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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: 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.)

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.)

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.)

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.)

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.