Kent Green

Ventilation inhomogeneity in children with primary ciliary dyskinesia

Background The lung clearance index (LCI) derived from the multiple breath inert gas washout (MBW) test reflects global ventilation distribution inhomogeneity. It is more sensitive than forced expiratory volume in 1 s (FEV1) for detecting abnormal airway function and correlates closely with structural lung damage in children with cystic fibrosis, which shares features with primary ciliary dyskinesia (PCD). Normalised phase III slope indices Scond and Sacin reflect function of the small conducting and acinar airways, respectively. The involvement of the peripheral airways assessed by MBW tests has not been previously described in PCD. Methods A cross-sectional MBW study was performed in 27 children and adolescents with verified PCD, all clinically stable and able to perform lung function tests. LCI, Scond (n=23) and Sacin (n=23) were derived from MBW using a mass spectrometer and sulfur hexafluoride as inert marker gas. MBW indices were compared with present age, age at diagnosis and spirometry findings, and were related to published normative values. Results LCI, Scond and Sacin were abnormal in 85%, 96% and 78% of patients with PCD and in 81%, 93% and 79%, respectively, of 13/27 subjects with normal FEV1. LCI and Sacin correlated significantly while Scond did not correlate with any other lung function parameters. None of the lung function measurements correlated with age or age at diagnosis. Conclusions PCD is characterised by marked peripheral airway dysfunction. MBW seems promising in the early detection of lung damage, even in young patients with PCD. The relationship of MBW indices to the outcome of long-term disease and their role in the management of PCD need to be assessed.

Aerobic Fitness in Children and Young Adults with Primary Ciliary Dyskinesia

Background Although aerobic fitness is regarded as an overall prognostic measure of morbidity and mortality, its evaluation in the chronic progressive sinopulmonary disease primary ciliary dyskinesia (PCD) has been infrequently and inconsistently reported. Here we assessed peak oxygen uptake (VO2peak) in a large well-characterized cohort of PCD patients, and explored whether VO2peak was associated with parameters of pulmonary function, self-reported physical limitations, and physical activity level. Methods VO2peak, spirometry, diffusing capacity, whole-body plethysmography, and nitrogen multiple breath inert gas washout (N2 MBW) were assessed in a cross-sectional, single-occasion study of clinically stable children and young adults with PCD. We used a questionnaire including self-reported physical limitations in everyday life or in vigorous activities, and estimation of weekly hours of strenuous physical activity. VO2peak in PCD patients was compared with that in matched, healthy control subjects and a national reference. Results Forty-four PCD patients aged 6–29 years exhibited reduced VO2peak compared to healthy controls (P<0.001) and the national reference. VO2peak was abnormal (z-score <–1.96) in 34% of PCD patients. Spirometric values, RV/TLC, and indices of N2 MBW were significantly abnormal, but VO2peak only correlated with FEV1 and DLCO/VA. VO2peak correlated with complaints of moderate or significant limitations in vigorous activities (P = 0.0001), exhibited by 39% of PCD patients. Conclusion One-third of PCD patients exhibited substantially lower aerobic fitness than healthy subjects. Aerobic fitness correlated with FEV1, DLCO/VA and self-reported complaints of limitations in vigorous physical activity. These findings are most likely explained by PCD pulmonary disease and its impact on pulmonary function and physical ability. Considering fitness as an important outcome and including regular strenuous physical activity in PCD treatment would probably altogether increase pulmonary clearance, lung function, aerobic fitness, and quality of life, and prevent lifestyle-related diseases.

Abbreviation modalities of nitrogen multiple-breath washout tests in school children with obstructed lung disease

Rationale: Nitrogen multiple‐breath washout (N2 MBW) is a promising tool for assessing early lung damage in children with chronic obstructive pulmonary disease, but it can be a time‐consuming procedure. We compared alternative test‐shortening endpoints with the most commonly reported N2 MBW outcome, the lung clearance index, calculated as lung volume turnovers required to reach 2.5% of the starting N2 concentration (LCI2.5). Methods: Cross‐sectional study of triplicate N2 MBW measurements obtained in cystic fibrosis (CF) patients (N = 60), primary ciliary dyskinesia (PCD) patients (N = 28), and matched healthy controls (N = 48) aged 5–18 years. Bland–Altman analysis was used to compare LCI2.5 with earlier LCI endpoints (3%, 4%, 5%, 7%, and 9% of starting N2 concentration), Cn@TO6 (defined as % of N2 starting concentration when reaching six lung volume turnovers), and LCI derived from only two N2 MBW runs in each session. N2 MBW endpoints were analyzed as z‐scores calculated from healthy controls. Results: In PCD, Cn@TO6 and LCI2.5 exhibited similar values (mean [95%CI] difference: 0.33 [−0.24; 0.90] z‐scores), reducing the test duration by one‐third (5.4 min; 95%CI: 4.0; 6.8). All other tested alternative endpoints exhibited increasing disagreement with increasing LCI2.5. With an average reduction in test duration of 40%, LCI2.5 derived from two runs exhibited good agreement in all children. Conclusions: Cn@TO6 may be suggested as a potential test‐shortening endpoint in school children with PCD. In CF, early test termination may reduce measurement power with advancing pulmonary disease, suggesting differences in underlying pathophysiology. Two technically acceptable N2 MBW runs may be sufficient in school children irrespective of diagnosis with CF or PCD. Pediatr Pulmonol. 2016;51:624–632.

Improved air trapping evaluation in chest computed tomography in children with cystic fibrosis using real-time spirometric monitoring and biofeedback☆

BACKGROUND The quality of chest Computed Tomography (CT) images in children is dependent upon a sufficient breath hold during CT scanning. This study evaluates the influence of spirometric breath hold monitoring with biofeedback software on inspiratory and expiratory chest CT lung density measures, and on trapped air (TA) scoring in children with cystic fibrosis (CF). This is important because TA is an important component of early and progressive CF lung disease. METHODS A cross sectional comparison study was completed for chest CT imaging in two cohorts of CF children with comparable disease severity, using spirometric breath hold monitoring and biofeedback software (Copenhagen (COP)) or unmonitored breath hold manoeuvres (Gothenburg (GOT)). Inspiratory-expiratory lung density differences were calculated, and TA was scored to assess the difference between the two cohorts. RESULTS Eighty-four chest CTs were evaluated. Mean (95%CI) change in inspiratory-expiratory lung density differences was 436 Hounsfield Units (HU) (408 to 464) in the COP cohort with spirometric breath hold monitoring versus 229 HU (188 to 269) in the GOT cohort with unmonitored breath hold manoeuvres (p<0.0001). The Mean TA (95%CI) score was 6.93 (6.05 to 7.82) in COP patients and 3.81 (2.89 to 4.73) in GOT (p<0.0001) patients. CONCLUSIONS In children with comparable CF lung disease, spirometric breath hold monitoring during examination yielded a large difference in lung volume between inhalation and exhalation, and allowed for a significantly greater measured change in lung density and TA score, compared to unmonitored breath hold maneuvers. This has implications to the clinical use of chest CT, especially in children with early CF lung disease.

Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis

BACKGROUND Knowledge of between-session variability of nitrogen multiple-breath washout (N2MBW) indices is crucial when designing longitudinal interventional studies and in disease monitoring using N2MBW as end-point. Such information is currently sparse. METHODS Monthly triplets of N2MBW were prospectively obtained from 14 children with CF during one year. Linear mixed models were used to analyze variability. Our aim was to assess between-session variability of N2MBW indices from repeated measurements and compare LCI derived from different software packages currently in use (TestPoint® vs. Spiroware®). RESULTS Baseline LCI (median; range) was 9.37 (6.82; 12.08). Between-session differences in LCI measurements were up to 25%. Intra Class Correlation-Coefficient was 0.82. There was no systematic difference between LCI measurements derived from the two software packages (p=0.18); however, variability was significantly higher using Spiroware®. CONCLUSIONS We report between-session variability of LCI using N2MBW in school-age children and adolescents with CF. LCI changes exceeding 25% may be considered clinically relevant. TestPoint® and Spiroware® can be used interchangeably in longitudinal studies.

Fitness and lung function in children with primary ciliary dyskinesia and cystic fibrosis

BACKGROUND Peak oxygen uptake (VO2peak) is associated with morbidity and mortality in health and disease, and provides important information of global physical health not achieved from standard pulmonary function tests. Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are genetically determined diseases involving different basic defects, but both showing impaired mucociliary clearance leading to chronic infections and pulmonary destruction early in life. PCD is generally considered a milder disease than CF and it is hypothesized that children with CF would have consistently lower VO2peak and pulmonary function than children with PCD. METHODS We performed a prospective, observational single-center, clinical cohort study of VO2peak and pulmonary function in age and gender matched schoolchildren, at two occasions 12 months apart. RESULTS VO2peak was persistently (at baseline and after 12 months) and significantly reduced in the 22 patients with PCD (z-score = -0.89 and -1.0) and 24 with CF (z-score = -0.94 and -1.1), included in the study. Abnormal VO2peak was detected in a larger proportion of children with PCD (≈30%) than CF (≈13%). Moreover, children with PCD exhibited persistently lower FEV1 (p < 0.0001 at first visit and p = 0.001 at second visit) while FEF25-75 and FVC differed only at baseline. Indeed, a retrospective analysis comparing lung function over the last year in our entire PCD and CF populations between 6 and 18 years of age, revealed lower values in patients with PCD (FEV1 z-score, p = 0.0004, FVC z-score p < 0.0001, FEF25-75 z-score p = 0.008). CONCLUSION This is the first report indicating that cardiopulmonary fitness is equally and consistently reduced in both children with PCD and CF along with a consistent lower pulmonary function in PCD compared with CF. A certain reservation for possible selection bias and the small number of patients is necessary. However, increased focus on early diagnosis, evidence-based treatment regimens and close clinical monitoring in PCD are warranted.

Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis

ABSTRACT Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: Sixty-four children with CF, median age (range) of 12.7 (6.4–18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4–46.8) with gas trapping of 40.7% (3.7–100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections (N = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% (p < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions: The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with increased scores in lung changes. Further investigation of impact of infections with different microorganisms on extent and progression of structural CF lung disease is needed.