low childhood lung function is crucial.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).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.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 (β, -0.021 kPa/L/s; 95% CI, -0.035 to -0.007; P = .003) and positively associated with FEV1 (β, 0.018 L; 95% CI, 0.005-0.031; P = .008) and forced vital capacity (β, 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 (β, 0.065 kPa/L/s; 95% CI, 0.028 to 0.102; P < .001 for R5 and β, -0.063 L; 95% CI, -0.099 to -0.028; P < .001 for FEV1).Low gestational 25(OH)D level and childhood asthma are important risk factors for decreased lung function in early childhood.

  View details for DOI 10.1016/j.jaci.2020.12.647

  View details for PubMedID 33485958

  View details for PubMedCentralID PMC8315297

• Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze. The European respiratory journal Knihtilä, H. M., Kelly, R. S., Brustad, N., Huang, M., Kachroo, P., Chawes, B. L., Stokholm, J., Bønnelykke, K., Pedersen, C. T., Bisgaard, H., Litonjua, A. A., Lasky-Su, J. A., Weiss, S. T. 2021; 58 (3)

  Abstract

  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.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.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).Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

  View details for DOI 10.1183/13993003.02012-2020

  View details for PubMedID 33653805

  View details for PubMedCentralID PMC8410880

• Pets, furry animal allergen components, and asthma in childhood CLINICAL AND TRANSLATIONAL ALLERGY Lajunen, K., Maatta, A. M., Malmstrom, K., Kalliola, S., Knihtila, H., Savinko, T., Malmberg, L., Pelkonen, A. S., Makela, M. J. 2024; 14 (2)

  View details for DOI 10.1002/clt2.12337

  View details for Web of Science ID 001157405300001

• Cord blood DNA methylation signatures associated with preeclampsia are enriched for cardiovascular pathways: insights from the VDAART trial. EBioMedicine Knihtilä, H. M., Kachroo, P., Shadid, I., Raissadati, A., Peng, C., McElrath, T. F., Litonjua, A. A., Demeo, D. L., Loscalzo, J., Weiss, S. T., Mirzakhani, H. 2023; 98: 104890

  Abstract

  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.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.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.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.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.

  View details for DOI 10.1016/j.ebiom.2023.104890

  View details for PubMedID 37995466

• The association of prenatal C-reactive protein and interleukin-8 levels with maternal characteristics and preterm birth. American journal of perinatology Chen, Y. S., Mirzakhani, H., Knihtila, H., Fichorova, R., Luu, N., Laranjo, N., Kelly, R., Weiss, S. T., Litonjua, A. A., Lee-Sarwar, K. 2022

  Abstract

  BACKGROUND: The determinants of preterm birth remain unknown. Excessive maternal inflammation during pregnancy may play an important role in the pathogenesis of preterm birth.OBJECTIVE: To describe the association of prenatal levels of pro-inflammatory C-reactive protein (CRP) and interleukin-8 (IL-8) with preterm birth in participants of the Vitamin D Antenatal Asthma Reduction Trial (VDAART).STUDY DESIGN: 528 subjects with both first and third trimester plasma available samples were included in this analysis. C-reactive protein and interleukin-8 were measured from maternal prenatal samples. We examined the association between prenatal CRP and IL-8 with maternal health characteristics and the outcome of preterm birth. We also described the patterns of change in CRP and IL-8 from first to third trimester and their association with preterm birth. A sub-group analysis comparing only those with a spontaneous preterm birth phenotype to those with term birth was also performed.RESULTS: Maternal characteristics including lower educational attainment, higher pre-pregnancy body mass index, gestational diabetes, lower vitamin D, and an unhealthy diet were associated with elevated levels of prenatal CRP and IL-8. Higher third trimester CRP and an increase in CRP from first to third trimester were associated with an increased odds of preterm birth when compared to lower levels of CRP (adjusted odds ratio (aOR) 1.49, 95% confidence interval 1.02, 2.23, P=0.04) or a decrease in CRP over pregnancy (aOR 3.06, 95% confidence interval 1.31,7.55, P=0.01), after adjusting for potential confounders. These associations were strengthened when comparing only subjects with spontaneous preterm birth (n=22) to those with term births.CONCLUSION: Higher levels of the pro-inflammatory markers CRP and IL-8 are associated with indicators of poor maternal health and preterm birth. Prenatal CRP levels may reflect maternal prenatal health status and serve as a predictor of preterm birth, especially among those with spontaneous preterm birth.

  View details for DOI 10.1055/a-1961-2425

  View details for PubMedID 36241210

• The association of prenatal C-reactive protein levels with childhood asthma and atopy. The journal of allergy and clinical immunology. In practice Chen, Y. S., Lee-Sarwar, K. A., Mirzakhani, H., O'Connor, G. T., Bacharier, L. B., Zeiger, R. S., Knihtila, H. M., Jha, A., Kelly, R. S., Laranjo, N., Fichorova, R. N., Luu, N., Weiss, S. T., Litonjua, A. A. 2022

  Abstract

  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: 522 maternal-offspring pairs from the Vitamin D Antenatal Asthma Reduction Trial (VDAART) were included. Prenatal plasma CRP was measured between 10-18 weeks gestation and between 32-38 weeks 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=0.02; late: aOR 2.45, 95% CI 1.47, 4.18, p<0.001; CRP increase aOR 2.06, 95% CI 1.26, 3.39, p<0.004). Prenatal CRP and childhood asthma associations were strengthened among offspring with atopic asthma (early: aOR 3.78, 95% CI 1.49, 10.64, p=0.008; late: aOR 4.84, 95% CI 1.68, 15.50, p=0.005, CRP increase aOR 3.01, 95% CI 1.06, 9.16, p=0.04). Early and late prenatal CRP mediated 96% and 86% of the association between maternal pre-pregnancy body mass index and offspring asthma, respectively.CONCLUSION: 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.

  View details for DOI 10.1016/j.jaip.2022.08.044

  View details for PubMedID 36108928

• Characteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype. American journal of respiratory and critical care medicine Rago, D., Pedersen, C. T., Huang, M., Kelly, R. S., Gürdeniz, G., Brustad, N., Knihtilä, H., Lee-Sarwar, K. A., Morin, A., Rasmussen, M. A., Stokholm, J., Bønnelykke, K., Litonjua, A. A., Wheelock, C. E., Weiss, S. T., Lasky-Su, J., Bisgaard, H., Chawes, B. L. 2021; 203 (7): 853-863

  Abstract

  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 COPSAC2010 (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.

  View details for DOI 10.1164/rccm.202008-3206OC

  View details for PubMedID 33535020

  View details for PubMedCentralID PMC8017574

• Metabolomic differences in lung function metrics: evidence from two cohorts. Thorax Kelly, R. S., Stewart, I. D., Bayne, H., Kachroo, P., Spiro Iii, A., Vokonas, P., Sparrow, D., Weiss, S. T., Knihtilä, H. M., Litonjua, A. A., Wareham, N. J., Langenberg, C., Lasky-Su, J. A. 2021

  Abstract

  The biochemical mechanisms underlying lung function are incompletely understood.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).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.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.The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.

  View details for DOI 10.1136/thoraxjnl-2020-216639

  View details for PubMedID 34650005

• Long-term Social Outcomes After Congenital Heart Surgery. Pediatrics Raissadati, A., Knihtilä, H., Pätilä, T., Nieminen, H., Jokinen, E. 2020; 146 (1)

  Abstract

  Patients are surviving decades after congenital heart surgery (CHS), raising the importance of postoperative quality of life as an outcome measure. We determined the long-term social outcomes after CHS performed during childhood.Between 1953 and 2009, 10 635 patients underwent surgery for congenital heart defects at <15 years of age in Finland. We obtained 4 control subjects per patient, matched by age, sex, birth time, and hospital district, from Statistics Finland, which also provided data on the highest education level, employment status, marital status, and progeny for both patients and control subjects. We included patients who were alive and ≥18 years of age at the end of the follow-up on December 31, 2017.A total of 7308 patients met inclusion criteria. Patients had on average similar high school or vocational education rates as the general population but lower undergraduate or higher education rates (female patients: risk ratio [RR] 0.8 [95% confidence interval (CI) 0.8-0.9]; male patients: RR 0.8 [95% CI 0.7-0.9]). Patients were less likely to be married or have progeny compared with the general population. The rate of employment was significantly lower (female patients: RR 0.8 [95% CI 0.8-0.9]; male patients: RR 0.8 [95% CI 0.8-0.9]) and the rate of retirement (female patients: RR 2.1 [95% CI 2.0-2.3]; male patients RR 3.1 [95% CI 2.9-3.5]) significantly higher among patients.Patients who undergo CHS at childhood age are, on average, more disadvantaged from both an educational and professional standpoint compared with the general population, regardless of the severity of the defect.

  View details for DOI 10.1542/peds.2019-3745

  View details for PubMedID 32503936

• Serum chitinase-like protein YKL-40 is linked to small airway function in children with asthmatic symptoms. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology Knihtilä, H., Kotaniemi-Syrjänen, A., Pelkonen, A. S., Savinko, T., Malmberg, L. P., Mäkelä, M. J. 2019; 30 (8): 803-809

  Abstract

  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.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.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 (rs  = .397, P = .005) but was not associated with biomarkers of eosinophilic inflammation.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.

  View details for DOI 10.1111/pai.13119

  View details for PubMedID 31487401

• The effect of sildenafil on pleural and peritoneal effusions after the TCPC operation. Acta anaesthesiologica Scandinavica Koski, T. K., Suominen, P. K., Raissadati, A., Knihtilä, H. M., Ojala, T. H., Salminen, J. T. 2019; 63 (10): 1384-1389

  Abstract

  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.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.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.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.

  View details for DOI 10.1111/aas.13431

  View details for PubMedID 31271655

• Small airway function in children with mild to moderate asthmatic symptoms. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Knihtilä, H., Kotaniemi-Syrjänen, A., Pelkonen, A. S., Mäkelä, M. J., Malmberg, L. P. 2018; 121 (4): 451-457

  Abstract

  Clinical significance of small airway obstruction in mild pediatric asthma is unclear.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).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 (Calv). Asthma control was evaluated with the Childhood Asthma Control Test (C-ACT), short-acting β2-agonist (SABA) use within the past month, and asthma exacerbations within the past year.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.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.

  View details for DOI 10.1016/j.anai.2018.07.026

  View details for PubMedID 30059790

• Assessment of Small Airway Function – Application of Impulse Oscillometry in Young Children with Asthmatic Symptoms Knihtilä, H. University of Helsinki, Faculty of Medicine. Helsinki. 2018 ; Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis (URN:ISSN:2342-317X): 1-93
• Small airway oscillometry indices: Repeatability and bronchodilator responsiveness in young children. Pediatric pulmonology Knihtilä, H., Kotaniemi-Syrjänen, A., Pelkonen, A. S., Kalliola, S., Mäkelä, M. J., Malmberg, L. P. 2017; 52 (10): 1260-1267

  Abstract

  The impulse oscillometry (IOS) indices absolute and relative difference between respiratory resistance at 5 and 20 Hz (R5-20 and R5-20%, respectively) and the area under the reactance curve (AX) are postulated to reflect small airway function. Data on their cutoff values to evaluate bronchodilator responsiveness (BDR) or between-visit changes after interventions are limited in young children.We evaluated the BDR of 103 healthy children aged 2-7 years, who received either salbutamol (n = 84) or placebo (n = 19) in order to determine cutoff values for BDR of R5-20, R5-20%, and AX. We then determined the repeatability within and between two IOS measurements 7-14 days apart in young children aged 4-8 years with asthmatic symptoms (n = 43), including cutoff values for significant between-visit changes.The investigated IOS parameters showed marked BDR (fifth percentile cutoff of 75-110% of the baseline value) in healthy children, whereas no significant changes were seen after inhalation of placebo. The agreement within the triplicate IOS measurement was excellent (ICC > 0.80), and the agreement of results between visits was good (ICC > 0.60). A change in R5-20, R5-20%, and AX of 0.65, 1.08, and 0.84 z-scores, respectively, would exceed 95% confidence intervals for between-visit variability.We introduce cutoff values for BDR of R5-20, R5-20%, and AX, and their repeatability indices and cutoff limits for significant between-visit changes. These IOS parameters may show greater variability than the conventional IOS indices during follow-up, but the between-visit agreement remains good, providing potentially useful endpoints for monitoring lung function in young children.

  View details for DOI 10.1002/ppul.23794

  View details for PubMedID 28834381

• Sensitivity of newly defined impulse oscillometry indices in preschool children. Pediatric pulmonology Knihtilä, H., Kotaniemi-Syrjänen, A., Pelkonen, A. S., Kalliola, S., Mäkelä, M. J., Malmberg, L. P. 2017; 52 (5): 598-605

  Abstract

  Early origins of chronic obstructive pulmonary disease have been recognized. Impulse oscillometry (IOS) is suitable for assessment of lung function also in preschool children, and some novel indices have been connected to assessment of small airway function. However, limited data exist on the sensitivity of these new indices to detect lung function deficits in young symptomatic children.IOS measurements of 103 healthy 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 children with late-onset troublesome lung symptoms (n = 20), a history of early wheeze (n = 37), or a history of bronchopulmonary dysplasia (BPD, n = 8) were compared to healthy children.None of the patient groups differed from healthy regarding respiratory resistance at 5 Hz (R5), and only children with a history of BPD differed from healthy regarding respiratory reactance at 5 Hz (X5). In contrast, z-scores of R5-20, R5-20%, and AX were significantly higher in all patient groups than in healthy children (P < 0.001), showing improved sensitivity (20-55%) compared to R5 and X5 (5-6%).R5-20, R5-20%, and AX are superior to conventional IOS parameters in distinguishing children with current or past lower respiratory tract symptoms from healthy, and may prove valuable for screening early lung function deficits. Pediatr Pulmonol. 2017;52:598-605. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ppul.23627

  View details for PubMedID 27736034

• Preschool oscillometry and lung function at adolescence in asthmatic children. Pediatric pulmonology Knihtilä, H., Kotaniemi-Syrjänen, A., Mäkelä, M. J., Bondestam, J., Pelkonen, A. S., Malmberg, L. P. 2015; 50 (12): 1205-13

  Abstract

  Reduced lung function in early childhood is associated with persistent symptoms and low lung function later in life. Impulse oscillometry (IOS) is feasible for assessing lung function also in preschool children, and some of the parameters, such as respiratory resistance at 5 Hz (Rrs5) and the frequency dependence of resistance (dRrs/df), have been suggested to reflect small airway dysfunction. Whether changes in preschool IOS predict later lung function remains unknown.The medical data of 154 asthmatic children with IOS performed at 2-7 years and spirometry at 12-18 years were analyzed. IOS and post-bronchodilator spirometry parameters were compared, and the association was estimated in a multivariate model.Measured at preschool age, particularly Rrs5 and dRrs/df were significantly correlated with post-bronchodilator forced expiratory volume in 1 sec (FEV1) at adolescence (Rrs5: r = -0.223, P = 0.005; dRrs/df: r = 0.234, P = 0.004). Although the number of children with decreased FEV1 was low, associations of increased Rrs5 (odds ratio (OR) 5.9, 95% confidence interval (CI) 1.7; 20.9) and decreased dRrs/df (OR 8.2, 95% CI 1.7; 39.6) with decreased FEV1 remained significant in multivariate analyses. Similar findings were observed also with other spirometric parameters.In asthmatic children, preschool IOS is associated with spirometric lung function at adolescence, but the scatter is wide. Normal preschool IOS seems to indicate favourable lung function outcome, whereas in some individuals IOS could potentially be of clinical use, at a younger age than spirometry, to screen lung function deficits and increased risk for later lung function impairment.

  View details for DOI 10.1002/ppul.23188

  View details for PubMedID 25823464