Lung function at 16-19 years in males and females born very prematurely.

OBJECTIVES: To determine if there were differences in lung function at 16-19 years of age between males and females born very prematurely. WORKING HYPOTHESIS: Females compared with males would have superior lung function and exercise capacity. STUDY DESIGN: Cohort study. PATIENT-SUBJECT SELECTION: Those born at less than 29 weeks of gestational age. METHODOLOGY: Lung function testing (spirometry, oscillometry, diffusion capacity, lung clearance index, and plethysmography), a shuttle sprint test for exercise capacity, and a respiratory symptoms questionnaire. RESULTS: Amongst 150 participants, males had poorer lung function compared with females with mean z score differences (95% CI [confidence interval]) after adjustment: forced expiratory flow at 75% (FEF75 ) (-0.60 [-0.97,-0.24]), forced expiratory flow at 50% (FEF50 ) (-0.39 [-0.72,-0.07]), forced expiratory flow at 25%-75% (FEF25-75 ) (-0.62 [-0.98,-0.26]), the ratio of the forced expiratory volume in the first one second to the forced vital capacity of the lungs (FEV1 :FVC ratio) (-0.71 [-1.09,-0.34]), diffusing capacity of the lungs for carbon monoxide (DLCO) (-0.41 [-0.78,-0.03]), diffusing capacity of the lung for carbon monoxide divided by alveolar volume (DLCO/VA) (-0.57 [-0.86,-0.28]). Exercise capacity and self-reported exercise were both significantly better in males than females (46% males achieving between 1250 and 1500 m shuttle sprint distance vs. 4.8% females) and 74% males versus 67% females undertaking some exercise. There were no significant differences by sex in the prevalence of either wheeze or current asthma. CONCLUSIONS: Males had poorer lung function than females at age 16-19 years, but their exercise capacity was superior to females.

Influence of bronchopulmonary dysplasia on lung function in adolescents who were born extremely prematurely.

OBJECTIVES: To assess if a previous diagnosis of bronchopulmonary dysplasia (BPD) was associated with poorer lung function at 16 to 19 years of age, regardless of whether postnatal corticosteroids had been administered. WORKING HYPOTHESIS: Infants with BPD will have poorer lung function at 16 to 19 years of age. STUDY DESIGN: Prospective follow-up study. PATIENT-SUBJECT SELECTION: One hundred and sixty-one participants aged between 16 and 19 years who were born at less than 29 weeks of gestation; 87 had had BPD. METHODOLOGY: Lung function was assessed by spirometry (FEV1 , FVC, FEV1 /FVC, FEF75 , FEF50 , FEF25 , FEF25 -75 , PEF), impulse oscillometry (R5Hz and R20Hz), plethysmography (FRCpleth , TLCpleth , RVpleth ), diffusion capacity of the lungs for carbon monoxide (DL CO, DL CO/VA) and lung clearance index (LCI). Questionnaires were used to quantify respiratory symptoms and a shuttle sprint test to assess exercise capacity. RESULTS: At 16 to 19 years, those who had had a diagnosis of BPD had poorer airway function (FEV1 , FEF75 , FEF50 , FEF25 -75 ) compared to those without. FVC and DL CO were also poorer in those who had BPD. Those differences remained significant after adjusting for sex, gestational age, and maternal smoking. When excluding those who had received postnatal corticosteroids, differences remained significant in FEV1 , FVC, and FEF75 . There were no significant differences in exercise capacity or respiratory symptoms between those with and without BPD. CONCLUSIONS: In adolescents and young adults born prematurely, those who had BPD had poorer lung function compared to those without, regardless of whether they had received postnatal corticosteroids.

Longitudinal changes in lung function in very prematurely born young people receiving high-frequency oscillation or conventional ventilation from birth.

OBJECTIVE: To examine changes in lung function over time in extremely prematurely born adolescents. WORKING HYPOTHESIS: Changes in lung function during adolescence would vary by ventilation mode immediately after birth. STUDY DESIGN: Longitudinal follow-up study. PATIENT SUBJECT SELECTION: Participants from the United Kingdom Oscillation Study who were randomized at birth to high-frequency oscillation (HFO) or conventional ventilation (CV) were assessed at 11-14 years (n = 319) and at 16-19 years (n = 159). METHODOLOGY: Forced expiratory flow (FEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and lung volumes including functional residual capacity (FRC) were reported as z-scores. The diffusion capacity of the lungs for carbon monoxide (DLCO) was measured. Lung function trajectories were compared by mode of ventilation using mixed models. Changes in z-scores were scaled to 5-year average follow-up. RESULTS: There were significant changes in the mean FEF75, FEF50, FEF25, FEV1, FVC, and DLCO z-scores within the CV and HFO cohorts, but no significant differences in the changes between the two groups. The mean FRC z-score increased in both groups, with an average change of greater than one z-score. The mean FEV1/FVC z-score increased significantly in the CV group, but not in the HFO group (difference in slopes: p = 0.02). Across the population, deterioration in lung function was associated with male sex, white ethnicity, lower gestational age at birth, postnatal corticosteroids, oxygen dependency at 36 weeks postmenstrual age, and lower birth weight, but not ventilation mode. CONCLUSIONS: There was little evidence that the mode of ventilation affected changes in lung function over time.

Intrauterine growth retardation and lung function of very prematurely born young people.

OBJECTIVES: To assess if intrauterine growth retardation (IUGR) was associated with reduced lung function at 16-19 years. WORKING HYPOTHESIS: Very prematurely born young people who had IUGR would have reduced lung function postpuberty. STUDY DESIGN: Prospective follow-up study. PATIENT-SUBJECT SELECTION: One hundred and fifty-nine 16-19 year olds born before 29 weeks of gestation; 37 had IUGR. METHODOLOGY: Lung function tests were performed: spirometry was used to assess forced expiratory volume in one second (FEV1), forced expiratory flow at 75%, 50% and 25% of expired vital capacity (FEF75, FEF50 and FEF25), peak expiratory flow (PEF) and forced vital capacity (FVC). Functional residual capacity (FRCpleth) total lung capacity (TLCpleth) and residual volume (RVpleth) were measured. Alveolar function was assessed by diffusion capacity within the lungs of carbon monoxide (DLCO). Impulse oscillometry was used to assess respiratory resistance and lung clearance index to assess ventilation homogeneity. Exercise capacity was assessed using a shuttle sprint test. RESULTS: After adjustment for BMI, the mean FEV-1/FVC, FEF75, FEF25-75, FRCpleth and RVpleth were poorer in those who had had IUGR, with differences between 0.56 and 0.75 z-scores. After further adjustment for BPD and postnatal corticosteroid use, only the difference in RVpleth z-scores remained statistically significant, adjusted difference (95% CI): 0.66 (0.18,1.13). Exercise capacity was lower in those with IUGR and this was more pronounced in males (p=0.04). CONCLUSIONS: At 16-19 years of age, those who had IUGR had poorer lung function and exercise capacity compared with those with adequate intrauterine growth.

Postnatal dexamethasone exposure and lung function in adolescents born very prematurely.

We previously demonstrated corticosteroid administration on the neonatal intensive care unit was associated with reduced lung function at 11 to 14 years of age in children born very prematurely. The objective of this observational study was to assess if lung function remained impaired at 16 to 19 years of age in those who had received postnatal corticosteroids and whether the trajectory of lung function with increasing age differed between those who had and had not received corticosteroids. One hundred and fifty-nine children born prior to 29 weeks of gestational age had comprehensive lung function measurements; 49 had received postnatal dexamethasone. Lung function outcomes were compared between those who had and had not received postnatal dexamethasone after adjustment for neonatal factors. Forced expiratory flow at 75%, 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes (total lung capacity and residual volume) were assessed. The majority of results were significantly lower in those who received dexamethasone (between 0.61 to 0.78 standard deviations). Lung function reduced as the number of courses of dexamethasone increased. Between 11 and 14 years and 16 to 19 years, lung function improved in the unexposed group, but forced expiratory flow at 75% of the expired vital capacity and forced expiratory volume in one second deteriorated in those who had received postnatal corticosteroids (p = 0.0006). These results suggest that prematurely born young people who received postnatal corticosteroids may be at risk of premature onset of chronic obstructive pulmonary disease.

Lung function and exercise capacity in prematurely born young people.

OBJECTIVES: To determine if lung function abnormalities in young people born very prematurely routinely exposed to antenatal corticosteroids and postnatal surfactant were associated with reduced exercise capacity. WORKING HYPOTHESIS: In the current era, lung function abnormalities would not be associated with exercise intolerance STUDY DESIGN: Follow-up of young people from the United Kingdom Oscillation study (UKOS). PATIENT-SUBJECT SELECTION: One hundred twenty-six young people of 797 recruited to UKOS, born at a mean gestational age of 27 weeks were assessed at a mean age of 17 years. METHODOLOGY: Forced expiratory flow at 75% of the expired vital capacity (FEF75 ), forced expiratory volume in 1 second (FEV1 ) and lung volumes (forced vital capacity [FVC]) and residual volume (RV) and functional residual capacity (FRCpleth ) were assessed. Abnormal lung function was below the fifth centile and very abnormal lung function below the 2.5th centile. Exercise capacity was assessed using a modified shuttle sprint test and self-reported hours of exercise. RESULTS: Thirty-nine young people had an abnormal FEF75 with an adjusted reduction in sprint distance of 114 m (P = .018) and an adjusted difference in self-reported exercise of 0.73 hours (P = .036). Twenty-seven young people had a very abnormal FEF75 with an adjusted reduction in sprint distance of 159 m (P = .002) and adjusted reduction in self-reported exercise of 1.15 hours (P = .002). CONCLUSION: Very prematurely born young people with abnormal airway function had a significant reduction in exercise capacity.

Lung function and respiratory outcomes in teenage boys and girls born very prematurely.

OBJECTIVES: Male sex in prematurely born infants has been associated with worse respiratory outcomes in early childhood. WORKING HYPOTHESIS: Respiratory outcomes at 11 to 14 years of age in children born very prematurely and routinely exposed to antenatal corticosteroids and postnatal surfactant would differ according to sex. STUDY DESIGN: Analysis of follow-up data. PATIENT-SUBJECT SELECTION: Three hundred and nineteen children born before 29 weeks of gestational age from the United Kingdom Oscillation Study. METHODOLOGY: Spirometry was used to assess forced expiratory flow at 75%, 50%, and 25% of expired vital capacity (FEF75 , FEF50 , and FEF25 ), forced expiratory volume in 1 second (FEV1 ), peak expiratory flow (PEF), and forced vital capacity (FVC). Lung volumes were measured using a helium dilution technique (FRCHe ) and by plethysmography (FRCpleth ). Total lung capacity (TLC) and residual volume (RV) were calculated. Mean lung function measurements were compared using linear mixed models and reported as unadjusted and adjusted for neonatal and age 11 to 14 years factors. The participants also completed health questionnaires and provided a urine sample for assessment of passive or active smoking. RESULTS: Three (FEF25 , FEF25-75 , FEV1 ) lung function measures showed significant differences in favor of females after adjustment. The percentage of children with abnormal lung function (below 5th centile for normal) had adjusted differences between 10 and 30 percentage points, for example, for FEF25 15% females compared with 26% males. CONCLUSIONS: Among extremely prematurely born school children airway function was significantly worse in males.

ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study.

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 × 10-4) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.

Nutritional status and pulmonary outcome in children and young people with cystic fibrosis.

BACKGROUND: Nutrition is closely related to mortality and pulmonary and respiratory muscle function in cystic fibrosis (CF) patients. We initially validated results from a bioelectrical impedance device against dual energy x-ray absorptiometry (DEXA). We then determined whether fat free mass assessed by a portable impedance device rather than body mass index (BMI) better correlated with pulmonary function, respiratory muscle strength and exercise capacity in CF patients. METHODS: Eighteen young people and adults (median age 19, range 12-39 years) with CF had dual energy X-ray absorptiometry and direct segmental multi-frequency impedance analysis. Body composition, pulmonary function, respiratory muscle function and exercise tolerance using the impedance device were measured in 29 young people with CF with median age 15 (range 12-19) years. MAIN FINDINGS: There was a significant correlation between impedance and absorptiometry results (r2 = 0.947). Fat free mass correlated with the forced vital capacity z-score (r = 0.442, p = 0.016), maximal inspiratory pressure (r = 0.451, p = 0.014) and exercise tolerance (r = 0. 707, p < 0.001). BMI z-scores did not significantly correlate with pulmonary or respiratory muscle function. Subjects with a fat free mass z-score of ≤2 had a lower forced expiratory volume in 1 s z-score (p = 0.007), lower forced vital capacity z-score (p = 0.001), higher residual volume z-score (p = 0.042), lower maximal inspiratory pressure (p = 0.039), more days of intravenous antibiotics per year (p = 0.016) and a higher rate of chronic infections (p = 0.006). PRINCIPAL CONCLUSIONS: Fat-free mass measured by impedance correlated better with pulmonary and respiratory muscle function and exercise capacity than BMI.

Effect of dexamethasone exposure on the neonatal unit on the school age lung function of children born very prematurely.

The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23-28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up.

Predicting healthcare outcomes in prematurely born infants using cluster analysis.

AIMS: Prematurely born infants are at high risk of respiratory morbidity following neonatal unit discharge, though prediction of outcomes is challenging. We have tested the hypothesis that cluster analysis would identify discrete groups of prematurely born infants with differing respiratory outcomes during infancy. METHODS: A total of 168 infants (median (IQR) gestational age 33 (31-34) weeks) were recruited in the neonatal period from consecutive births in a tertiary neonatal unit. The baseline characteristics of the infants were used to classify them into hierarchical agglomerative clusters. Rates of viral lower respiratory tract infections (LRTIs) were recorded for 151 infants in the first year after birth. RESULTS: Infants could be classified according to birth weight and duration of neonatal invasive mechanical ventilation (MV) into three clusters. Cluster one (MV ≤5 days) had few LRTIs. Clusters two and three (both MV ≥6 days, but BW ≥or <882 g respectively), had significantly higher LRTI rates. Cluster two had a higher proportion of infants experiencing respiratory syncytial virus LRTIs (P = 0.01) and cluster three a higher proportion of rhinovirus LRTIs (P < 0.001) CONCLUSIONS: Readily available clinical data allowed classification of prematurely born infants into one of three distinct groups with differing subsequent respiratory morbidity in infancy.

Longitudinal assessment of lung function in extremely prematurely born children.

OBJECTIVES: To assess longitudinally small airway function in children born extremely prematurely and whether there was a correlation between airway function in infancy and at 11-14 years. WORKING HYPOTHESES: There would be tracking of airways obstruction and small airway function would deteriorate during childhood in those born extremely prematurely. STUDY DESIGN: A longitudinal study. PATIENT-SUBJECT SELECTION: Thirty-five children with a mean gestational age of 26 weeks had lung function assessed at 1 year corrected and 11-14 years of age. METHODOLOGY: Lung volumes were measured by helium gas dilution (FRCHe ) and plethysmography (FRCpleth ) and small airway function assessed by calculating the FRCHe :FRCpleth ratio. Airway function was assessed at 1 year corrected by measurement of airway resistance (Raw ) and at 11-14 years by assessment of Raw , forced expiratory flow from 75% of vital capacity (FEF75 ), and forced expiratory volume at one second (FEV1 ). RESULTS: At the first assessment, the children had a mean (SD) FRCHe :FRCpleth of 0.90 (0.13) and at the second, 0.83 (0.12) (P = 0.035). There was a significant 0.54% decrease (95%CI: -1.02%, -0.06%) in FRCHe :FRCpleth for increased age per year after adjusting for birth weight, gestational age, sex, and bronchopulmonary dysplasia (P = 0.027). There were significant correlations between Raw at the first assessment and Raw (P = 0.012), FEF75 (P = 0.034), and FEV1 (P = 0.04) at 11-14 years. CONCLUSIONS: These results demonstrate in those born extremely prematurely there is tracking of airway function during childhood.

The influence of dilution on the offline measurement of exhaled nitric oxide.

OBJECTIVE: Measurement of fractional exhaled nitric oxide (FeNO) is used to determine the presence and severity of eosinophilic airway inflammation in asthma and other wheezing illnesses. The gold standard of online measurement during a single prolonged exhalation is not suitable for use in young children. The international guidelines for offline measurements recommend collection of exhaled gas in an appropriate reservoir for later analysis in young children. The apparatus required for gas collection, however, creates dead space within the system, which may result in sample dilution and hence inaccuracy. Our objective was to investigate the effect such dilution might have on the accuracy of offline FeNO by comparing the results to online results. APPROACH: Thirty-five adult subjects without respiratory disease underwent online measurement of FeNO and, thereafter, undertook offline FeNO measurements via exhalation into a collection reservoir using one, five or ten inhalation-exhalation cycles. Fifteen of the subjects also exhaled using the five-breath technique via apparatus with additional dead space. An equation incorporating dead space volume and the number of breaths was used to predict the degree of dilution; the predicted results were compared to the measured results. MAIN RESULTS: The median (IQR) FeNO from a one-breath technique (22 (15-28) ppb was not significantly different to online values (19 (12-27) ppb, p = 1.00), but the results from the five-breath technique (11 (4-19) ppb, p < 0.0001), the ten-breath technique (6 (4-15) ppb, p < 0.0001) and the additional dead space experiment (6 (3-8) ppb, p = 0.0006) were significantly lower than online FeNO. Measured values were consistently significantly different to those predicted by the dilution equation, even when incorporating the exact exhaled volume of gas. SIGNIFICANCE: Offline FeNO results may be inaccurate when subjects are unable to fill the collection reservoir with a single exhalation, thus the technique may not be suitable for preschool children.

Heterogeneity of respiratory disease in children and young adults with sickle cell disease.

To detect and characterise different phenotypes of respiratory disease in children and young adults with sickle cell disease (SCD), 11 lung function and haematological biomarkers were analysed using k-means cluster analysis in a cohort of 114 subjects with SCD aged between 5 and 27 years. Three clusters were detected: cluster 1 had elevated pulmonary capillary blood volume, mixed obstructive/restrictive lung disease, hypoxia and moderately severe anaemia; cluster 2 were older patients with restrictive lung disease; and cluster 3 were younger patients with obstructive lung disease, elevated serum lactate dehydrogenase and bronchodilator reversibility. These results may inform more personalised management strategies to improve outcomes.

Parasternal intercostal muscle activity during methacholine-induced bronchoconstriction.

NEW FINDINGS: What is the central question of this study? The parasternal intercostal electromyogram (EMGpara) is known to provide an accurate, non-invasive index of respiratory load-capacity balance. Although relationships between EMGpara and both airflow obstruction and hyperinflation have been shown, the independent contribution of each factor has not been examined. What is the main finding and its importance? Reductions in airway calibre and inspiratory capacity along with increases in EMGpara were induced via methacholine challenge. A strong inverse relationship was observed between EMGpara and airway obstruction, with no influence of inspiratory capacity. These data suggest that EMGpara is more strongly influenced by airway calibre than by changes in end-expiratory lung volume during airway challenge testing. Neural respiratory drive, measured via the parasternal intercostal electromyogram (EMGpara), provides a non-invasive index of the load-capacity balance of the respiratory muscle pump. Previous studies in patients with obstructive lung disease have shown strong relationships between EMGpara and the extent of both airflow obstruction and hyperinflation. The relative influence of the two factors has not, however, been described. Airflow obstruction was induced via methacholine challenge testing in 25 adult humans. Forced expiratory volume in 1 s (FEV1 ) and surface EMGpara during tidal breathing were measured after each dose, with 20 of the participants also undergoing measurements of inspiratory capacity (IC) at each stage. Linear mixed model analysis was used to assess dose-wise changes in FEV1 and EMGpara, and thereafter to determine the influence of changes in FEV1 and IC on change in EMGpara. Median (interquartile range) FEV1 decreased significantly [from 96.00 (80.00-122.30) to 67.80 (37.98-92.27)% predicted, P < 0.0001] and EMGpara increased significantly [from 5.37 (2.25-8.92) to 6.27 (3.37-19.60) µV, P < 0.0001] from baseline to end of test. Linear mixed model analysis showed a significant interaction between methacholine dose and induced change in EMGpara, with an increase in EMGpara of 0.24 (95% confidence interval 0.11-0.37) µV per methacholine dose2 . Change in FEV1 further influenced this relationship [increase in slope of 0.002 (0.004-0.001) µV dose-2 per % predicted fall in FEV1 , P = 0.011], but not with change in IC. These data suggest that bronchoconstriction exerts a more potent influence on levels of EMGpara than changes in end-expiratory lung volume during methacholine challenge.

Respiratory load perception in overweight and asthmatic children.

Overweight asthmatic children report greater symptoms than normal weight asthmatics, despite comparable airflow obstruction. This has been widely assumed to be due to heightened perception of respiratory effort. Three groups of children (healthy weight controls, healthy weight asthmatics, overweight asthmatics) rated perceived respiratory effort throughout an inspiratory resistive loading protocol. Parasternal intercostal electromyogram was used as an objective marker of respiratory load; this was expressed relative to tidal volume and reported as a ratio of the baseline value (neuroventilatory activity ratio (NVEAR)). Significant increases in perception scores (p<0.0001), and decreases in NVEAR (p<0.0001) were observed from lowest to highest resistive load. Higher BMI increased overall perception scores, with no influence of asthma or BMI-for-age percentile on the resistance-perception relationships. These data, indicating elevated overall respiratory effort in overweight asthmatic children but comparable responses to dynamic changes in load, suggest that the greater disease burden in overweight asthmatic children may be due to altered respiratory mechanics associated with increased body mass.

Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) often have obstructive lung function abnormalities which could be due to asthma or increased pulmonary blood volume; it is important to determine the underlying mechanism to direct appropriate treatment. In asthmatics, exhaled nitric oxide (FeNO) is elevated. FeNO, however, can also be raised due to increased alveolar production. Our aim, therefore, was to determine if airway or alveolar NO production differed between SCD children and ethnic and age-matched controls. METHODS: Lung function, airway NO flux and alveolar NO production, and effective pulmonary blood flow were assessed in 18 SCD children and 18 ethnic and age-matched controls. RESULTS: The SCD children compared to the controls had a higher respiratory system resistance (P = 0.0008), alveolar NO production (P = 0.0224), and pulmonary blood flow (P < 0.0001), but not airway NO flux. There was no significant correlation between FeNO and respiratory system resistance in either group, but in the SCD children, there were correlations between alveolar NO production (P = 0.0006) and concentration (P < 0.0001) and pulmonary blood flow. CONCLUSION: Airway NO flux was not elevated in the SCD children nor correlated with airways obstruction, suggesting that airways obstruction, at least in some SCD children, is not due to asthma.

Lung function, transfusion, pulmonary capillary blood volume and sickle cell disease.

Lung function abnormalities occur in children with sickle cell disease (SCD) and may be associated with elevated pulmonary blood volume. To investigate that association, we determined whether blood transfusion in SCD children acutely increased pulmonary capillary blood volume (PCBV) and increased respiratory system resistance (Rrs5). Measurements of Rrs5 and spirometry were made before and after blood transfusion in 18 children, median age 14.2 (6.6-18.5) years. Diffusing capacity for carbon monoxide and nitric oxide were assessed to calculate the PCBV. Post transfusion, the median Rrs5 had increased from 127.4 to 141.3% predicted (p<0.0001) and pulmonary capillary blood volume from 39.7 to 64.1 ml/m2 (p<0.0001); forced expiratory volume in one second (p=0.0056) and vital capacity (p=0.0008) decreased. The increase in Rrs5 correlated with the increase in PCBV (r=0.50, p=0.0493). Increased pulmonary capillary blood volume may at least partially explain the lung function abnormalities in SCD children.

Longitudinal assessment of lung function in children with sickle cell disease.

OBJECTIVES: To prospectively assess longitudinal lung function in children with sickle cell disease (SCD). WORKING HYPOTHESIS: Lung function in SCD children deteriorates with increasing age and the decline is more marked in younger children who have recently suffered ACS episodes. STUDY DESIGN: Two prospective longitudinal studies. PATIENT-SUBJECT SELECTION: Two cohorts of SCD children and age and ethnic matched controls were recruited. Cohort One (47 SCD and 26 controls) had a median age of 8.8 years and follow up of 2 years and Cohort Two (45 SCD and 26 controls) a median age of 10.2 years and follow up of 10 years. METHODOLOGY: Forced expiratory volume in one second (FEV1 ), vital capacity (VC), forced expiratory flow between 25% and 75% of VC (FEF 25-75 ), total lung capacity (TLC) and residual volume (RV) were measured on two occasions. RESULTS: In both groups of SCD children, lung function declined significantly, but in neither control group. ACS episodes were more frequent during the follow up period in Cohort One than Cohort Two (P < 0.0001). The rate of decline was greater in Cohort One than Cohort Two for FEV1 (P = 0.008), VC (P = 0.001), FEF25-75 (P = 0.030), TLC (P = 0.004), and RV (P = 0.043). In Cohort Two restrictive abnormalities were more common at follow up (P = 0.006). CONCLUSIONS: Lung function deteriorated with increasing age in SCD children and the rate of decline was greater in younger children in whom ACS episodes were more common. Pediatr Pulmonol. 2016;51:717-723. © 2015 Wiley Periodicals, Inc.