Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient.

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.

New reference ranges for interpreting forced expiratory manoeuvres in infants and implications for clinical interpretation: a multicentre collaboration.

UNLABELLED: The raised volume rapid thoracoabdominal compression (RVRTC) technique is commonly used to obtain full forced expiratory manoeuvres from infants, but reference equations derived from 'in-house' equipment have been shown to be inappropriate for current commercially available devices. AIM: To explore the impact of equipment differences on RVRTC outcomes, derive robust equipment-specific RVRTC reference ranges and investigate their potential clinical impact on data interpretation. METHOD: RVRTC data from healthy subjects using Jaeger BabyBody or the 'Respiratory Analysis Software Program, RASP' systems were collated from four centres internationally. Data were excluded if gestational age <37 weeks or birth weight <2.5 kg. Reference equations for RVRTC outcomes were constructed using the LMS (lambda-mu-sigma) method, and compared with published equations using data from newborn screened infants with cystic fibrosis (CF). RESULTS: RVRTC data from 429 healthy infants (50.3% boys; 88% white infants) on 639 occasions aged 4-118 weeks were available. When plotted against length, flows were significantly higher with RASP than Jaeger, requiring construction of separate equipment-specific regression equations. When comparing results derived from the new equations with those from widely used published equations based on different equipments, discrepancies in forced expiratory volumes and flows of up to 2.5 z-scores were observed, the magnitude of which increased with age. According to published equations, 25% of infants with CF fell below the 95% limits of normal for FEV0.5, compared with only 10% when using the new equations. CONCLUSIONS: Use of equipment-specific prediction equations for RVRTC outcomes will enhance interpretation of infant lung function results; particularly during longitudinal follow-up.

Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants.

RATIONALE: Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants. OBJECTIVE: To assess changes in pulmonary function during the first year of life in CF NBS infants. METHODS: Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV0.5) were measured at 3 months and 1 year of age. MAIN RESULTS: Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year. CONCLUSIONS: This is the first study reporting improvements in FEV0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs.

Age and height dependence of lung clearance index and functional residual capacity.

The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.

Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening.

BACKGROUND: Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. HYPOTHESIS: With early diagnosis and commencement of standardised treatment, lung function at ∼3 months of age is normal in NBS infants with CF. METHODS: Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age ∼3 months. RESULTS: Compared with controls, and after adjustment for body size and age, LCI, FRC(MBW) and FRC(pleth) were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p=0.02; 0.4 (0.1 to 0.7), p=0.02 and 0.9 (0.4 to 1.3), p<0.001, z-scores, respectively), while forced expiratory volume (FEV(0.5)) and flows (FEF(25-75)) were significantly lower (-0.9 (-1.3 to -0.6), p<0.001 and -0.7 (-1.1 to -0.2), p=0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (>1.96 z-scores) and 25% (17/68) an abnormally low FEV(0.5) (below -1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV(0.5), using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC(pleth) >1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF(25-75) (r=-0.43, p<0.001) but not with LCI or FEV(0.5). CONCLUSION: Despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.

Development of Lung Function in Preterm Infants During the First Two Years of Life.

INTRODUCTION: It remains unclear if prematurity itself can influence post delivery lung development and particularly, the bronchial size. AIM: To assess lung function during the first two years of life in healthy preterm infants and compare the measurements to those obtained in healthy term infants during the same time period. METHODS: This observational longitudinal study assessed lung function in 74 preterm (30+0 to 35+6 weeks' gestational age) and 76 healthy term control infants who were recruited between 2011 and 2013. Measurements of tidal breathing, passive respiratory mechanics, tidal and raised volume forced expirations (V'maxFRC and FEF25-75, respectively) were undertaken following administration of oral chloral hydrate sedation according to ATS/ERS recommendations at 6- and 18-months corrected age. RESULTS: Lung function measurements were obtained from the preterm infants and full term controls initially at 6 months of age. Preterm infants had lower absolute and adjusted values (for gestational age, postnatal age, sex, body size, and confounding factors) for respiratory compliance and V'maxFRC. At 18 months corrected postnatal age, similar measurements were repeated in 57 preterm infants and 61 term controls. A catch-up in tidal volume, respiratory mechanics parameters, FEV0.5 and forced expiratory flows was seen in preterm infants. CONCLUSION: When compared with term controls, the lower forced expiratory flows observed in the healthy preterm group at 6 months was no longer evident at 18 months corrected age, suggesting a catch-up growth of airway function.

Minimal change in structural, functional and inflammatory markers of lung disease in newborn screened infants with cystic fibrosis at one year.

BACKGROUND: With the widespread introduction of newborn screening for cystic fibrosis (CF), there has been considerable emphasis on the need to develop objective markers of lung health that can be used during infancy. We hypothesised that in a newborn screened (NBS) UK cohort, evidence of airway inflammation and infection at one year would be associated with adverse structural and functional outcomes at the same age. METHODS: Infants underwent lung function testing, chest CT scan and bronchoscopy with bronchoalveolar lavage (BAL) at 1 year of age when clinically well. Microbiology cultures were also available from routine cough swabs. RESULTS: 65 infants had lung function, CT and BAL. Mean (SD) lung clearance index and forced expiratory volume in 0.5 s z-scores were 0.9(1.2) and -0.6(1.1) respectively; median Brody II CF-CT air trapping score on chest CT =0 (interquartile range 0-1, maximum possible score 27). Infants isolating any significant pathogen by 1 yr of age had higher LCI z-score (mean difference 0.9; 95%CI:0.4-1.4; p = 0.001) and a trend towards higher air trapping scores on CT (p = 0.06). BAL neutrophil elastase was detectable in 23% (10/43) infants in whom BAL supernatant was available. This did not relate to air trapping score on CT. CONCLUSIONS: In this UK NBS cohort at one year of age, lung and airway damage is much milder and associations between inflammation, abnormal physiology and structural changes were at best weak, contrary to our hypothesis and previously published reports. Continued follow-up will clarify longer term implications of these very mild structural, functional and inflammatory changes.

Lung function from infancy to the preschool years after clinical diagnosis of cystic fibrosis.

RATIONALE: After recent standardization of forced expiratory maneuvers for both infants and preschool children, longitudinal measurements are now possible from birth. OBJECTIVES: The aim of this study was to investigate the evolution of lung function during the first 6 years of life after a clinical diagnosis of cystic fibrosis (CF) in infancy in children with CF and in healthy control subjects. METHODS: The raised volume technique was used during infancy and incentive spirometry during the preschool years. MEASUREMENTS AND MAIN RESULTS: Forty-eight children with CF and 33 healthy control subjects had up to seven (median, 3) measurements. Over these early years, the diagnosis of CF itself accounted for a significant mean reduction of 7.5% (95% confidence interval, 0.9 - 13.6%) in FEV(0.75) and 15.1% (95% confidence interval, 3.6 - 25.3%) in FEF(25-75). Wheeze on auscultation, recent cough, and Pseudomonas aeruginosa (PsA) infection (even if apparently effectively treated) were all independently associated with further reductions in lung function. Premorbid lung function did not predict infection with PsA. CONCLUSIONS: This is the first study to describe physiologic measurements from infancy through the preschool years in subjects with CF and healthy control subjects, the understanding of which is critical for future intervention trials. Airflow obstruction in uncomplicated CF persists through the preschool years despite treatment, with PsA acquisition being associated with further deterioration in lung function, even when apparently eradicated. This suggests that new therapies are needed to treat the airflow obstruction of uncomplicated CF, and rigorous strategies to prevent PsA acquisition.

Development of Lung Function in Preterm Infants During the First Two Years of Life / Desarrollo de la función pulmonar en lactantes pretérmino durante los 2 primeros años de vida

Introduction: It remains unclear if prematurity itself can influence post delivery lung development and particularly, the bronchial size.AimTo assess lung function during the first two years of life in healthy preterm infants and compare the measurements to those obtained in healthy term infants during the same time period.MethodsThis observational longitudinal study assessed lung function in 74 preterm (30+0 to 35+6 weeks’ gestational age) and 76 healthy term control infants who were recruited between 2011 and 2013. Measurements of tidal breathing, passive respiratory mechanics, tidal and raised volume forced expirations (V’maxFRC and FEF25–75, respectively) were undertaken following administration of oral chloral hydrate sedation according to ATS/ERS recommendations at 6- and 18-months corrected age.ResultsLung function measurements were obtained from the preterm infants and full term controls initially at 6 months of age. Preterm infants had lower absolute and adjusted values (for gestational age, postnatal age, sex, body size, and confounding factors) for respiratory compliance and V’maxFRC. At 18 months corrected postnatal age, similar measurements were repeated in 57 preterm infants and 61 term controls. A catch-up in tidal volume, respiratory mechanics parameters, FEV0.5 and forced expiratory flows was seen in preterm infants.ConclusionWhen compared with term controls, the lower forced expiratory flows observed in the healthy preterm group at 6 months was no longer evident at 18 months corrected age, suggesting a catch-up growth of airway function. (AU)

Introducción: Todavía no está claro si la prematuridad por sí sola puede tener influencia en el desarrollo pulmonar tras el parto y, en particular, en el tamaño bronquial.ObjetivoValorar la función pulmonar durante los 2 primeros años de vida en lactantes pretérmino sanos y comparar las medidas con las obtenidas en lactantes nacidos a término sanos durante el mismo periodo de tiempo.MétodosEste ensayo longitudinal observacional valoró la función pulmonar en 74 lactantes pretérmino (30+0 a 35+6 semanas de edad gestacional) y 76 lactantes nacidos a término sanos como controles, que se seleccionaron entre 2011 y 2013. Se llevaron a cabo las mediciones de la respiración corriente, la mecánica respiratoria pasiva, los flujos espiratorios forzados a volumen corriente y con insuflación previa (V’maxFRC y FEF25-75, respectivamente) tras la sedación con hidrato de cloral siguiendo las recomendaciones de las ATS/ERS a la edad corregida de 6 y 18 meses.ResultadosInicialmente se obtuvieron las medidas de función pulmonar de los lactantes pretérmino y los controles a término a los 6 meses de edad. Los lactantes pretérmino presentaron unos valores absolutos y ajustados (a la edad gestacional, la edad posnatal, el sexo, el tamaño corporal y los factores de confusión) menores para la distensibilidad pulmonar y la V’maxFRC. A los 18 meses de edad posnatal corregida, se repitieron las mismas mediciones en 57 lactantes pretérmino y 61 controles a término. Se observó una recuperación del volumen corriente, los parámetros de mecánica respiratoria, el FEV0,5 y los flujos espiratorios forzados en los lactantes pretérmino.ConclusiónEn comparación con los controles a término, los flujos espiratorios forzados más bajos observados en el grupo de pretérminos sanos a los 6 meses no se observaron a los 18 meses de edad corregida, lo que evidencia un crecimiento de recuperación de la función de la vía respiratoria. (AU)

Influence of jacket tightness and pressure on raised lung volume forced expiratory maneuvers in infants.

While the use of the raised volume rapid thoraco-abdominal compression (RVRTC) technique has been shown to provide new insights into airway and pulmonary pathophysiology in infants, and appears to resemble the spirometric techniques used in older subjects, there is as yet no consensus regarding measurement procedures, which are known to vary considerably between laboratories (Gappa [1999] Pediatr Pulmonol 28:391-393). The aims of this study were to assess the effects of tightness of jacket fit, the efficiency with which pressure is transmitted from the jacket to the intrathoracic airways, and the effect of jacket pressure on parameters derived from the RVRTC technique. Paired forced expiratory maneuvers were performed in 20 infants with the jacket snugly or loosely wrapped around the infant's torso, and in a further 21 infants using "optimal" or a higher jacket pressure (P(j)) (1-2 kPa above "optimal" P(j)). When either a loosened jacket or a higher than "optimal" P(j) was used, forced expired flow at low lung volumes (FEF(75)) was significantly reduced by, on average, 8% and 7%, respectively. There were, however, minimal changes in forced vital capacity (FVC) or forced expired volume in 0.4 sec (FEV(0.4)). The observed changes may have been due to the increased pressure transmitted to the intrathoracic structures under these experimental conditions, and emphasize the need to assess optimal jacket pressure within each infant when using the RVRTC technique. In addition, when using a loosened jacket or a higher than "optimal" P(j), chest wall and upper airway reflexes such as glottic closure, peripheral airway closure, and negative flow dependence were more evident.

Effect of airway inflation pressure on forced expiratory maneuvers from raised lung volume in infants.

The raised lung volume technique is increasingly used to measure forced expiratory maneuvers in infants. However, there is no consensus regarding the optimal airway inflation pressure (P(inf)) required for such maneuvers, or the influence of small changes in P(inf) within and between infants. The aim of this study was to assess the effect of small differences (0.2-0.3 kPa) in P(inf) on forced vital capacity (FVC), forced expired volume in 0.5 sec (FEV(0.5)), and forced expired flow at 75% of vital capacity (FEF(75)), all derived from the raised volume rapid thoraco-abdominal compression (RVRTC) technique. Randomized paired forced expiratory maneuvers were obtained in 32 healthy infants ( 3.9-39.3 weeks old, 3.8-9.9 kg) with the safety pressure relief valve for P(inf) set to 2.7 kPa or 3.0 kPa (27 or 30 cm H(2)0). When mean (SD) P(inf) was increased by 8.4 (2.8)%, there was a significant (P < 0.01) increase in mean (SD) FVC, FEV(0.5), and FEF(75) by 5.8 (5.7)%, 6.1 (6)%, and 8.3 (16.2)%, respectively. In conclusion, relatively small differences in P(inf) will result in significant differences in FVC, FEV(0.5), and FEF(75) by RVRTC technique. Precision in setting and reporting the applied P(inf) is therefore essential, particularly if data are to be compared between centers.

Impact of ethnicity and extreme prematurity on infant pulmonary function.

The impact of birth before 27 completed weeks of gestation on infant pulmonary function (PF) was explored in a multi-ethnic population in comparison to more mature preterm controls (PTC) and healthy fullterm infants. Plethysmographic lung volume (FRCpleth ) and forced expired volume (FEV0.5 ) were obtained at ∼12 months post-term age in 52 extremely preterm (EP) infants (median [range] gestational age [GA]: 26 [23-27] weeks; 40% White mothers; 79% with BPD), 41 PTC (GA:35 [30-36] weeks; 37% White mothers) and 95 fullterm infants (GA:40 [37-42] weeks; 86% White mothers). Using reference equations based on identical equipment and techniques, results were expressed as z-scores to adjust for age, sex and body size. FEV0.5 was significantly lower in EP infants when compared with PTC (mean difference [95% CI]: -1.02[-1.60; -0.44] z-scores, P < 0.001), as was forced vital capacity (FVC) but there were no significant differences in FRCpleth or FEV0.5 /FVC ratio. FEV0.5 , FVC, and FEV0.5 /FVC were significantly lower in both preterm groups when compared with fullterm controls. On multivariable analyses of the combined preterm dataset: FEV0.5 at ∼1 year was 0.11 [0.05; 0.17] z-scores higher/week GA, and 1.28 (0.49; 2.08) z-scores lower in EP infants with prior BPD. Among non-white preterm infants, FEV0.5 was 0.70 (0.17; 1.24) z-scores lower, with similar reductions in FVC, such that there were no ethnic differences in FEV0.5 /FVC. Similar ethnic differences were observed among fullterm infants. These results confirm the negative impact of preterm birth on subsequent lung development, especially following a diagnosis of BPD, and emphasize the importance of taking ethnic background into account when interpreting results during infancy as in older subjects.

New reference equations to improve interpretation of infant lung function.

RATIONALE: With increasing use of infant pulmonary function tests (IPFTs) in both clinical and research studies, appropriate interpretation of results is essential. OBJECTIVES: To investigate the potential bias associated with "normalising" IPF by expressing results as a ratio of body size and to develop reference ranges for tidal breathing parameters, passive respiratory mechanics (compliance [Crs] and resistance [Rrs]) and plethysmographic functional residual capacity (FRCp ) for white infants during the first 2 years of life. METHODS: IPFTs were measured using the Jaeger BabyBody system and standardized protocols. Reference equations, adjusted for body size, age, and sex where appropriate, were created using multilevel modeling. RESULTS: The ratio of lung function to body length changes markedly with growth, thereby precluding its use for any outcome. While the ratio of tidal volume and Crs to body weight remained relatively constant with growth, this was not the case for FRCp . Even in healthy infants, a strong inverse relationship was observed between lung function/body weight and weight z-score which could distort interpretation of results in growth-restricted infants with lung disease, such as cystic fibrosis. Reference equations were derived from 153 healthy white infants on 232 test occasions (median age 35.5 weeks [range: 2.6-104.7]). Crown-heel length was the strongest predictor of IPF. CONCLUSIONS: When reporting IPF, use of size-corrected ratios should be discouraged, with interpretation instead based on appropriate reference equations. The current equations are applicable to white infants and young children up to 2 years of age, studied using the same commercially available equipment. The extent to which these equations are applicable to infants and young children of other ethnic backgrounds or who are tested with different equipment needs to be established.

Bronchodilator responsiveness using spirometry in healthy and asthmatic preschool children.

OBJECTIVE: To assess repeatability and reproducibility of spirometry measurements, and bronchodilator responsiveness (BDR), in healthy 3-6-year-old preschool children and those with asthma. DESIGN: Spirometry was performed before and 20 minutes after administering either inhaled placebo (for repeatability) or 400 µg salbutamol (for BDR) on two separate occasions (reproducibility) 3-23 days apart in asthmatic preschoolers and healthy controls. SETTINGS: Lung Function Laboratory, Hospital de Dona Estefania, Lisbon. PARTICIPANTS: Healthy preschool children and those with physician-diagnosed asthma, recruited from local Health Clinics and Outpatient Clinic. MAIN OUTCOME MEASURES: Paired measurements of forced expired volume in 0.75 s (FEV(0.75)) and forced mid-expiratory flows (FEF(25-75)). RESULTS: Technically successful baseline results were obtained in 86% of children assessed. Paired data were obtained in 43 asthmatic and 22 controls (median (range) age: 5.1 (3.4-6.8) years). Baseline FEV(0.75) was significantly lower in asthmatic children (mean (SD): 90 (15)% predicted) than in controls (102 (13) % predicted; p<0.001). Within-occasion coefficient of repeatability following placebo was similar in both groups, being 10.4% in asthma and 13.2% in controls for FEV(0.75). Following bronchodilator, FEV(0.75) increased significantly more in asthmatic preschoolers (mean (SD): 15.0 (12) %) than in controls (4.5 (5) %; p<0.001), with no significant difference between groups post-bronchodilator. Between-occasion variability was similar to within-day repeatability in controls, but almost twice as high in asthmatic children. CONCLUSIONS: BDR can be assessed reliably using FEV(0.75) in wheezy preschoolers, provided within-subject variability and responsiveness in health are taken into consideration.

Positive parental attitudes to participating in research involving newborn screened infants with CF.

BACKGROUND: Information regarding recruitment of infants to research studies following the diagnosis of cystic fibrosis (CF) via newborn screening (NBS) is not currently available. This study aimed to assess parental attitudes and the feasibility of recruiting and retaining both NBS infants with CF and healthy control infants to a longitudinal, observational study. METHODS: All infants underwent pulmonary function tests (PFTs) at ~3 and ~12months of age. Infants with CF had additional combined chest high resolution computed tomography (HRCT), bronchoscopy and broncho-alveolar lavage (BAL) at ~12months of age. Parental attitude questionnaires (PAQs) were administered to all parents following the ~3month PFTs and to parents of infants with CF after completion of all tests at ~12months. RESULTS: 86% (92/107) of families whose infant had CF consented to participate, of whom 92% had PFTs at ~3months of age with 99% of these having PFTs at ~12months of age. Recruitment of healthy controls was feasible but more challenging; 29% of those contacted agreed to participate; 73% of these had PFTs at ~3months of age; of whom 83% had repeated PFTs at ~12months of age. Completed PAQs were received from 71% of parents, (both of CF and healthy infants) at ~3months and from 58% parents of infants with CF at ~12months. Responses from the PAQs were generally positive, 95% of parents indicated they would recommend participation in such studies to other families. Discrepancies between responses at 3 and 12months suggested that parental understanding of what the research entailed developed during the course of the study. CONCLUSIONS: The high recruitment and retention rates for newly diagnosed CF NBS infants to this observational study are encouraging. These findings will help inform future study design both in the field of CF and other conditions diagnosed by NBS.

Potential misinterpretation of infant lung function unless prospective healthy controls are studied.

UNLABELLED: SUMMARY RATIONALE: Reliable interpretation of pulmonary function tests relies on appropriate reference data, which remain very limited for infants. OBJECTIVES: This study aimed to assess the validity of published reference equations for forced expiratory flow-volume (FEFV) data in infants when using current, commercially available equipment, and how this could impact on interpretation of results from infants with lung disease. METHODS: The Jaeger Masterscreen BabyBody (v4.67) equipment was used to perform partial and raised volume FEFV maneuvers in healthy infants and those with cystic fibrosis (CF). Results were initially expressed as Z-scores using published reference equations. Multilevel modeling was used to calculate differences, if any, from predicted scores in healthy infants. RESULTS: Data were available from 66 healthy full term infants on 89 test occasions; [median (range) postnatal age 49.4 (12-101) weeks. All FEFV outcomes were significantly lower than predicted, with mean (SD) Z-score differences of -0.4 (1.1) for FVC; -0.6 (1.0) for FEV(0.5); -1.0 (1.0) for FEF(25-75) and -1.4 (1.1) for V'(maxFRC). After adjustments using multilevel modeling, mean Z-scores were within 0.1 (SD approximately 1.0) predicted for all outcomes in healthy infants. Among 50 infants with CF, studied on 85 test occasions, results were "abnormal" (<-1.96 Z-scores) on 35 (41%) and 37 (45%) test occasions for FEV(0.5) and FEF(25-75), respectively, when using published equations. This fell to 24 (28%) and 20 (24%), respectively, after adjustment. CONCLUSIONS: Dependence on published equations for interpreting FEFV data in infants may lead to misinterpretation of lung function status, which could impact adversely both in the research setting and on clinical management. Use of a contemporary control group or establishment of equipment-specific reference data is essential for meaningful interpretation of infant lung function data.

Respiratory function during infancy in survivors of the INNOVO trial.

RATIONALE: Despite encouraging reports suggesting that inhaled nitric oxide (iNO) appear to improve outcome in hypoxemic term and near term infants by improving oxygenation and reducing need for ECMO, the long-term benefits of iNO remain unclear. This study aimed to compare lung function at approximately 1 year in infants who were and were not randomly allocated to iNO as part of their neonatal management for severe respiratory failure at birth. Furthermore, results were compared to lung function of healthy infants. METHODS: Maximal expiratory flow at functional residual capacity (V'maxFRC) was measured at approximately 1 year of age (corrected for any prematurity) in survivors of the INNOVO trial. Results were expressed as Z-scores, adjusted for sex and body size, based on data from healthy controls using identical techniques. RESULTS: Technically satisfactory results were obtained in 30 infants (53% < 34 weeks gestation), 19 of whom were randomized to receive iNO V'maxFRC. Z-score was significantly reduced in infants with prior respiratory failure, whether or not they had been allocated to iNO (mean (SD) Z-score: -2.0 (1.2) and -2.6 (1.1), respectively, 95% CI difference; iNO vs. no iNO: -0.3; 1.6, P = 0.2). There was significant respiratory morbidity in both groups during the first year of life. CONCLUSIONS: These results suggest that airway function remains reduced at 1 year of age following severe respiratory failure at birth, whether or not iNO is administered.

Airway function in infants treated with inhaled nitric oxide for persistent pulmonary hypertension.

RATIONALE: Inhaled nitric oxide (iNO), used for treatment of persistent pulmonary hypertension of newborn (PPHN), is an oxygen free radical with potential for lung injury. Deferring ECMO with iNO in these neonates could potentially have long-term detrimental effects on lung function. We studied respiratory morbidity (defined as occurrence of respiratory infections requiring treatment, episodes of wheezing, and/or need for ongoing medications following discharge) and airway function at 1 year postnatal age in term neonates treated with iNO but not ECMO for PPHN, and compared data from similar infants recruited to the UK ECMO Trial randomized to receive ECMO or conventional management (CM). METHODS: Maximal expiratory flow at FRC (V(') (maxFRC)) was measured in infants treated with iNO for PPHN (oxygenation index >or=25) at birth. RESULTS: V(') (maxFRC) was measured in 23 infants and expressed as z-scores, to adjust for sex and body size and compared to data from 71 (46 ECMO, 25 CM) infants studied at a similar age in the ECMO Trial. Respiratory morbidity was low in iNO group. V(') (maxFRC) z-score was lower than predicted in all groups (P < 0.001), with no significant difference between those treated with iNO [mean (SD) z-score: -1.65 (1.2)] and those treated with ECMO [-1.59 (1.2)] or CM [-2.1(1.0)]. Within iNO, ECMO and CM groups; 26%, 37% and 56%, respectively, had V(') (maxFRC) z-scores below normal. CONCLUSIONS: Respiratory outcome at 1 year in iNO treated neonates with moderately severe PPHN is encouraging, with no apparent increase in respiratory morbidity when compared to the general population. Sub-clinical reductions in airway function are evident at 1 year, suggesting that continuing efforts to minimize lung injury in the neonatal period are warranted to maximize lung health in later life.

Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests.

BACKGROUND: Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple-breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown. OBJECTIVES: To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco-abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls. METHODS: Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres. RESULTS: Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow-volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV(0.5) and FEF(25-75 )) than boys (mean (95% CI girls-boys): -1.2 (-2.1 to -0.3) for FEV(0.5) Z score; FEF(25-75): -1.2 (-2.2 to -0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed. CONCLUSIONS: These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.

Development of airway function in infancy after preterm delivery.

OBJECTIVE: To assess airway function at 1 year and compare this with similar measurements made shortly after birth in preterm infants without clinical neonatal respiratory disease. STUDY DESIGN: Infants born at