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Background: Several techniques can be used to assess bronchodilator response (BDR) in preschool-aged children, including spirometry, respiratory oscillometry, the interrupter technique, and specific airway resistance. However, there has not been a systematic comparison of BDR thresholds across studies yet., Methods: A systematic review was performed on all studies up to May 2023 measuring a bronchodilator effect in children 2-6 years old using one of these techniques (PROSPERO CRD42021264659). Studies were identified using MEDLINE, Cochrane, EMBASE, CINAHL via EBSCO, Web of Science databases, and reference lists of relevant manuscripts., Results: Of 1224 screened studies, 43 were included. Over 85% were from predominantly European ancestry populations, and only 22 studies (51.2%) calculated a BDR cutoff based on a healthy control group. Five studies included triplicate testing with a placebo to account for the within-subject intrasession repeatability. A relative BDR was most consistently reported by the included studies (95%) but varied widely across all techniques. Various statistical methods were used to define a BDR, with six studies using receiver operating characteristic analyses to measure the discriminative power to distinguish healthy from wheezy and asthmatic children., Conclusion: A BDR in 2- to 6-year-olds cannot be universally defined based on the reviewed literature due to inconsistent methodology and cutoff calculations. Further studies incorporating robust methods using either distribution-based or clinical anchor-based approaches to define BDR are required., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Rhinovirus (RV) positive bronchiolitis episodes in infancy confer a higher risk to develop asthma in later childhood with associated lung function impairments. We aimed to investigate the association between the type of virus causing a bronchiolitis hospitalization episode and lung ventilation inhomogeneities at preschool age., Methods: Infants hospitalized with a clinical diagnosis of moderate (ward admission) or severe (pediatric intensive care ward admission) bronchiolitis were prospectively followed-up at preschool age to assess nitrogen (N 2 ) multiple breath washout (MBW). Lung clearance index (LCI), functional residual capacity (FRC), and concentration normalized phase III slope analysis (Sn III ) indices were reported from ≥2 technically acceptable trials. Differences between groups were calculated using logistic and linear regression and adjusted for confounders (sex, age at bronchiolitis admission, height at visit, maternal asthma, and doctor-diagnosed asthma, including interaction terms between the latter three). An interaction term was included in a regression model to test for an interaction between RV bronchiolitis severity and MBW parameters at preschool age., Results: One hundred and thirty-nine subjects attended preschool follow-up, of which 84 out of 103 (82%) performing MBW had technically acceptable data. Children with a history of RV positive bronchiolitis (n = 39) had increased LCI (adjusted β-coefficient [aβ] = 0.33, 95% confidence interval [CI] 0.02-0.65, p = 0.040) and conductive airways ventilation inhomogeneity [S cond ] (aβ = 0.016, CI 0.004-0.028, p = 0.011) when compared with those with a RV negative bronchiolitis history (n = 45). In addition, we found a statistical interaction between RV bronchiolitis and bronchiolitis severity strengthening the association with LCI (aβ = 0.93, CI 0.20-1.58, p = 0.006)., Conclusion: Children with a history of hospital admission for RV positive bronchiolitis in infancy might be at a higher risk of lung ventilation inhomogeneities at preschool age, arising from the peripheral conducting airways., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Fetal exposure to tobacco smoking throughout pregnancy is associated with wheezing in infancy. We investigated the influence of in utero smoking exposure on lung ventilation homogeneity and the relationship between lung ventilation inhomogeneity at 7 weeks of age and wheezing in the first year of life., Methods: Maternal smoking was defined as self-reported smoking of tobacco or validated by exhaled (e)CO > 6 ppm. Lung function data from healthy infants (age 5-9 weeks) born to asthmatic mothers and parent-reported respiratory questionnaire data aged 12 months were collected in the Breathing for Life Trial (BLT) birth cohort. Tidal breathing analysis and SF 6 -based Multiple Breath Washout testing were performed in quiet sleep. Descriptive statistics and regression analysis were used to assess associations., Results: Data were collected on 423 participants. Infants born to women who self-reported smoking during pregnancy (n = 42) had higher lung clearance index (LCI) than those born to nonsmoking mothers (7.90 vs. 7.64; p = .030). Adjusted regression analyzes revealed interactions between self-reported smoking and LCI (RR: 1.98, 95% CI: 1.07-3.63, 0.028, for each unit increase in LCI) and between eCO > 6 ppm and LCI (RR: 2.25, 95% CI: 1.13-4.50, 0.022) for the risk of wheeze in the first year of life., Conclusion: In utero tobacco smoke exposure induces lung ventilation inhomogeneities. Furthermore, an interaction between smoke exposure and lung ventilation inhomogeneities increases the risk of having a wheeze in the first year of life., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Multiple breath washout (MBW) is used for early detection of cystic fibrosis (CF) lung disease, with SF 6 MBW commonly viewed as the reference method. The use of N 2 MBW in infants and toddlers has been questioned for technical and physiological reasons, but a new correction of the N 2  signal has minimized the technical part. The present study aimed to assess the remaining differences and the contributing mechanisms for the differences between SF 6 and N 2 MBW,corrected-such as tidal volume reduction during N 2 washout with pure O 2 ., Method: This was a longitudinal multicenter cohort study. SF 6 MBW and N 2 MBW were performed prospectively at three CF centers in the same visits on 154 test occasions across 62 children with CF (mean age: 22.7 months). Offline analysis using identical algorithms to the commercially available program provided outcomes of N 2,original and N 2,corrected for comparison with SF 6 MBW., Results: Mean functional residual capacity, FRC N2,corrected was 14.3% lower than FRC N2, original , and 1.0% different from FRC SF6 . Lung clearance index, LCI N2,corrected was 25.2% lower than LCI N2,original , and 7.3% higher than LCI SF6 . Mean (SD) tidal volume decreased significantly during N 2 MBW corrected , compared to SF 6 MBW (-13.1 ml [-30.7; 4.6], p < 0.0001, equal to -12.0% [-25.7; 1.73]), but this tidal volume reduction did not correlate to the differences between LCI N2,corrected and LCI SF6 . The absolute differences in LCI increased significantly with higher LCI SF6 (0.63/LCI SF6 ) and (0.23/LCI SF6 ), respectively, for N 2,original and N 2,corrected , but the relative differences were stable across disease severity for N 2,corrected , but not for N 2,original ., Conclusion: Only minor residual differences between FRC N2,corrected and FRC SF6 remained to show that the two methods measure gas volumes very similar in this age range. Small differences in LCI were found. Tidal volume reduction during N 2 MBW did not affect differences. The corrected N 2 MBW can now be used with confidence in young children with CF, although not interchangeably with SF 6 ., (© 2022 Wiley Periodicals LLC.)

Objectives: Telehealth and home spirometry feasibility for children has been established, but their impact on cystic fibrosis (CF) disease progression remains unassessed. We aimed to evaluate the effects of telehealth and home spirometry on CF disease progression and care., Methods: Children with CF aged 5-17 years from all Swedish CF centers were provided with home spirometers. A minimum of two in-person visits were replaced with telemedicine visits and participants were instructed to conduct home spirometry before visits. Linear mixed-effects models were used to compare annual CF disease trajectories during the intervention period and prepandemic period (1 January 2019 to 28 February 2020). Participants and caregivers completed study questionnaires., Results: A total of 59 individuals completed the study over a mean (SD) period of 6.8 (1.4) months, made 3.1 (1.0) physical visits and 2.2 (0.6) telehealth visits per patient year during the study period. The mean difference (95% CI) between the intervention and prepandemic period progression rate for FEV 1 %, lung clearance index and BMI were -0.4 (-1.3 to 0.5, p = 0.39), 0.11 (-0.07 to 0.28, p = 0.25) and -0.02 (-0.13 to 0.08, p = 0.70), respectively. There were no major shifts in the incidence of airway pathogens, sputum cultures, or antibiotics use between the periods (p > 0.05). The intervention did not increase stress. Almost all participants and caregivers expressed a desire to continue with home spirometry and telemedicine., Conclusion: Combining telehealth and physical visits with access to home spirometry demonstrated comparable effectiveness as exclusively in-person care with enhanced flexibility and personalization of CF care., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Rationale: Lung T1 MRI is a potential method to assess cystic fibrosis (CF) lung disease that is safe, quick, and widely available, but there are no data in children with mild CF lung disease., Objective: Assess the ability of lung T1 MRI to detect abnormalities in children with mild CF lung disease., Methods: We performed T1 MRI, multiple breath washout (MBW), chest computed tomography (CT), and spirometry in a cohort of 45 children with mild CF lung disease (6-11 years of age)., Main Results: Despite mean normal ppFEV1 values, the majority of children with CF in this study exhibited mild lung disease evident in lung clearance index (LCI) measured by MBW, chest CT Brody scores, and percent normal lung perfusion (%NLP) measured by T1 MRI. The %NLP correlated with chest CT Brody scores, as did LCI, but %NLP and LCI did not correlate with each other. Analysis of the Brody subscores showed that %NLP and LCI largely correlated with different Brody subscores., Conclusions: T1 MRI can detect mild CF lung disease in children and correlates with chest CT findings. The %NLP from T1 MRI and LCI correlate with different chest CT Brody subscores, suggesting they provide complementary information about CF lung disease., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated., Aim: To evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL)., Methods: Childhood ALL survivors, aged 7 to 18 years, greater than 6 months posttreatment were recruited. Exclusion criteria included HSCT or proven bacterial/fungal respiratory infection during treatment. Subjects were classified into "viral" or "control" groups according to retrospective medical records that documented the presence of laboratory-proven RVIs during chemotherapy. Symptom questionnaires (Liverpool, ISAAC) and lung function testing (spirometry, plethysmography, diffusing capacity, forced oscillation technique to ATS/ERS standards) were then performed cross-sectionally at the time of recruitment., Results: Fifty-four patients (31 viral, 23 control) were recruited: median (range) age 11.2 (7.2-18.1) years, and at 4.9 (0.5-13) years posttherapy. Abnormalities were detected in 17 (31%) individuals (8 viral, 9 control), with the most common being DLCO impairment (3 viral, 4 control) and reduced respiratory reactance at 5 Hz (5 viral, 6 control). Children with RVIs during chemotherapy reported more current respiratory symptoms, particularly wheeze (odds ratio [OR], 3.0; 95% confidence interval [CI]: 0.9-10.0; P = .09) and cough (OR, 2.7; 95% CI: 0.8-9.5; P = .11). No differences in lung function tests were observed between the two groups., Conclusions: Our study found children with RVIs during chemotherapy developed more long-term respiratory symptoms than controls; however, differences did not reach statistical significance. No differences in static lung function were found between the two groups. Overall, pulmonary abnormalities and/or significant ongoing respiratory symptoms were detected in nearly a third of ALL survivors treated without HSCT. Larger, prospective studies are warranted to evaluate the etiology and clinical significance of these findings., (© 2019 Wiley Periodicals, Inc.)

The multiple breath washout (MBW) test is widely reported in the context of Lung Clearance Index (LCI). LCI reflects global ventilation inhomogeneity but does not provide information regarding the localization of disease along the respiratory tree. The MBW-derived normalized phase III slope (S nIII ) indices (S cond and S acin ), instead, can distinguish between convective-dependent and diffusion-convection-dependent ventilation inhomogeneity considered to occur within the conductive and acinar airways, respectively. In cystic fibrosis, S cond tends to become abnormal even earlier than LCI and spirometry. The value of S cond and S acin in clinical practice has been recently explored in other respiratory conditions, including asthma, primary ciliary dyskinesia, bronchopulmonary dysplasia, bronchiolitis obliterans, and sickle cell disease. In this narrative review we offer an overview on the theoretical background, potentialities, and limitations of S nIII analysis in children, including challenges and feasibility aspects. Moreover, we summarize current evidence on the use of S nIII -derived indices across different groups of pediatric chronic respiratory disease and we highlight the gaps in knowledge that need to be addressed in future studies., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: Major methodological issues with the existing algorithm (WBreath) used for the analysis of speed-of-sound-based infant sulfur hexafluoride (SF 6 ) multiple-breath washout (MBW) measurements lead to implausible results and complicate the comparison between different age groups and centers., Methods: We developed OASIS-a novel algorithm to analyze speed-of-sound-based infant SF 6 MBW measurements. This algorithm uses known context of the measurements to replace the dependence of WBreath on model input parameters. We validated the functional residual capacity (FRC) measurement accuracy of this new algorithm in vitro, and investigated its use in existing infant MBW data sets from different infant cohorts from Switzerland and South Africa., Results: In vitro, OASIS managed to outperform WBreath at FRC measurement accuracy, lowering mean (SD) absolute error from 5.1 (3.2) % to 2.1 (1.6) % across volumes relevant for the infant age range, in variable temperature, respiratory rate, tidal volume and ventilation inhomogeneity conditions. We showed that changes in the input parameters to WBreath had a major impact on MBW results, a methodological drawback which does not exist in the new algorithm. OASIS produced more plausible results than WBreath in longitudinal tracking of lung clearance index (LCI), provided improved measurement stability in LCI over time, and improved comparability between centers., Discussion: This new algorithm represents a meaningful advance in obtaining results from a legacy system of lung function measurement by allowing a single method to analyze measurements from different age groups and centers., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N 2 MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (S acin *VT)., Methods: For this randomized, sham-controlled crossover trial, two N 2 MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH 2 0) or a sham (<5 cmH 2 0) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N 2 MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models., Results: The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted S acin *VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L -1 . There was no statistically significant difference in S cond *VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L -1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively., Conclusion: Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on S acin *VT with pressure range 10-15 cmH 2 0. Measurement with the N 2 MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Purpose: The purpose of this study was to compare (i) the exercise capacity and (ii) lung function prior to and immediately post cardiopulmonary exercise tests (CPET) of children who underwent early life lung resection for Congenital Pulmonary Airway Malformations (CPAM) to healthy control children., Method: Eight children with CPAM (four males, age 9.6 ± 1.8 years) and eight control children without respiratory disease (three males, age 9.4 ± 1.4 years) performed a CPET on a cycle ergometer, during which maximal oxygen consumption (V̇O 2max ) and heart rate were measured. Prior to and immediately post CPET, lung function measures including Nitrogen Multiple Breath Washout (MBW) and spirometry were performed., Results: There were no significant between group differences in pre CPET lung function (P > 0.05) or maximal exercise capacity (V̇O 2max CPAM: 39.4 mL . kg -1. min -1 , Control: 40.5 mL . kg -1. min -1 ). Post CPET, FEV 1 was significantly lower in the CPAM group, with two participants diagnosed subsequently with exercise induced bronchospasm based on post-CPET spirometry and follow-up clinical investigations., Conclusion: Early life lung resection for CPAM does not appear to have negative implications for exercise capacity later in childhood. Clinicians should be aware that dyspnoea following exercise may be due to asthma rather than residual effects of CPAM in these children., (© 2017 Wiley Periodicals, Inc.)

Introduction: Various functional residual capacity (FRC) repeatability criteria have been proposed for lung clearance index (LCI) measurement by multiple breath washout (MBW). Adult guidelines recommend three technically acceptable tests with FRC values within 10%, whilst preschool guidelines recommend two such tests. Feasibility of and need for recommendations in children is unclear., Methods: Retrospective analysis of MBW data was undertaken in healthy control (n = 90) and cystic fibrosis (CF) subjects (n = 108) encompassing infancy, pre-school and school age ranges. Feasibility of FRC repeatability recommendations was investigated in those with three technically acceptable tests. Validity of mean LCI from the first two tests alone (vs. all three) was investigated by comparing mean data and sensitivity to detect abnormal peripheral airway function in CF., Results: LCI coefficient of variation (CoV) was related to FRC CoV (P < 0.001) and disease category (P = 0.002). Application of adult repeatability criteria decreased LCI CoV (4.7 vs. 8.5%, P < 0.001), but had poor feasibility beyond infancy (62/150, 41%). Preschool recommendations increased feasibility but only to 70% overall. There was no difference in mean LCI (All three minus 1st two tests) in healthy controls [mean (95% CI) difference: 0.02 (-0.01, 0.06; P = 0.15)], this difference being statistically but not clinically significant in CF subjects [0.07 (0.00,0.13; P = 0.04)]. Sensitivity in CF subjects was unaffected., Conclusion: Adult FRC repeatability recommendations improved LCI repeatability in pediatric subjects, but poor feasibility limited utility. In an experienced pediatric MBW center, recent preschool recommendations can be extended to two technically acceptable tests, irrespective of FRC repeatability, without significantly affecting mean LCI or compromising sensitivity., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The use of alternative more sensitive measures has become a focus of research in CF. The utility of indexes of ventilation, Lung Clearance Index (LCI) and peak aerobic capacity (peak VO(2)), were studied as assessment tools in gauging response to intravenous (IV) therapy in acute pulmonary exacerbation, in comparison to the more commonly used index of forced expiratory volume in 1 sec (FEV(1)). The utility of a previously published clinical score was further explored., Methods: Patients aged 8-18 years admitted for IV antibiotic treatment of a pulmonary exacerbation were recruited. Spirometry, plethysmography, multiple breath nitrogen washout, exercise testing, and Cystic Fibrosis Clinical Score (CFCS) were performed on admission and prior to discharge., Results: Twenty-eight patients were recruited, with a mean (range) age of 13.7 (8; 17) years, 16 female and 12 male. Mean (range) admission FEV(1) was 61.4 (28; 92)% predicted, or z-score -3.09 (-6.15; -0.52), FVC 83.0 (38; 120)% predicted, or z-score -1.71 (-5.66; -1.17), and Shwachman-Kulczycki 68.9 (50; 90). FEV(1) increased by 7.0% (P < 0.01) from admission to discharge. Mean (range) admission LCI, 10.10 (6.87; 14.83), decreased by 3.8% (P = 0.03). Mean (range) admission peak VO(2) (ml/kg/min), 31.2 (23.4; 45.4), increased on discharge by 6.6% (P < 0.01). Proposed clinical thresholds, based on the available variability data, highlighted the heterogeneity of response in lung function tests. Mean (range) admission CFCS, 26.5 (19; 39), decreased to 19.9 (13; 31) on discharge, a 25.2% improvement (P < 0.01). CFCS demonstrated improvement in 27 of 28 patients. Changes in peak VO(2) (r = -0.50, P = 0.02) and LCI (r = 0.48, P = 0.01) correlated with CFCS change., Conclusions: In children with mild-to-moderate CF, whilst statistically significant improvement in both LCI and peak VO(2) were seen, heterogeneity of response was evident. The most consistent improvement was seen in CFCS. Correlation of LCI and peak VO(2) with change in clinical score (CFCS) was seen. The full clinical significance of these changes in LCI and peak VO(2) needs to be evaluated further with additional variability data. The CFCS may be useful in the assessment of response to treatment in CF but requires formal validation.

Multiple breath inert gas washout (MBW) is now regarded as "an insightful, sound, and useful tool to explore the lung and its response to injury in all of its compartments". We describe the important finding of pronounced intra-acinar airways response to indirect challenge testing, detected using MBW but missed by spirometry, in an adolescent with evidence of airway inflammation, and a background of severe respiratory syncytial virus (RSV) infection as an infant. These tests were performed as part of an 18-year follow up of a cohort with severe RSV infection (requiring hospitalization) in the first year of life, and has previously reported significantly higher rates of symptoms of allergic asthma and other features of atopic disease at 13 years in comparison to age matched controls. Small airway dysfunction and ventilation inhomogeneity have emerged as important features of early respiratory disease processes, and this case report provides further evidence supporting its important role in reactive airways disease.

Pulmonary physiology is a core element of pediatric pulmonology care and research. This article reviews some of the notable publications in physiology that were published in Pediatric Pulmonology in 2021 and 2022., (© 2023 Wiley Periodicals LLC.)

Introduction: No data are available on the values and role of lung clearance index (LCI) in cystic fibrosis (CF) Screen Positive Inconclusive Diagnosis (CFSPID) progressed to CF diagnosis (CFSPID > CF). This study aimed to assess the value of the LCI in correctly predicting the progression of CFSPID to CF., Methods: This is a prospective study carried out at the CF Regional Center of Florence, Italy from September 1, 2019. We compared LCI values in children with CF diagnosed for positive newborn screening (NBS), CFSPID or CFSPID > CF for pathological sweat chloride (SC). The Exhalyzer-D (EcoMedics AG, Duernten, Switzerland, software version 3.3.1) was used to conduct the LCI tests, every 6 months on stable children., Results: Forty-two cooperating children were enrolled (mean age at LCI tests: 5.4 years, range: 2.7-8.7): 26 (62%) had CF, 8 (19%) were CFSPID > CF for positive SC, while 8 (19%) kept the CFSPID label at last LCI test. The mean LCI value for patients with CF (7.39; 5.98-10.24) was statistically higher compared to both the mean LCI in the CFSPID > CF (6.62; 5.69-7.58) and in CFSPID (6.56; 5.64-7.21)., Conclusions: Most of asymptomatic CFSPID or progressed to CF have normal LCI. Further data on the longitudinal course of LCI during follow up of CFSPID and on larger cohorts is needed., (© 2023 Wiley Periodicals LLC.)

The etiology of autism spectrum disorders (ASDs) is poorly understood, although it is clear that genetic factors play a major role. ASDs appear to be a heterogeneous group of disorders, making genetic analysis difficult in the absence of etiologically definable subgroups. The excess of males in the affected population has led to suggestions that an X-linked locus could play a role in the causation of autism or a related pervasive developmental disorder. To examine this, we have investigated the genotypes of 31 families with two or more affected boys, at a series of 16 highly polymorphic loci distributed along the X chromosome with an average interlocus distance of 12 cM, in order to identify regions of significantly increased concordance among pairs of affected brothers. No locus tested showed a significant increase in concordance, supporting findings by others that there are no genes of major effect located on the X chromosome that contribute to increased susceptibility to ASD., (Copyright 2002 Wiley-Liss, Inc.)

Autism, a neurodevelopmental disability characterized by repetitive stereopathies and deficits in reciprocal social interaction and communication, has a strong genetic basis. Since previous findings showed that some families with autistic children have a low level of serum dopamine beta-hydroxylase (DbetaH), which catalyzes the conversion of dopamine to norepinephrine, we examined the DBH gene as a candidate locus in families with two or more children with autism spectrum disorder using the affected sib-pair method. DBH alleles are defined by a polymorphic AC repeat and the presence/absence (DBH+/DBH-) of a 19-bp sequence 118 bp downstream in the 5' flanking region of the gene. There was no increased concordance for DBH alleles in affected siblings, but the mothers had a higher frequency of alleles containing the 19-bp deletion (DBH-), compared to an ethnically similar Canadian comparison group (chi(2) = 4.20, df = 1, P = 0.02 for all multiplex mothers; chi(2) = 4.71, df = 1, P < 0.02 for mothers with only affected sons). Although the odds ratios suggested only a moderate relevance for the DBH- allele as a risk allele, the attributable risk was high (42%), indicating that this allele is an important factor in determining the risk for having a child with autism. DBH genotypes also differed significantly among mothers and controls, with 37% of mothers with two affected sons having two DBH- alleles, compared to 19% of controls (chi(2) = 5.81, df = 2, P = 0.03). DbetaH enzyme activity was lower in mothers of autistic children than in controls (mean was 23.20 +/- 15.35 iU/liter for mothers vs. 33.14 +/- 21.39 iU/liter for controls; t = - 1.749, df = 46, P = 0.044). The DBH- allele was associated with lower mean serum DbetaH enzyme activity (nondeletion homozygotes: 41.02 +/- 24.34 iU/liter; heterozygotes: 32.07 +/- 18.10 iU/liter; and deletion homozygotes: 22.31 +/- 13.48 iU/liter; F = 5.217, df = 2, P = 0.007) in a pooled sample of mothers and controls. Taken together, these findings suggest that lowered maternal serum DbetaH activity results in a suboptimal uterine environment (decreased norepinephrine relative to dopamine), which, in conjunction with genotypic susceptibility of the fetus, results in autism spectrum disorder in some families., (Copyright 2001 Wiley-Liss, Inc.)

Background: In children with primary ciliary dyskinesia (PCD), measures more sensitive than spirometry are needed to characterize underlying pulmonary impairment. Electrical impedance tomography (EIT) is a promising noninvasive method for monitoring the distribution of lung ventilation, and it does not require patient collaboration. We aimed to provide an assessment of the feasibility and clinical usefulness of EIT in characterizing lung impairment in children with PCD, compared to spirometry and multiple breath nitrogen washout (MBWN 2 ) test., Methods: Children and adolescents with PCD underwent MBWN 2 test as first respiratory assessment, followed by EIT monitoring and spirometry during outpatient follow-up., Results: We included 12 out of 16 individuals regularly followed at our clinic. A total of 41.7% (5/12) showed abnormal forced expiratory volume in 1 s (FEV 1 ), whereas 11/12 (91.7%) had abnormal ventilation inhomogeneity measured with MBWN 2 test. Using EIT, the global inhomogeneity (GI TOT ) index showed moderate to strong correlation with FEV 1 (ρ = -0.55, 95% confidence interval [CI]: -0.87 to 0.02) and ranged from 37 to 44, with the highest inhomogeneity detected in the dorsal right quadrant. GI TOT was moderately correlated with RV/TLC %predicted (ρ = 0.38, 95% CI: -0.17 to 0.74), while we detected a weak correlation between GI TOT and lung clearance index (ρ = 0.29, 95% CI: -0.45 to 0.82)., Conclusion: EIT appears promising as a noninvasive technique to characterize ventilation distribution in children with PCD, thus providing a complementary assessment to static and dynamic lung function measures of PCD disease., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

A gene responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a family with five affected males in three generations was localized to Xp21.1-p22.13 by linkage analysis. Recombination events placed the gene between DXS1226 distally and DXS1238 proximally, defining an interval of approximately 14 cM. A peak lod score of 2.71 was found with several loci in Xp21.1 (DXS992, DXS1236, DXS997, and DXS1036) at a recombination fraction of zero. The map intervals of 5 X-linked mental retardation loci, MRX2 (Xp22.1-p22.2), MRX19 (Xp22), MRX21 (Xp21.1-p22.3), MRX29 (Xp21.2-p22.1), and MRX32 (Xp21.2-p22.1), and two syndromal mental retardation loci, Partington syndrome (PRTS; Xp22) and Coffin-Lowry syndrome (CLS; Xp22.13-p22.2), overlap this region. As none of these display the same phenotype seen in the family reported here, this X-linked mental retardation locus may represent a new entity.

Rationale: The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and physiologically relevant changes in LCI during routine clinical surveillance., Objectives: To evaluate the long-term variability of LCI and propose a threshold for a physiologically relevant change., Methods: In children aged 4-18 years with CF, LCI was measured every 3 months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for physiologically relevant changes., Results: Repeated LCI measurements of acceptable quality (N = 858) were available in 100 patients with CF; for 74 patients, 399 visits at clinical stability were available. The variability of repeated LCI measurements over time expressed as the coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%., Conclusion: We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes., (© 2022 Wiley Periodicals LLC.)

Background: Data on the prevalence and type of lung function impairment in preschool and school-aged children previously diagnosed with persistent tachypnea of infancy (PTI) are scarce. Therefore, this study aims to assess pulmonary function in this age group., Methods: Children diagnosed with PTI over 3 years old were admitted for follow-up visits and healthy controls were enrolled. The study group included children who were able to complete pulmonary function tests (PFTs). Medical history, physical examination, and pulmonary function (spirometry, body plethysmography, impulse oscillometry, nitrogen multiple breath washout test, diffusing capacity for carbon monoxide [DL CO ]) were assessed., Results: Thirty-seven children (26 boys, 11 girls; median age: 5.6 years) diagnosed with PTI and 37 healthy controls were recruited. Forced expiratory volume in 1 s and forced vital capacity were significantly lower (-1.12 vs. 0.48, p = 0.002 and -0.83 vs. 0.31, p = 0.009, respectively); respiratory resistance at 5 Hz (0.06 vs. -0.62, p = 0.003), resonant frequency (1.86 vs. 1.36, p = 0.04), residual volume (RV) (2.34 vs. -1.2, p < 0.0001), RV%TLC (total lung capacity) (2.63 vs. -0.72, p < 0.0001), and specific airway resistance (5.4 vs. 2.59, p = 0.04) were significantly higher in PTI patients as compared with controls (data were presented as median z-score). Air trapping was found in 60.0%, and abnormally high lung clearance index and DL CO  were found in 73.3% and 90.9% of PTI patients, respectively., Conclusions: This study demonstrated that lung function is affected in most children with PTI. PFTs showed that peripheral airways are the major zone of functional impairment., (© 2022 Wiley Periodicals LLC.)

Background: Pulmonary exacerbations (PEx), pathogens colonizing the respiratory tract, and patients' age are associated with progressive worsening of lung function among patients with cystic fibrosis (CF). However, the effect of these factors on longitudinal changes of Lung Clearance Index (LCI) remains unclear., Aim: To assess the role of age, different types of bronchial infection, and PEx on LCI deterioration., Methods: We conducted a retrospective study assessing multiple-breath washout (MBW) and spirometry changes among CF patients evaluated at quarterly outpatient clinic visits over 8 years. MBW and spirometry were performed at each visit, sputum samples and/or cough swabs were obtained for culture, whereas respiratory symptoms and clinical examination findings were recorded. Patients who had ≥5 serial MBW measurements, one of which coincided with a pulmonary exacerbation, were reviewed., Results: Seventy-six patients were included in the study: mean age of 10.61 years (range 1.75-23.75). A total of 1152 MBW tests and 1047 spirometry tests were performed. LCI was significantly higher among CF patients aged 11-15, 16-20, and over 20 years than those under 5 years of age; ΔLCI: 1.16 (confidence interval [CI] 0.43-1.90) and 3.25 (CI 2.33-4.17), respectively. Furthermore, LCI was significantly elevated in CF patients with positive cultures for Pseudomonas aeruginosa (0.52 LCI [CI -0.12 to 0.71]) and Stenotrophomonas Maltophilia (1.41 LCI [CI 0.61-2.21]). Moreover, increased values of LCI in CF patients were significantly associated with increased risk of PEx (odds ratio [OR] 1.19, CI [1.14-1.25], p < 0.001)., Conclusion: LCI demonstrates a progression of lung disease and corresponds to changes in bacterial infections and PEx among patients with CF. LCI may be a valuable marker for tracking disease deterioration and may have a role in the routine clinical care of patients with CF., (© 2022 Wiley Periodicals LLC.)

Objectives: To describe the short- and medium-term repeatability of lung clearance index at 2.5% (LCI 2.5 ) in infants and calculate the number of patients needed to enroll in a study (N) using LCI 2.5 as a primary outcome., Methods: An 8-month follow-up observational study was employed for assessing short-term [coefficient of repeatability (CR) and intraclass correlation (ICC)] and medium-term repeatability (Bland-Altman method) of LCI 2.5 in infants with cystic fibrosis (CF) or recurrent wheeze (RW) measured by the nitrogen multiple-breath washout test (N 2 -MBW). Using these variability data, the N to reach 90% test power at the level of statistical significance (0.05) was calculated., Results: Forty infants with CF and 21 with RW were enrolled. Initial N 2 -MBW testing was successful in 33 and 17 patients, respectively. Follow-up data were available for 23 and 11 infants, respectively. Short-term repeatability of LCI 2.5 was high (CR = 1.10 and 1.04 in CF and RW patients, respectively; ICC = 0.88 and 0.83 in CF and RW patients, respectively). The between-subject standard deviation was <13% of the actual LCI 2.5 value. In clinically stable patients, LCI 2.5 did not significantly change during the 8-month follow-up. Mean LCI 2.5 change was -0.08 (1% of baseline) in CF and -0.05 (0.6%) in RW, with 95% limits of agreement being (-1.70; 1.53) in CF and (-1.51; 1.40) in RW patients. N = 23 infants if both intragroup differences of LCI 2.5 and minimal difference to be detected would be 2.0., Conclusion: N 2 -MBW may be a reproducible tool with reasonable test power to detect differences in infant studies., (© 2022 Wiley Periodicals LLC.)

Background: Pulmonary exacerbations (PE) tend to complicate the course of cystic fibrosis (CF) and worsen the disease prognosis. One of the diagnostic criteria for an exacerbation is the forced expiratory volume in the first second (FEV 1 ) decline. Not all children, however, are able to perform spirometry. Therefore, the aim of this study was to evaluate alternative lung function tests in the diagnosis of PE., Methods: We assessed retrospectively the results of impulse oscillometry (IOS) and lung clearance index in multiple breath washout (MBW) during 259 visits in 47 CF paediatric patients. The differences in the results were compared between patients diagnosed with PE (ΔPE) and those in stable condition (ΔS)., Results: Among the whole group of patients, we found significant differences between the changes during exacerbation (ΔPEs) and stable condition (ΔSs) values for lung clearance index (LCI), S acin , R5Hz, R5-20Hz, X10Hz, AX, and Fres. The predictive values of Fres and X10Hz in IOS (AUC ROC 0.71 both parameters) were higher than those of LCI (AUC ROC 0.67). There was no difference in the predictive values (AUC ROC ) of Δ LCI and IOS parameters in the subgroups of patients stratified based on FEV 1 z-score cut-off value of -1.64. In both groups of patients, predictive values of LCI were slightly lower than of IOS parameters (AUC 0.66 for LCI vs. 0.69 for both ΔX10Hz z-score and Δ Fres z-score in patients with FEV 1 z-score ≥-1.64 and AUC 0.67 for LCI vs 0.69 for both ΔX10Hz zscore and Δ Fres zscore in patients with FEV 1 <1.64., Conclusions: Both IOS and MBW measurements are useful in the assessment of pediatric CF patients with PE. LCI has a similar predictive value to IOS in children with CF independently of their FEV 1 value., (© 2022 Wiley Periodicals LLC.)

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF., Methods: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV 1 , LCI 2.5 , body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models., Results: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI 2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV 1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy., Conclusions: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

The field of pediatric rare and diffuse lung disease continues its maturation as research advances the understanding of diagnosis and treatment of children's interstitial lung disease, noncystic fibrosis bronchiectasis, and primary ciliary dyskinesia. The rarity and breadth of these conditions make them challenging to study, yet we continue to make progress in our understanding of pathophysiology, genotype/phenotype relationships, and treatment. Papers published on these topics in Pediatric Pulmonology and other journals in 2023 describe the power of multicenter cooperation and patient registries, enhance our understanding of pathophysiology and genotype/phenotype relationships, and report progress in treatments. In this review, we hope to increase awareness and knowledge of these conditions and to inspire future research., (© 2024 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Application of the principles of pulmonary physiology and lung development to the care and management of respiratory disease in children is a distinguishing feature of pediatric pulmonology. In 2023, this was evident in numerous publications in Pediatric Pulmonology and other journals. This review will highlight some of the papers in this area., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Multiple-breath inert gas washout (MBW) is a sensitive technique to assess lung volumes and ventilation inhomogeneity in infancy. Poor agreement amongst commercially available setups and a lack of transparency in the underlying algorithms for the computation of infant MBW outcomes currently limit the widespread application of MBW as a surveillance tool in early lung disease., Methods: We determined all computational steps in signal processing and the calculation of MBW outcomes in the current infant WBreath/Exhalyzer D setup (Exhalyzer D device, Eco Medics AG; WBreath software version 3.28.0, ndd Medizintechnik AG; Switzerland). We developed a revised WBreath version based on current consensus guidelines and compared outcomes between the current (3.28.0) and revised (3.52.3) WBreath version. We analyzed 60 visits from 40 infants with cystic fibrosis (CF) and 20 healthy controls at 6 weeks and 1 year of age., Results: Investigation into the algorithms in WBreath 3.28.0 revealed discrepancies from current consensus guidelines, which resulted in a potential overestimation of functional residual capacity (FRC) and underestimation of lung clearance index (LCI). We developed a revised WBreath version (3.52.3), which overall resulted in 6.7% lower FRC (mean (SD) -1.78 (0.99) mL/kg) and 14.1% higher LCI (1.11 (0.57) TO) than WBreath version 3.28.0., Conclusion: Comprehensive investigation into the signal processing and algorithms used for analysis of MBW measurements improves the transparency and robustness of infant MBW data. The revised software version calculates outcomes according to consensus guidelines. Future work is needed to validate and compare outcomes between infant MBW setups., (© 2021 Wiley Periodicals LLC.)

Despite early diagnosis of cystic fibrosis (CF) through newborn screening, a substantial proportion of infants and young children with CF still demonstrate physiologic and structural evidence of lung disease progression, such as obstructive airway disease and bronchiectasis. The growing availability of highly effective CF transmembrane conductance regulatory modulator therapy to the vast majority of people with CF has led to the potential to alter the natural history of CF lung disease, but to assess the full impact of these therapies on CF lung disease and to help guide treatment, sensitive measures of early and mild disease are needed. Chest imaging using computed tomography or magnetic resonance imaging is one approach, but technologic barriers and/or concern about exposure to ionizing radiation may limit its use. However, advances in physiologic measurement techniques and exhaled breath analysis offer another option for assessment of CF lung disease., (© 2020 Wiley Periodicals LLC.)

Background: Multiple breath washout (MBW) is increasingly used in the clinical assessment of patients with cystic fibrosis (CF). Guidelines for MBW quality control (QC) were developed primarily for retrospective assessment and central overreading. We assessed whether real-time QC of MBW data during the measurement improves test acceptability in the clinical setting., Methods: We implemented standardized real-time QC and reporting of MBW data at the time of the measurement in the clinical pediatric lung function laboratory in Bern, Switzerland, in children with CF aged 4-18 years. We assessed MBW test acceptability before (31 tests; 89 trials) and after (32 tests; 96 trials) implementation of real-time QC and compared agreement between reviewers. Further, we assessed the implementation of real-time QC at a secondary center in Zurich, Switzerland., Results: Before the implementation of real-time QC in Bern, only 58% of clinical MBW tests were deemed acceptable following retrospective QC by an experienced reviewer. After the implementation of real-time QC, MBW test acceptability improved to 75% in Bern. In Zurich, after the implementation of real-time QC, test acceptability improved from 38% to 70%. Further, the agreement between MBW operators and an experienced reviewer for test acceptability was 84% in Bern and 93% in Zurich., Conclusion: Real-time QC of MBW data at the time of measurement is feasible in the clinical setting and results in improved test acceptability., (© 2020 Wiley Periodicals LLC.)

Introduction: Childhood cancer survivors (CSs) might face an increased lifelong risk of lung function impairment. The lung clearance index (LCI) has been described as being more sensitive than spirometry in the early stages of some lung diseases. The aim of this study was to evaluate this index in a cohort of patients with a history of childhood cancer for the first time., Materials and Methods: We evaluated 57 off-treatment CSs aged 0-18 years old and 50 healthy controls (HCs). We used the multiple-breath washout method to study LCI and spirometry., Results: CSs did not show any differences from the controls in ventilation homogeneity (LCI 6.78 ± 1.35 vs. 6.32 ± 0.44; p: not significant [ns]) or lung function (FEV1 99.9 ± 11.3% vs. 103.0 ± 5.9% of predicted; p: ns; FVC 98.2 ± 10.3% vs. 101.1 ± 3.3% of predicted). LCI significantly correlated with the number of years since the last chemotherapy (r = .35, p < .05)., Conclusions: Our study describes the trend of LCI in a cohort of CSs and compares it with the results obtained from HCs. The results show that patients maintain both good values of respiratory function and good homogeneity of ventilation during childhood. Moreover, as LCI increases and worsens as the years pass after the end of the treatment could identify the tendency toward pulmonary fibrosis, which is typical of adult CSs, at an earlier time than spirometry., (© 2020 Wiley Periodicals LLC.)

Introduction: Lung disease in cystic fibrosis (CF) begins early in life but the capabilities for detecting abnormalities of pulmonary dysfunction in children remain limited., Objective: The study aimed to evaluate the early progression of lung function by the analysis of pulmonary hyperinflation, ventilation inhomogeneity (VI), trapped gas and airway obstruction with age., Methods: One hundred CF children aged 7 to 18, divided into two groups aged 7 to 12 (n = 40) and 13 to 18 (n = 60), were enrolled. Patients performed multiple-breath nitrogen washout (MBNW) tests and plethysmography for measurements of lung clearance index (LCI), functional residual capacity (FRC pleth , FRC MBNW ), volume of trapped gas (V T ), total resistance, and effective and specific effective airway resistance (R eff , sR eff )., Results: We obtained a positive correlation of FRC pleth , FRC MBNW , and LCI with age. A linear correlation between FRC MBNW and FRC pleth (P < .0001) was observed. VI was higher in the group of older patients (9.79 in the group aged 7-12 and 11.67 in the group aged 13-18). An increased effective specific airway resistance >2 (z-score) was present in 58% of all subjects (50% and 63.3%, respectively). Pulmonary hyperinflation (FRC pleth >2 z-score) was observed in 33% of all patients: 25% and 36.6%, respectively. Trapped gas (V T  > 2 z-score) was present in 18% of all children: 30% and 10%, respectively., Conclusion: A gradual decline in lung function is associated with an increase in VI, airway obstruction, pulmonary hyperinflation and development of trapped gas. In children who cannot perform either spirometry or plethysmography, MBNW can deliver a measurement of LCI connecting with VI as well as FRC MBNW to indicate indirectly the increase of hyperinflation., (© 2020 Wiley Periodicals LLC.)

Background: S cond is a multiple breath washout (MBW) index that measures convection-dependent ventilation inhomogeneity (CDI) arising within conductive airways, but the calculation method is unreliable in subjects with advanced cystic fibrosis (CF) lung disease. A new CDI index, S cond *, has been proposed for use in adults with CF and moderate to severe ventilation inhomogeneity. We aimed to evaluate the most appropriate CDI index in children and adolescents with CF and various degrees of inhomogeneity, and from that the most appropriate diffusion-convection-interaction index (S acin or S acin *)., Methods: S cond , S acin  and the alternative indices, S cond *, and S acin * were retrospectively calculated in subjects with CF aged 3 to 18 years and age-matched controls, who underwent sulfur hexafluoride MBW between 2003 and 2015. The upper limit of normal was based on 95th percentile of the control population., Results: One hundred and twenty-seven subjects with CF (44% male; mean age ± SD: 7.5 years ± 4.9) and 94 controls (53% male; 7.9 years ± 5.1) were included in the final analysis. All measures of ventilation inhomogeneity were significantly higher in children with CF. As predicted, S cond reached a maximum value at lung clearance index (LCI) values of approximately 9. In subjects with LCI ≥ 9 S cond * showed good correlation with LCI, whilst S cond had no relationship with LCI (Spearman rank correlation S cond */LCI, 0.49; P < .01; S cond /LCI, -0.068; P = .46). In subjects with mild disease (LCI < 9) S cond was more frequently abnormal than S cond * (37% vs 16%; P = .01)., Conclusions: S cond and S acin are sensitive indices of early regional inhomogeneity, but are of no value when LCI ≥ 9. In these subjects, S cond * & S acin * are potential alternatives., (© 2020 Wiley Periodicals LLC.)

Introduction: The multiple breath nitrogen washout (MBW) test offers a sensitive measure of airway function. In this study we aim to (a) assess the validity of the EasyOne Pro LAB (MBW ndd ) in an in vitro lung model, (b) assess the feasibility, repeatability, and reproducibility of MBW ndd and (c) compare outcomes with the Exhalyzer D (MBW EM ) and body plethysmography., Methods: In vitro, functional residual capacity (FRC) measurements were assessed using a lung model under quasi-physiological conditions and compared to measured FRC. In vivo plethysmography and MBW were performed in a prospective study of children at two visits (n = 45 healthy; n = 41 cystic fibrosis [CF]). Bland-Altman plots were used to compare agreement between FRC and lung clearance index (LCI) measurements., Results: In vitro FRC ndd measurements were repeatable but lung volumes were underestimated (mean relative difference -5.4% (limits of agreement [LA] -9.6%; -1.1%), 95% confidence interval (CI) -6.27; -4.45). In vivo, compared to plethysmography, FRC ndd was consistently lower (-19.3% [-40.5; 1.9], 95% CI [-23.9; -14.7]), and showed a volume dependency. LCI ndd values were also higher in children with smaller lung volumes. The within-test coefficient of variation of the FRC ndd and LCI ndd were 4.9% in health, and 5.6% and 6.9% in CF respectively. LCI ndd was reproducible between-visits (mean relative difference [LA] -3.7% [-14.8, -7.5; 95% CI -6.6; -0.73] in health [n = 17] and 0.34% [-13.2, 22.8; 95% CI -5.0; 5.69] in CF [n = 23]). When calculated using the same algorithm, LCI ndd was similar to LCI EM in health., Conclusions: MBW ndd measurements are feasible, repeatable, and reproducible, however, MBW-derived outcomes are not interchangeable with MBW EM ., (© 2020 Wiley Periodicals LLC.)

Background: Compartment analysis (CA) based on nitrogen multiple-breath washout (N 2 MBW) has been shown to allow the assessment of specific volume and ventilation of faster- and slower-ventilating lung compartments of the lung in adults with cystic fibrosis (CF). The aim of this study was to extend previous findings into the pediatric age range., Methods: Cross-sectional multicenter observational study in children with CF and healthy controls (HC) was done with the assessment of N 2 MBW and spirometry. A two-lung compartment model-based analysis (CA) was used to estimate size and function of faster- and slower-ventilating lung compartments from N 2 MBW., Results: A total of 125 children with CF and 177 HC, median age 10.8 (range, 2.8-18.9) years, were included in the analysis. CA could be calculated in 66 (53%) children with CF compared with 48 (27%) HC (P < .0001). The proportion of the slower-ventilating lung compartment was significantly smaller in children with CF (53.5%; 95% confidence interval [CI]: 51.9%-55.7%) compared with HC (62.2%; 95% CI: 59.0%-65.0%) The regional specific ventilation of the slower compartment (rV T ,slow/rFRC,slow, %) was significantly lower in children with CF (4.9%; 95% CI: 4.5-5.9) compared with HC (9.7%, 95% CI: 9.2-10.9), and showed inverse correlation to lung clearance index (r 2  = -.65; P < .0001), S acin  × VT (r 2  = -.36; P = .003) and S cond  × VT (r 2  = -.51; P < .0001). There was no significant difference in pulmonary parameters between children with CF with and without feasible CA., Conclusion: CA is less feasible in children than in adults and correlated to other MBW parameters. The clinical value of CA is still unclear and is yet to be established., (© 2020 Wiley Periodicals, Inc.)

Introduction: Survivors of extreme prematurity may have disrupted lung development. We hypothesized that the multiple breath washout (MBW) index Scond, which is intended to reflect ventilation inhomogeneity from the conducting airways, could be a sensitive marker of respiratory impairment in this group., Methods: Spirometry, TLco, and MBW were cross-sectionally evaluated at 8 to 14 years of age in children born at <28 weeks between 2004 and 2010 in Udine, Italy. Age-matched controls born at term were also included. Bronchopulmonary dysplasia (BPD) was defined as oxygen-dependence at 36 weeks postmenstrual age. The limits of normal were the 5th percentile of the reference population (Global Lung Initiative) for spirometry and TLco and the 95th percentile of controls for Lung Clearance Index, Scond, and Sacin from MBW., Results: Results were obtained in 47 extremely preterm children (53% boys, mean ± standard deviation age 11.3 ± 2.0 years, 40% with BPD) and 60 controls (50% boys, 11.6 ± 1.9 years). There were significant differences between preterm children and controls in all lung function outcomes, except for Sacin. Among children born <28 weeks, Scond tended to be frequently abnormal than FEV 1 z-score (29% vs 14%, P = .06). At multivariable linear regression, in the preterm group, current asthma was significantly associated with a higher Scond (B = 0.019, 95% confidence interval, 0.000-0.038), whereas BPD was not., Conclusion: Almost a third of extremely preterm children at school age showed Scond alterations that affected also children without BPD. Longitudinal studies should clarify the prognostic meaning of Scond abnormalities in this group., (© 2020 Wiley Periodicals, Inc.)

Background: Elexacaftor in combination with Tezacaftor and Ivacaftor (ETI) became licensed in the United Kingdom in early 2022 for children aged 6-11 years with cystic fibrosis (CF) and an eligible mutation. Many in this age group have excellent prior lung health making quantitative measurement of benefit challenging. Clinical trials purport that lung clearance index (LCI 2.5 ) measurement is most suitable for this purpose., Objectives: This study aimed to understand the clinical utility of LCI 2.5 in detecting change after commencing ETI in the real world., Patient Selection/methods: Baseline anthropometric data were collected along with spirometry (forced expiratory volume in 1 s [FEV 1 ], forced vital capacityFV and LCI 2.5 measures in children aged 6-11 years with CF before starting ETI. Measures were repeated after a mean (range) of 8.2 (7-14) months of ETI treatment. The primary endpoint was a change in LCI 2.5 , with secondary endpoints including change in FEV 1 and change in body mass index (BMI) also reported., Results: Twelve children were studied (seven male, mean age 9.5 years at baseline). Our study population had a mean (SD) LCI 2.5 of 7.01 (1.14) and FEV 1 of 96 (13) %predicted at baseline. Mean (95% confidence interval) changes in LCI 2.5 [-0.7 (-1.4, 0), p = .06] and BMI [+0.7 (+0.1, +1.3), p = .03] were observed, along with changes in FEV 1 of +3.1 (-1.9, +8.1) %predicted., Conclusions: Real-world changes in LCI 2.5 (-0.7) are different to those reported in clinical trials (-2.29). Lower baseline LCI 2.5 as a result of prior modulator exposure, high baseline lung health, and new LCI 2.5 software analyses all contribute to lower LCI 2.5 values being recorded in the real world of children with CF., (© 2024 Wiley Periodicals LLC.)

Background: The introduction of modulator therapy for cystic fibrosis (CF) has led to an increased interest in the detection of small airway disease (SAD) as sensitive marker of treatment response. The particles in exhaled air (PExA) method, which records exhaled particle mass (PEx ng/L) and number (PExNR), detects SAD in adult patients. Our primary aim was to investigate if PExA outcomes in children with CF are different when compared to controls and associated with more severe disease. Secondary aims were to assess feasibility and repeatability of PExA in children with CF and to correlate PExA to multiple breath nitrogen washout (MBNW) as an established marker of SAD., Methods: Thirteen healthy children (HC), 17 children with CF with normal lung function (CF-N) (FEV 1 z-score ≥ -1.64) and six with airway obstruction (CF-AO) (FEV 1 z-score < -1.64) between 8 and 18 years performed MBNW followed by PExA and spirometry. Children with CF repeated the measurements after 3 months., Results: PEx ng/L and PExNR/L per liter of exhaled breath were similar between the three groups. The lung clearance index (LCI) was significantly higher in both CF-N and CF-AO compared to HC. All participants, except one, were able to perform PExA. Coefficient of variation for PEx ng/l was (median) 0.38, range 0-1.25 and PExNR/l 0.38, 0-1.09. Correlation between LCI and PEx ng/l was low, r s 0.32 (p = .07)., Conclusion: PExA is feasible in children. In contrast to LCI, PExA did not differentiate healthy children from children with CF suggesting it to be a less sensitive tool to detect SAD., (© 2024 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Several factors may influence quality of life (QOL) for patients with primary ciliary dyskinesia (PCD). We aimed to evaluate the association between pulmonary functions, nasal symptoms and QOL in PCD patients., Methods: A prospective single center study. Patients performed spirometry, whole body plethysmography, forced oscillation technique (FOT), lung clearance index (LCI), 6-min walk test (6MWT), and filled two questionnaires: a specific PCD QOL questionnaire (PCD-QOL) and Sino-nasal outcome test (SNOT-22) questionnaire, assessing symptoms of chronic rhinosinusitis and health related QOL., Results: Twenty-seven patients (56% females), age 19.4 ± 10.5 years were included; their, FEV1 was 74.6 ± 22.7%, and RV/TLC was (157.3 ± 39.3% predicted). Health perception and lower respiratory symptoms domains of PCD-QOL had the lowest score (median [IQR]: 50 [33.3-64.6] and 57.1 [38.9-72.2], respectively). FOT parameters correlated with several PCD-QOL domains. R5 z-score (indicating total airway resistance) and AX z-score (indicating airway reactance) correlated negatively with physical domain (r = -0.598, p = .001, and r = -0.42, p = .03, respectively); R5 z-score also correlated negatively with hearing domain (r = -0.57, p = .002). R5-20 z-score (indicating small airway resistance) correlated negatively with role domain (r = -0.49, p = .03). SNOT-22 score correlated negatively with several PCD-QOL domains (lower respiratory symptoms r = -0.77, p < .001; physical r = -0.72, p < .001; upper respiratory symptoms r = -0.66, p < .001). No correlations were found between spirometry values, LCI, 6MWT, and PCD-QOL., Conclusions: FOT suggested small airway dysfunction, and correlated negatively with several PCD-QOL domains. Nasal symptoms had strong negative correlations with PCD-QOL. Larger longitudinal studies will further elucidate factors affecting QOL in PCD., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: No age-specific pediatric guidelines exist for the management of spontaneous pneumothorax (SP) in children and adolescents. Treatment remains heterogeneous and center dependent. The role of computed tomography (CT) has yet to be defined., Aims: Review the management of SP in children and adolescents, with emphasis on conservative management and role of CT., Methods: Retrospective analysis of 61 consecutive patients with SP at single tertiary center. Clinical, radiological, surgical data, follow-up, and outcomes were revised., Results: First-line management was conservative for 32 (53%) patients and operative for 29 (47%). Asymptomatic/paucisymptomatic patients managed conservatively experienced less first-line treatment failure. Furthermore, the patients needing at least a chest drain or surgery during the follow-up were significantly lower in the conservative group. Conservative and operative patients showed no significant differences regarding ipsilateral recurrences or contralateral occurrences. Of the 61 overall CTs performed, 14 (23%) had an impact on management. Forty-three (70%) patients had at least a CT, in 22 (51%) the CT was positive for blebs. For 10 of these patients (45%) the presence of blebs had an impact on management. Patients with and without blebs showed no differences regarding ipsilateral recurrence, contralateral occurrences, or the need for at least a chest drain or surgery during the follow-up., Conclusions: First-line conservative management had a significantly shorter hospitalization and better outcome, with a similar incidence of recurrences. The presence of blebs at CT does not predict the risk of recurrence. The CT scan should be reserved for a small number of selected patients who have post-VATS refractory or recurrent pneumothorax., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Effective work of breathing and bronchial hygiene requires synergy of inspiratory and expiratory muscles. Inspiratory muscle training (IMT) is a part of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD). There is some evidence of its efficacy in cystic fibrosis (CF) and, recently, in long COVID-19. We are not aware of studies on IMT in primary ciliary dyskinesia (PCD). Our aim was to assess the effect of IMT on respiratory muscle strength and pulmonary function in PCD and CF patients., Methods: A single center pilot study. Spirometry, lung clearance index (LCI), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were measured at baseline (visit 1), after a month of IMT with ®POWERbreathe (visit 2), and at follow-up (visit 3)., Results: The cohort included 27 patients (19 PCD, 8 CF); mean age 18.4 ± 9.8 years. After a month of IMT, there was a significant increase in MIP and MIP% (6.19-7.44, p = .015; and 81.85%-100.41%, p = .046, respectively), which was sustained at visit 3. Compliance ≥90% led to higher improvement in MIP. In sub-group analysis, improvement in MIP and MIP% remained significant for PCD patients (p = .026 and p = .049, respectively). No significant changes were found in spirometry, MEP or LCI., Conclusions: IMT was well-tolerated and led to improved inspiratory muscle strength in PCD patients. The clinical implication of improved MIP should be further investigated. Larger, long-term studies are needed to evaluate long-term effects of IMT on pulmonary function, respiratory muscle strength, pulmonary exacerbations, and quality of life., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: The utility of the forced oscillations technique (FOT) in cystic fibrosis (CF) remains uncertain. The aim of this study was to explore the ability of lower-frequency FOT indices, alone and after adjustment for the lung volume, to assess the extent of ventilation inhomogeneity in CF patients with varying disease severity., Methods: Forty-five children, adolescents, and adults with CF (age 6.9-27 years) underwent spirometry, FOT, and nitrogen multiple-breath washout (N2-MBW) measurements. The respiratory resistance and reactance at 5 Hz (Rrs5 and Xrs5, respectively) were recorded, and a novel FOT index, the specific respiratory conductance (sGrs), was computed as the reciprocal of Rrs5 divided by the functional residual capacity., Results: The sGrs correlated well with the lung clearance index (LCI) (Spearman's r: -.797), whereas the correlation of Rrs5 and Xrs5 with the LCI, albeit significant, was weaker (r: .643 and -.631, respectively). The sGrs emerged as the most robust predictor of LCI regardless of the severity of lung disease, as reflected by patients' age and lung function measurements. Most importantly, the relationship between sGrs and LCI remained unaffected by lung hyperinflation, as opposed to that of the LCI with the spirometric and standard FOT indices., Conclusions: In CF patients, the FOT indices at 5 Hz and the novel, volume-adjusted parameter sGrs, reflect the extent of lung involvement and the underlying ventilation inhomogeneity in a way comparable to N2-MBW. Future research should explore the role of lower-frequency FOT in assessing the severity and monitoring the progression of CF lung disease., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)