Assessing gastro-intestinal related quality of life in cystic fibrosis: Validation of PedsQL GI in children and their parents.

BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF. METHODS: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months. RESULTS: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20). CONCLUSIONS: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials.

Home videos of cystic fibrosis patients using tobramycin inhalation powder: Relation of flow and cough.

BACKGROUND: Many cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa are on maintenance tobramycin inhalation therapy. Cough is reported as a side effect of tobramycin inhalation powder (TIP) in 48% of the patients. Objectives of this study were to investigate the association between the inspiratory flow of TIP and cough and to study the inhalation technique. We hypothesized that cough is related to a fast inhalation. MATERIALS AND METHODS: In this prospective observational study, CF patients ≥ 6 years old on TIP maintenance therapy from four Dutch CF centers were visited twice at home. Video recordings were obtained and peak inspiratory flow (PIF) was recorded while patients inhaled TIP. Between the two home visits, the patients made three additional videos. CF questionnaire-revised, spirometry data, and computed tomography scan were collected. Two observers scored the videos for PIF, cough, and mistakes in inhalation technique. The associations between PIF and cough were analyzed using a logistic mixed-effects model accounting for FEV1 % predicted and capsule number. RESULTS: Twenty patients were included, median age 22 (18-28) years. No significant associations were found between PIF and cough. The risk of cough was highest after inhalation of the first capsule when compared to the second, third, and fourth capsule (P ≤ .015). Fourteen patients (70%) coughed at least once during TIP inhalation. A breath-hold of less than 5 seconds after inhalation and no deep expiration before inhalation were the most commonly observed mistakes. CONCLUSION: PIF is not related to cough in CF patients using TIP.

Clinical validation of an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy through a prospective interventional study in paediatric patients with Cystic Fibrosis.

BACKGROUND: A method to adjust Pancreatic Enzyme Replacement Therapy in Cystic Fibrosis is not currently available. OBJECTIVES: To assess the in vivo efficacy of a method to adjust the dose of enzymatic supplement in CF extrapolated from previous in vitro digestion studies (theoretical optimal dose, TOD). Secondly, to assess how individual patient characteristics influence the expected coefficient of fat absorption (CFA) and thus to identify an individual correction factor to improve TOD. METHODS: A prospective interventional study in 43 paediatric patients with CF from 5 European centres. They followed a 24h fixed diet with the theoretical optimal dose for each meal. Faecal collection was carried out between colorimetric markers in order to include all the faeces corresponding to the fixed diet. Beta regression models were applied to assess the associations of individual patient characteristics with the CFA. RESULTS: Median CFA was 90% (84, 94% 1st, 3rd Q.) with no significant differences among centres. Intestinal transit time was positively associated with CFA (p = 0.007), but no statistical associations were found with and age, gender, phenotype or BMI. Regression model showed no improvement of the in vitro predicted theoretical optimal dose when taking individual patient characteristics into account. CONCLUSION: Strict adherence to the theoretical optimal dose of enzymatic supplement for a prescribed meal, led to median CFA levels at the clinical target of 90% with a low variability between patients. The proposed method can be considered as a first approach for an evidence-based method in PERT dosing based on food characteristics. Results have to be confirmed in free dietary settings.

Pulmonary ventilation and micro-structural findings in congenital diaphragmatic hernia.

BACKGROUND: With increasing survival of patients with more severe forms of congenital diaphragmatic hernia (CDH) and risk of long-term respiratory morbidity, studies on lung morphology are needed. We used hyperpolarised (3) He MRI and anatomical (1) H MRI in a cohort of young adult CDH patients to image regional lung ventilation and microstructure, focusing on morphological and micro-structural (alveolar) abnormalities. METHODS: Nine patients with left-sided CDH, born 1975-1993, were studied. Regional ventilation was imaged with hyperpolarised (3) He MRI, and the (3) He apparent diffusion coefficient (ADC) was computed separately for the ipsilateral and contralateral lungs. (1) H MRI was used to image lung anatomy, total lung volume and motion during free-breathing. RESULTS: (3) He MRI showed ventilation abnormalities in six patients, ranging from a single ipsilateral ventilation defect (3 patients) to multiple ventilation defects in both lungs (one patient treated with extra corporeal membrane oxygenation). In eight patients, (3) He ADC values for the ipsilateral lung were significantly higher than those for the contralateral lung. CONCLUSIONS: Functional and micro-structural changes persist into adulthood in most CDH patients. Ipsilateral elevated (3) He ADC values are consistent with enlargement of mean dimensions of the confining lung micro-structure at the alveolar level.

Tracking CF disease progression with CT and respiratory symptoms in a cohort of children aged 6-19 years.

INTRODUCTION: Cystic fibrosis (CF) lung disease is characterized by bronchiectasis and trapped air on chest computed tomography (CT). OBJECTIVE: We aim to validate bronchiectasis and trapped air as outcome measures by evaluating associations between changes in bronchiectasis, trapped air and patient-reported respiratory symptoms. METHODS: A longitudinal cohort study has been conducted. CF patients (aged 6-19 years) who had two routine CTs and completed twice a Cystic Fibrosis Questionnaire-Revised within 2 years (referred to as T1 and T2 ), in the period of July 2007 to January 2012 were included. Bronchiectasis and trapped air were scored using the CF-CT scoring system. Correlation coefficients and student's paired t tests were performed. RESULTS: In total 40 patients were included with a median age at T1 of 12.6 years (range 6-17 years), and at T2 14.5 years (range 8-19 years). At T1 , bronchiectasis (r = -0.49, P < 0.01) and trapped air (r = -0.34, P = 0.04) correlated with CFQ-R Respiratory Symptoms Scores (CFQ-R RSS). At T2 similar correlations were found with the CFQ-R RSS. Over 2 years, there was significant progression in bronchiectasis (P = 0.03) and trapped air (P = 0.03), but not in CFQ-R RSS. Changes in bronchiectasis and trapped air were not associated with changes in CFQ-R RSS. CONCLUSION: Our results indicate that bronchiectasis and trapped are sensitive outcome measures in CF lung disease, showing a significant association with CFQ-R RSS at two-time points. However, progression of bronchiectasis and trapped air over 2 year does not necessarily correlate to changes in quality of life.

Impact of bronchiectasis and trapped air on quality of life and exacerbations in cystic fibrosis.

Cystic fibrosis (CF) is primarily characterised by bronchiectasis and trapped air on chest computed tomography (CT). The revised Cystic Fibrosis Questionnaire respiratory symptoms scale (CFQ-R RSS) measures health-related quality of life. To validate bronchiectasis, trapped air and CFQ-R RSS as outcome measures, we investigated correlations and predictive values for pulmonary exacerbations. CF patients (aged 6-20 years) underwent CT, CFQ-R RSS and 1-year follow-up. Bronchiectasis and trapped air were scored using the CF-CT scoring system. Correlation coefficients and backward multivariate modelling were used to identify predictors of pulmonary exacerbations. 40 children and 32 adolescents were included. CF-CT bronchiectasis (r = -0.38, p<0.001) and CF-CT trapped air (r = -0.35, p = 0.003) correlated with CFQ-R RSS. Pulmonary exacerbations were associated with: bronchiectasis (rate ratio 1.10, 95% CI 1.02-1.19; p = 0.009), trapped air (rate ratio 1.02, 95% CI 1.00-1.05; p = 0.034) and CFQ-R RSS (rate ratio 0.95, 95% CI 0.91-0.98; p = 0.002). The CFQ-R RSS was an independent predictor of pulmonary exacerbations (rate ratio 0.96, 95% CI 0.94-0.97; p<0.001). Bronchiectasis, trapped air and CFQ-R RSS were associated with pulmonary exacerbations. The CFQ-R RSS was an independent predictor. This study further validated bronchiectasis, trapped air and CFQ-R RSS as outcome measures in CF.

Methodological aspects of exhaled nitric oxide measurements in infants.

Guidelines for the measurement of fractional exhaled nitric oxide (FE(NO)) recommend refraining from lung function tests (LFT) and certain foods and beverages before performing FE(NO) measurements, as they may lead to transiently altered FE(NO) levels. Little is known of such factors in infants. The aim of the present study was to evaluate whether forced expiratory maneuvers, sedation, nasal contamination, and breastfeeding affect FE(NO) values in infants. FE(NO) was measured off-line during tidal breathing by means of a facemask covering nose and mouth. FE(NO) measurements were performed in 45 sedated infants (mean age 12.1 months) who underwent LFT because of airway diseases and in 83 unsedated healthy infants (mean age 4.3 months). In infants with airway diseases, no difference was found in FE(NO) values before and 5 min after LFT (n = 19 infants, p = 0.7) and FE(NO) values before sedation did not differ from FE(NO) values during sedation (n = 10 infants, p = 0.2). Oral FE(NO) values were significantly lower than mixed (nasal + oral) FE(NO) (n = 42 infants, p < 0.001). FE(NO) values before and 5 min after breastfeeding were not different (n = 11 healthy infants, p = 0.57). The short-term reproducibility in healthy infants (n = 54) was satisfactory (intraclass correlation coefficient = 0.94). We conclude that, in infants with airway diseases, LFT prior to FE(NO) measurement did not influence FE(NO) values and FE(NO) values did not change after sedation. Oral FE(NO) values were significantly lower than mixed (oral + nasal) FE(NO), and breastfeeding did not influence FE(NO). Short-term reproducibility in awake healthy infants was good.

Exhaled nitric oxide differentiates airway diseases in the first two years of life.

Fractional exhaled nitric oxide (FE(NO)) levels are increased in children and adults with asthma, whereas low levels have been found in cystic fibrosis and primary ciliary dyskinesia. The aim of this study was to investigate whether FE(NO) measurements could distinguish between children below the age of 2 with different airway diseases. FE(NO) measurements were performed in 118 infants aged between 4.6 and 25.2 mo: 74 infants with recurrent wheezing (RW), 24 with bronchopulmonary dysplasia (BPD), and 20 with cystic fibrosis (CF). FE(NO) was measured also in 100 healthy controls aged between 1.1 and 7.7 mo. Geometric mean (95% confidence interval) FE(NO) values were 10.4 (9.1-12.0) parts per billion (ppb) in healthy infants, 18.6 (15.6-22.2) ppb in wheezy infants, 11.7 (8.2-16.8) ppb in BPD infants and 5.9 (3.4-10.1) ppb in CF infants. FE(NO) in wheezers was higher than in controls, BPD, and CF (p = 0.009, p = 0.038, and p < 0.001, respectively). Atopic wheezers showed higher FE(NO) than nonatopic wheezers (p = 0.04). CF infants had lower FE(NO) than healthy controls and BPD infants (p = 0.003 and p = 0.043, respectively). FE(NO) values in BPD and control infants were not different. We conclude that FE(NO) is helpful to differentiate various airway diseases already in the first 2 y of life.

Predictive value of infant lung function testing for airway malacia.

Airway malacia is present in a small proportion of wheezing infants. The usefulness of infant lung-function testing (ILFT) in ruling out malacia in wheezy infants is unknown. We assessed the predictive value of ILFT parameters for airway malacia diagnosed by flexible bronchoscopy. Thirty-two term infants (mean (SD) age, 11.0 (4.6) months) with chronic wheeze unresponsive to asthma treatment underwent ILFT prior to bronchoscopy. Functional residual capacity measured by plethysmograph (FRCp), maximal flow at FRC (V'max(FRC)), and tidal breathing parameters were obtained. Expiratory flow-volume curves were visually examined for tidal flow limitation. Malacia was observed during bronchoscopy in 20 infants. V'max(FRC) (Z-score) was significantly lower in the group with malacia as compared with the group without malacia. Lung-function measurements had a low negative predictive value and sensitivity. While flow limitation during tidal breathing was highly predictive and 100% specific for airway malacia, only half of the infants with malacia had tidal flow limitation. In this selected group of infants, routine lung function testing could not discriminate between infants with and without airway malacia. However, the presence of tidal flow limitation was 100% predictive and specific for airway malacia.

Efficacy of fluticasone propionate on lung function and symptoms in wheezy infants.

The role of inhaled corticosteroids in the treatment of recurrent or persistent wheeze in infancy remains unclear. We evaluated the effect of 3 months of treatment with inhaled fluticasone propionate, 200 microg daily (FP200), on lung function and symptom scores in wheezy infants. Moreover, we evaluated whether infants with atopy and/or eczema respond better to FP200 as compared with non-atopic infants. Forced expiratory flow (Vmax(FRC)) was measured at baseline and after treatment. Sixty-five infants were randomized to receive FP200 or placebo, and 62 infants (mean age, 11.3 months) completed the study. Mean Vmax(FRC), expressed as a Z score, was significantly below normal at baseline and after treatment in both groups. The change from baseline of Vmax(FRC) was not different between the two treatment arms. After 6 weeks of treatment, and not after 13 weeks, the FP200 group had a significantly higher percentage of symptom-free days and a significant reduction in mean daily cough score compared with placebo. Separate analysis of treatment effect in infants with atopy or eczema showed no effect modification. We conclude that in wheezy infants, after 3 months of treatment with fluticasone, there was no improvement in lung function and no reduction in respiratory symptoms compared with placebo.

Aerosol therapy and the fighting toddler: is administration during sleep an alternative?

Insufficient cooperation during administration of aerosols by pressurized metered dose inhaler (pMDI)/spacers is a problem in nearly 50% of treated children younger than 2 years. For these children, administration during sleep might be more efficient. However, it is unknown how much aerosol reaches the lungs during sleep. The aim of this study was to determine in vitro the lung dose in young children from a pMDI/spacer during sleep and while being awake. Breathing patterns were recorded by a pneumotachograph in 18 children (age 11 +/- 5.1 months) during sleep and wakefulness. Next, breathing patterns were replayed by a computer-controlled breathing simulator to which an anatomically correct nose-throat model of a 9-month-old child was attached. One puff of budesonide (200 microg) was administered to the model via a metal spacer. Aerosol was trapped in a filter placed between model and breathing simulator. The amount of budesonide on the filter (5 lung dose) was analyzed by HPLC. For each of the 36 breathing patterns, lung dose was measured in triplicate. The sleep breathing patterns had significantly lower respiratory rate and peak inspiratory flows, and smaller variability in respiratory rate, tidal volume, and peak inspiratory flows. Lung dose (mean +/- SD) was 6.5 +/- 3.2 and 11.3 +/- 3.9 microg (p = 0.004) for the wake and sleep breathing pattern, respectively. This infant model-study shows that the lung dose of budesonide by pMDI/spacer is significantly higher during sleep compared to inhalation during wake breathing. Administration of aerosols during sleep might, therefore, be an efficient alternative for uncooperative toddlers.

Worsening of V'maxFRC in infants with chronic lung disease in the first year of life: a more favorable outcome after high-frequency oscillation ventilation.

Little is known about the development of maximal flow at functional residual capacity, a measure of airway patency, in infants with chronic lung disease (CLD). In a follow-up study, we evaluated V'maxFRC in very low birth weight infants with CLD, treated with high-frequency oscillation ventilation (HFOV) or conventional mechanical ventilation. In 36 infants with CLD, V'maxFRC was evaluated at 6 and/or 12 months corrected age, and the relationship between perinatal factors and lung function was studied. Mean (SD) birth weight and gestational age were 837 (152) g and 26.8 (1.7) weeks, respectively. At 6 and 12 months, mean V'maxFRC was significantly below normal. Between 6 and 12 months, there was a mean (95% confidence interval) reduction in V'maxFRC (Z score) of 0.5 (0.2-0.7) (p < 0.001). At 12 months, the mean V'maxFRC (Z score) was higher for children initially treated with HFOV (n = 15), as compared with children treated with conventional mechanical ventilation (n = 16): mean (95% confidence interval) difference was 0.6 (0.2-1.0) (p = 0.008). We conclude that very low birth weight infants with CLD have decreased V'maxFRC that worsen during the first year of life. Initial treatment with HFOV was associated with a more favorable outcome of V'maxFRC at 12 months corrected age.