Search

BackgroundThe majority of patients with childhood interstitial lung disease (chILD) caused by pathogenic variants in ATP binding cassette subfamily A member 3 (ABCA3) develop severe respiratory insufficiency within their first year of life and succumb to disease if not lung transplanted. This register-based cohort study reviews patients with ABCA3 lung disease who survived beyond the age of 1 year.MethodOver a 21-year period, patients diagnosed as chILD due to ABCA3 deficiency were identified from the Kids Lung Register database. 44 patients survived beyond the first year of life and their long-term clinical course, oxygen supplementation and pulmonary function were reviewed. Chest CT and histopathology were scored blindly.ResultsAt the end of the observation period, median age was 6.3 years (IQR: 2.8–11.7) and 36/44 (82%) were still alive without transplantation. Patients who had never received supplemental oxygen therapy survived longer than those persistently required oxygen supplementation (9.7 (95% CI 6.7 to 27.7) vs 3.0 years (95% CI 1.5 to 5.0), p=0.0126). Interstitial lung disease was clearly progressive over time based on lung function (forced vital capacity % predicted absolute loss −1.1% /year) and on chest CT (increasing cystic lesions in those with repetitive imaging). Lung histology pattern were variable (chronic pneumonitis of infancy, non-specific interstitial pneumonia, and desquamative interstitial pneumonia). In 37/44 subjects, theABCA3sequence variants were missense variants, small insertions or deletions with in-silico tools predicting some residual ABCA3 transporter function.ConclusionThe natural history of ABCA3-related interstitial lung disease progresses during childhood and adolescence. Disease-modifying treatments are desirable to delay such disease course.

BackgroundPaediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome.MethodsA retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years.ResultsData of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0–12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function.ConclusionsPaediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined.

High-flow nasal therapy (HFNT) is a safe and simple way to deliver humidified air and oxygen for respiratory support in infants and children. HFNT is well established in an inpatient setting, but home HFNT lacks evidence. In the current study, we studied characteristics and outcomes of pediatric patients with home HFNT. In a monocentric retrospective analysis of data for 10 years (April 2010–April 2020), patient characteristics from the time point of the first discharge from hospital with home HFNT-treatment and the subsequent course were analyzed. Patients were divided into three HFNT indication groups: (1) bronchopulmonary dysplasia (BPD), (2) upper airway obstruction (UAO), and (3) other indications. Forty patients received home HFNT in the study period. Seventeen patients were treated for BPD, 15 for UAO, and 8 had other indications. Twenty-two patients (55%) were successfully weaned from HFNT (12 [70.6%] BPD, 7 [46.7%] UAO, 3 [37.5%] other), while seven patients (17.5%) died during follow-up (4 BPD, 2 UAO, 1 other). Twenty-three patients (57.5%) required (intermittent) additional oxygen application (14 [82.4%] BPD, 6 [40%] UAO, 4 [50%] other). Weaning success and need for additional oxygen were significantly more probable in BPD patients compared to the UOA group. In conclusion, HFNT plays an increasing role in home treatment of respiratory insufficiency of various etiologies in childhood. It often represents a temporary intervention, especially for children with BPD but might also serve as long-term treatment for children in whom other forms of ventilatory support are not feasible or desired.

Background Obstructive sleep apnea (OSA), nocturnal hypoxemia and excessive daytime sleepiness (EDS) are common comorbidities in people with cystic fibrosis (pwCF). Most of the data showing this originates from children and adolescents. The aim of this study was to collect data on sleep parameters, EDS and pulmonary function from a large cohort of adult pwCF. Methods Full overnight polysomnography (PSG) was performed. EDS was determined using the Epworth Sleepiness Scale (ESS). Demographic and clinical data (body mass index [BMI], pulmonary function, capillary blood gases) were collected. Results A total of 52 adult pwCF were included (mean age 30.7 ± 8.0 years, mean percent predicted forced expiratory volume in 1 s [ppFEV1] of 52.1 ± 14.8). Overall AHI was in the normal range (4.5 ± 4.0/h); 21/52 pwCF (40%) had an apnea-hypopnea index > 5/h. Nocturnal hypoxemia was found in 25% of participants and this was associated with ppFEV1 (p = 0.014), awake oxygen saturation (SpO2; p = 0.021) and awake partial pressure of oxygen (pO2; p = 0.003); there were no significant differences in age, lung function and BMI were found for pwCF with versus without OSA (all p > 0.05). Eight pwCF (15%) had an ESS score > 10 (indicating EDS). OSA was best predicted by awake pO2 (area under the curve [AUC] 0.66, p = 0.048), while nocturnal hypoxemia was best predicted by ppFEV1 (AUC 0.74, p = 0.009), awake pO2 (AUC 0.76, p = 0.006) and awake SpO2 (AUC 0.71; p = 0.025). Conclusion OSA, nocturnal hypoxemia and EDS were common in adult pwCF, but no strong predictors were identified. Therefore, we suggest regular PSG and ESS scoring in adult pwCF, regardless of disease severity.

Der Ubergang von einer kindorientierten zu einer erwachsenenorientierten Gesundheitsfursorge bei Patienten mit Mukoviszidose (zystischer Fibrose [CF]) hat in den letzten Jahrzehnten an Bedeutung gewonnen, da die Lebenserwartung von Menschen mit Mukoviszidose kontinuierlich gestiegen ist. Der Ubergangsprozess (Transition) beginnt gewohnlich in der Adoleszenz und wird mit dem physischen Transfer des jungen Erwachsenen in die Erwachsenenmedizin abgeschlossen. Die historisch als „Kinderkrankheit“ geltende Mukoviszidose ruckt durch das steigende Alter der Patienten zunehmend in den Fokus der Erwachsenenmedizin. Hier gilt es, entsprechende medizinische Versorgungsstrukturen fur diese komplexe Erkrankung vorzuhalten und Kapazitaten zu schaffen, um die Kinderkliniken zu entlasten, die haufig die Versorgung bereits erwachsener Patienten aufrechterhalten haben. Die altersbedingt erhohte Komplikationsrate stellt spezielle Anforderungen an die Versorgung von erwachsenen Mukoviszidosepatienten. Hierzu zahlen nicht nur das Erkennen und Behandeln von Komplikationen, sondern auch eine medizinische Versorgungsstruktur, die darauf ausgerichtet ist, die mit der Mukoviszidose assoziierten Komorbiditaten wie den Diabetes mellitus oder die CF-Hepatopathie adaquat zu versorgen. Ein Behandlerteam aus Arzten, erfahrener CF-Pflege, Physiotherapie, Ernahrungstherapie, Psychologie und sozialem Dienst muss in der weiterfuhrenden Versorgung zu Verfugung gestellt werden, um dem Anspruch an eine allumfassende Behandlung der komplexen Erkrankung Mukoviszidose gerecht zu werden.

Background In this study we tested the hypothesis that in patients with cystic fibrosis (pwCF) respiratory rate (RR) is associated with antibiotic treatment, exacerbation status, forced expiratory volume in one second (FEV1) and C-reactive protein (CRP). Methods Between June 2018 and May 2019, we consecutively enrolled pwCF who were referred to our hospital. We determined RR and heart rate (HR) by using the minimal-impact system VitaLog during the hospital stay. Furthermore, we performed spirometry and evaluated CRP. Results We included 47 patients: 20 with pulmonary exacerbation and 27 without. RR decreased in patients with exacerbation (27.5/min (6.0/min) vs. 24.4/min (6.0/min), p = 0.004) and in patients with non-exacerbation (22.5/min (5.0/min) vs. 20.9/min (3.5/min), p = 0.024). Patients with exacerbation showed higher RR than patients with non-exacerbation both at the beginning (p = 0.004) and at the end of their hospital stay (p = 0.023). During the hospital stay, HR did not change in the total cohort (66.8/min (11.0/min) vs. 66.6/min (12.0/min), p = 0.440). Furthermore, we did not find significant differences between patients with exacerbation and patients with non-exacerbation (67.0/min (12.5/min) vs. 66.5/min (10.8/min), p = 0.658). We observed a correlation of ρ = -0.36 between RR and FEV1. Moreover, we found a correlation of ρ = 0.52 between RR and CRP. Conclusion In pwCF requiring intravenous therapy, respiratory rate is higher at their hospital admittance and decreased by the time of discharge; it is also associated with C-reactive protein. Monitoring RR could provide important information about the overall clinical conditions of pwCF.

Background: Sleep-disordered breathing (SDB) and disturbed sleep are common, often underrecognized, comorbidities in people with cystic fibrosis (pwCF). Objectives: We studied the effect of CFTR triple combination therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on sleep in pwCF. Method: This was a prospective, observational sleep study in clinically stable adult pwCF. All participants underwent overnight polysomnography (PSG), before (T0) and after (T1) initiation of CFTR modulator therapy with ELX/TEZ/IVA. In addition, pulmonary function tests, calculation of BMI, and sweat chloride testing were performed. Results: Twenty-nine pwCF (mean age 32 ± 8 years; 15 female) participated in the study. Mean time between T0 and T1 was 194 ± 21 days. Total sleep time (TST) was 298 ± 40 min, with decreased sleep efficiency (SE) (76 ± 109) and increased sleep latency (SL) (73 ± 38 min). Sleep stages for NREM (N1–3) and REM sleep were within the normal range. Nocturnal respiratory events mainly occur during REM sleep (T0: AHI REM 8.3 ± 9.0/h; ODI REM 9.4 ± 10.6/h), whereas the overall AHI was normal (3.6 ± 3.7/h). After initiation of ELX/TEZ/IVA, we saw significant improvements in ppFEV1 (p < 0.001) and BMI (p < 0.001) and a reduction in sweat chloride levels (p < 0.001). In parallel, there was a reduction in AHI (p = 0.003), ODI (p = 0.001), and nocturnal respiratory rate (p < 0.001), both in total, REM and NREM sleep. Neither TST, SL, SE, nor sleep architecture was influenced (all p > 0.05). Conclusions: Initiation of ELX/TEZ/IVA resulted in significant improvements in SDB in adult pwCF.

BackgroundElexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation.MethodsWe conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40–90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972.FindingsBetween Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (−1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], pInterpretationThe elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Background:Transition from child-oriented to adult-oriented health care in Cystic Fibrosis (CF) has become more important over recent decades as the survival of people with this disease has increased. The transition process usually begins in adolescence, with full transfer completed in early adulthood.Objective:This study investigated the impact of a short-term transfer program on clinical markers in an adult CF cohort still being managed by pediatricians.Methods:Clinically relevant data from the year before (T-1), the time of Transfer (T) and the year after the transfer (T+1) were analysed retrospectively.Results:39 patients (median age 29.0 years; 64% male) were transferred between February and December 2016. Lung function had declined significantly in the year before transfer (in % predicted: Forced Expiratory Volume in 1 second (FEV), 62.8vs.57.7,pvs.71.1,pP. aeruginosa, Methicillin-Resistant Staphylococcus aureus (MRSA) andBurkholderiasp. during the observation period. The number of patient contacts increased significantly in the year after versus the year before transfer (inpatient: 1.51vs.2.51,pvs.3.41,pConclusions:Our data show that, within the framework of a structured transfer process, it is possible to transfer a large number of adult CF patients, outside a classic transition program, from a pediatric to an adult CF center in a short period of time, without any relevant changes in clinical markers and, stability.

IntroductionMassive haemoptysis is a life-threatening event in advanced cystic fibrosis (CF) lung disease with bronchial artery embolisation (BAE) as standard of care treatment. The aim of our study was to scrutinise short-term and long-term outcomes of patients with CF and haemoptysis after BAE using coils.MethodsWe carried out a retrospective cohort study of 34 adult patients treated for massive haemoptysis with super selective bronchial artery coil embolisation (ssBACE) between January 2008 and February 2015. Embolisation protocol was restricted to the culprit vessel(s) and three lobes maximum. Demographic data, functional end-expiratory volume in 1 s in % predicted (FEV1% pred.) and body mass index before and after ssBACE, sputum colonisation, procedural data, time to transplant and time to death were documented.ResultsPatients treated with ssBACE showed significant improvement of FEV1% pred. after embolisation (p=0.004) with 72.8% alive 5 years post-ssBACE. Mean age of the patients was 29.9 years (±7.7). Mean FEV1% pred. was 45.7% (±20.1). Median survival to follow-up was 75 months (0–125). Severe complication rate was 0%, recanalisation rate 8.8% and 5-year-reintervention rate 58.8%. Chronic infection with Pseudomonas aeruginosa was found in 79.4%, Staphylococcus areus in 50% and Aspergillus fumigatus in 47.1%.DiscussionssBACE is a safe and effective treatment for massive haemoptysis in patients with CF with good results for controlling haemostasis and excellent short-term and long-term survival, especially in severely affected patients with FEV

BACKGROUND: Home noninvasive ventilation (NIV) improves disease courses of patients with respiratory insufficiency due to neuromuscular diseases. Data about appropriate ventilator settings for pediatric patients are missing. METHODS: In this retrospective study, ventilator settings of 128 subjects with neuromuscular disease aged 0–17 y with NIV were compared between 4 age groups (< 1 y, 0–5 y, 6–11 y, and 12–17 y). Additionally, correlations of ventilator settings with age and vital capacity were investigated in an ungrouped approach. RESULTS: Ventilator backup rate decreased significantly with age, leading to significant backup rate differences between all groups except the oldest two. Median (interquartile range) backup rates were 36 (11.5), 24 (4), 20 (4), and 20 (3) breaths/min in groups 1–4, respectively. Median [IQR] expiratory positive airway pressures (4 [0.5], 4 [0], 4 [0], 4 [1] cm H(2)O, respectively) and median [IQR] inspiratory positive airway pressures (12 [1.5], 12 [5], 12 [2.3], and 14 [4] cm H(2)O, respectively) showed no significant differences. However, correlation analyses indicated an increase of inspiratory positive airway pressure with age and decreasing FVC, as well as an increase of backup rates with decreasing FVC. CONCLUSIONS: Similar NIV settings fit all age groups of pediatric subjects with neuromuscular disease. Thus, we propose an expiratory positive airway pressure of 4–5 cm H(2)O, an inspiratory pressure delta of 8–10 cm H(2)O, and an age-oriented backup rate as a starting point for NIV titration. Patients with advanced disease stages might require slightly higher inspiratory positive airway pressures and backup rates.

Introduction Hypersensitivity pneumonitis (HP) in children is a severe interstitial lung disease and potentially, a chronic condition, if not treated appropriately. No evidence-based guidelines are available; in particular, the role of systemic glucocorticoid therapy is unclear. Methods The aim of this randomized, double-blind, placebo-controlled, parallel-group, multi-center, phase II trial in pediatric HP was to assess the outcome of HP in children after 6 months of treatment and to compare 3 months of treatment with oral prednisolone or placebo. Results After 1.5 years and the inclusion of only four children, we terminated the study prematurely. Two of the children randomized to prednisolone did not achieve the predefined response of FVC to normal. One child treated with placebo recovered to normal, similar to another child treated with prednisolone. All children treated with steroids developed drug-related side effects. Discussion This uncompleted study illustrates the urgent medical need for evidence-based treatment protocols for this condition. We discuss the hurdles which were specific for completion of this trial in a rare condition. Among other options, we suggest the inclusion of children into an all-age study of HP, as in adults the same questions are unanswered.

Background. Regular physical activity plays an important role in the treatment of patients with cystic fibrosis (CF). This study is aimed at investigating the effects of a 12-month partially supervised exercise program on attributes of health-related and motor performance fitness, lung function (ppFEV1), BMI, and habitual physical activity (HPA, steps/day) in adults with CF. Methods. Attributes of health-related and motor performance fitness were examined at the beginning (T0), after 6 (T1), and 12 months (T2) on the basis of five test items: forward bend (FB), bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Additionally, we recorded HPA by accelerometry, peak exercise performance ( W peak ) by an incremental cycle test, ppFEV1, and BMI. During the first six months, there was close supervision by an experienced sport therapist. Results. 26 CF patients (8 female, mean age 26.5 ± 7.9 years; ppFEV1 53.7 ± 21.0 ) completed the exercise program. Significant improvements were recorded from T0 to T1 (FB: p ≤ 0.05 ; PLR, OLS: p ≤ 0.01 ) and from T0 to T2 (FB, PLR: p ≤ 0.01 and HE, OLS: p ≤ 0.05 ). W peak , ppFEV1, BMI, and HPA showed no significant improvement between the single test points and over the entire study period (all p > 0.05 ). Conclusion. Our results show trainability of adults with CF in aspects of health-related and motor performance fitness during a partially supervised exercise program. Close supervision positively influences the results. Using a simple test setup seems to be a promising tool for evaluating the effects of exercise programs in CF and could serve as an additional outcome parameter in future clinical trials. Trial registration: ClinicalTrials.gov (retrospectively registered May 8, 2018).

Introduction In pediatric patients, flexible bronchoscopy requires deep sedation. Different sedation regimes are common, but only some of them include opioids. Due to their antitussive effect, the use of short-acting opioids may be beneficial for this particular indication, but additional respiratory depression may lead to an increase in adverse events. Here, we systematically compared sedation regimes in children undergoing flexible bronchoscopy with either propofol alone, or a combination of propofol and remifentanil. The primary outcome parameter was the frequency of coughing episodes during the intervention. Secondary outcome parameters were frequency and types of complications, patient satisfaction, examiner satisfaction, and recovery time after finishing the sedation. Methods Fifty children aged 1-17 years undergoing flexible bronchoscopy under deep sedation with propofol were randomly assigned to two groups: PR receiving propofol and remifentanil and PP receiving propofol only. Sedation depth was predefined as Comfort Score 10-13. Results We found significantly less coughing episodes ([med (IQR)] PR: 0.73 (0.28-2.45)/min; PP: 1.98 (1.26-3.12)/min; p = .010) and shorter recovery time in Group PR (PR: 13.5 (8-17.5) min; PP: 21.0 (14-27) min; p = .011). Examiner's satisfaction was higher in Group PR (PR: 10 (8-10); PP: 9 (7-9); p = .012). The number of adverse events, patient satisfaction, and required propofol dose during the intervention did not differ between groups. Conclusion We suggest the combination of propofol with remifentanil instead of using propofol alone in pediatric procedural sedation for flexible bronchoscopy.

BACKGROUND: Sleep disturbances and poor sleep quality are a known phenomenon in patients with Cystic Fibrosis (CF). Habitual physical activity (HPA) plays an important role in the treatment of CF patients due to its positive influence on progression of disease and quality of life. The aim of this work is to create a home-based sleep and activity profile and to investigate the influence of habitual physical activity (HPA) on sleep quality of children, adolescents and adults with CF. METHODS: One hundred and nine CF patients (64 male, mean age 22.7±12.0 years; mean ppFEV1 63.0±26.7) were equipped with an actigraph (Actigraph Corp., Pensacola, FL, United States) for home-based collection of activity and sleep data for a total of 4 weeks. Evaluation of recorded raw data was performed by ActiLife software, Version 6.11.9 (Actigraph Corp., Pensacola, FL, United States). RESULTS: CF patients under the age of 18 show the best sleep efficiency (92%±3%), the longest time in bed (TIB) (545±71 min) and Total Sleep Time (504±72 min) and the lowest Wake after sleep Onset (WASO) (39±15 min). With increasing age there is a decrease in Sleep efficiency (SE) (P0.05). In terms of lung function, CF patients with FEV1 values > 70%pred. have the best SE (92%±3%), the highest TST (490±72 min) and TIB (531±71 min) and the lowest WASO (39±13 min). As FEV1 deteriorates, a change in sleeping behavior can be detected. SE (P0.05) decrease, whereas WASO (P>0.05) increases. Interestingly, there is no difference in the number of awakenings between the different age and FEV1 groups (all P>0.05). Statistical analysis was performed using version 25 of the SPSS statistics package (SPSS Inc., Chicago, USA). CONCLUSIONS: Besides younger age and higher FEV1, daily activity in higher intensities influences sleep of CF patients in a positive way. Patients with poor quality and disturbances of sleep possibly benefit from an intensification of physical activity in the home environment.

The aim of this study was to examine motor performance and trainability in youths with cystic fibrosis (CF).Twenty-two children and adolescents (11 f/11 m), age range 6-17 years (11.3 ± 3.3 years), mean FEV1 91.0 ± 21.7% pred.finished the partially monitored 12-months exercise program. Patients performed the Deutsche Motorik Test (DMT) to assess flexibility, balance, strength, power and totalmotor performance. An incremental ergometer cycle test was used to assess maximal exercise capacity (Wpeak). All tests were performed before (T1), after 6 months of monitored exercise training (T3) and another 6 months without monitoring (T4).Motor Competence in total and test-items of the DMT (except foreward bend) improved to T3 (p .05). No further improvement could be observed after the end of the monitoring (T3). However, the values remained stable at the improved level (T4). Girls scored lower in test items depending on strength/power but scored higher in balancing compared to boys (p .05). Wpeak and FEV1 were not influenced by the training program. From T3 to T4 a slight decrease was observed (p ≤ .05).The findings demonstrate benefits of an individualizedmonitored long-term exercise intervention on motor performance in CF with improvements of test-tasks to predicted normal. Monitoringseems to be a facilitator in maintaining motivation toward physical activity as no further increase in motor performance was observed after stopping supervision. The results suggest that an individually tailored monitoredregular exercise program should include all aspects of physical fitness with a variety of movement experiences.

OBJECTIVES The lung clearance index (LCI) is determined by multiple-breath washout lung function (MBW). It is increasingly used as an endpoint in clinical trials. Chest physiotherapy (CP) is part of routine cystic fibrosis (CF) care. Whether the LCI is useful in detecting short-term treatment effects of CP has not been sufficiently investigated. We assessed the short-term influence of CP with highly standardized high-frequency chest wall oscillation (HFCWO) on the LCI in CF patients. METHODS In this randomized controlled study, the LCI was obtained in 20 CF patients (7-34 years) hospitalized for infective pulmonary exacerbation prior to and immediately after a single treatment of HFCWO. Twenty-one control group CF patients (7-51 years) received no treatment. We calculated the coefficient of repeatability (CR) to estimate the clinical relevance of possible treatment effects. RESULTS HFCWO improved (ie, decreased) the LCI by a median of 0.9 (range −0.45; 3.47; P = 0.002); the LCI decreased in 15 of 20 intervention group patients. In five patients the decrease in LCI exceeded the CR (2.15), indicating a clinically relevant treatment effect; in five patients the LCI increased but did not exceed the CR. The LCI did not change significantly in the control group patients. CONCLUSIONS HFCWO can have a short-term decreasing effect on the LCI, but the treatment response is heterogeneous. In future trials using LCI as an endpoint, the timing of CP in relation to MBW should be considered a possible bias.

BACKGROUND: Culturing of bronchoalveolar lavage (BAL) fluid is a commonly used method for pathogen detection in pneumonia. However, the sensitivity is low, especially in patients pre-treated with anti-infective agents. The early detection of a pathogen is crucial for the outcome of respiratory tract infections. For bloodstream infections, a multiplex polymerase chain reaction (PCR) assay (SeptiFast®, SF) is available for improved pathogen detection from blood. OBJECTIVE: The aim of the present study was to determine whether the SF assay is applicable to the BAL of children with pulmonary infections and whether the frequency of pathogen detection is enhanced by the use of this multiplex PCR method. METHODS: We investigated 70 BAL samples of 70 children simultaneously by culture and multiplex PCR. The frequency of pathogen detection was compared. RESULTS: Pathogens were detected more frequently by SF than by culture (83% vs. 31%; p

Background In patients with severe neurological impairment, recurrent respiratory tract infections frequently occur as a result of impaired clearance of airway secretions and microbial airway colonisation. We hypothesised that inhaled antibiotic therapy may improve the morbidity of these patients. Methods A retrospective data analysis of 20 patients (11 nontracheotomised and nine tracheotomised) with neurological impairment and microbial airway colonisation was carried out at a children's university hospital. Two questionnaires that asked about the number of respiratory tract infections, antibiotic therapies and hospitalisations were distributed to the patients/caregivers: a first questionnaire representing the 12 months prior to the initiation of inhaled antibiotics and a second questionnaire describing the first 12 months under therapy. Results During the first 12 months of therapy, the frequency of respiratory tract infections among all participants was reduced from a mean of 6.8 episodes (median (interquartile range (IQR)) 6.0 (4.0–10.0) episodes) to a mean of 2.5 episodes (median (IQR) 2.0 (1.0–3.0) episodes; p, Inhaled antibiotic therapy offers a novel approach to the prevention of respiratory tract infections in patients with severe neurological impairment who have chronic microbial airway colonisation and recurrent respiratory tract infections http://bit.ly/2HQRyz0

Background and objective Inherited neuromuscular disorders (NMD) inevitably result in severe lung volume restriction and cough insufficiency associated with high morbidity and mortality. The aim of this retrospective study was to evaluate whether the airways of patients with NMD are colonized with potential pathogenic microorganisms that might contribute to the pulmonary morbidity in NMD. Methods In this cross-sectional study, cough swabs were obtained and cultured for microbiological analyses from 77 patients with NMD and different degrees of lung volume restriction and cough insufficiency. Upper airway microbial colonization was compared to lung function parameters and cough peak flow values. Results Upper airway microbial colonization with potential pathogenic pathogens was identified in 39/77 (51%) of the subjects. Upper airway microbial colonization was associated with lower forced vital capacity (% pred.) 26.6 ± 19.7 versus 41.8 ± 20.4, P

Inherited neuromuscular disorders inevitably result in severe lung volume restriction associated with high morbidity and mortality. The aim of this retrospective study was to evaluate the long-term effects of the regular use of mechanical insufflation/exsufflation on the course of the vital capacity. This retrospective data analysis included 21 patients (16.1 ± 6.5 years) with neuromuscular disorders and severe lung volume restriction using nocturnal noninvasive ventilation. The patients were advised to regularly use the mechanical insufflation/exsufflation twice a day for 10 minutes applying sets of three insufflation/exsufflation breath via face mask irrespective of respiratory tract infection. Data on the course of vital capacity were collected 2 years prior and 2 years after the introduction of regular use of mechanical insufflation/exsufflation. Before the introduction of mechanical insufflation/exsufflation vital capacity decreased from 0.71 ± 0.38 L to 0.50 ± 0.24 L in the last year and from 0.88 ± 0.45 L to 0.71 ± 0.38 L in the next to last year. In the first year, after regular use of mechanical insufflation/exsufflation vital capacity significantly increased by 28% (from 0.50 L to 0.64 L)—after the second year the vital capacity increase remained stable (0.64 vs. 0.65 L). These data suggest that the regular use of mechanical insufflation/exsufflation improves vital capacity in patients with neuromuscular disorders and severe lung volume restriction.

Background: Bloodstream pathogens can be identified by multiplex PCR (SeptiFast (SF)) or blood culture (BC); whether these pathogens are present in cystic fibrosis (CF) patients during febrile pulmonary exacerbations (FPE) has not been sufficiently studied. Methods: In this prospective observational study, blood from CF patients experiencing FPE was tested with SF and BC before the initiation of antibiotic treatment. Results: After contaminants had been excluded, 9 of 72 blood samples tested positive by BC or SF. SF exclusively detected four pathogens; BC, one. Pulmonary pathogen transmission was likely in all cases except for 2 cases of candidaemia, which were believed to be caused by catheter-related infections. For three cases, test results caused us to change the antibiotic regimen. Sensitivity (85.7% vs. 42.9%) and negative predictive value (98.4% vs. 87.0%) tended to be higher for SF than for BC. Conclusions: The results of SF and BC show that bacteraemia and fungaemia are present in CF patients during FPE and may affect antibiotic therapy. SF can help rule out catheter-related bloodstream infections. OA gold

Introduction. Antibiotic treatment regimens againstPseudomonas aeruginosalung infection in cystic fibrosis (CF) patients often include aminoglycoside antibiotics that may cause chronic renal failure after repeated courses. Aminoaciduria is an early marker of acute aminoglycoside-induced renal tubular dysfunction. We hypothesized that urinary amino acid reabsorption is decreased after repeated once-daily tobramycin therapies.Methods. In this prospective cross-sectional study creatinine clearance was estimated by the Schwartz and the Cockcroft-Gault formula. Tubular amino acid reabsorption was determined by ion exchange chromatography in 46 patients with CF who received multiple tobramycin courses (6.3±10.1(1–57)) in a once-daily dosing regimen and 10 who did not.Results. Estimated creatinine clearance employing the Cockcroft-Gault was mildly reduced in 17/46 (37%) of the patients who received tobramycin and 5/10 (50%) of the patients who did not but in none using the Schwartz formula. No association with lifetime tobramycin courses was found. Tubular amino acid reabsorption was not influenced by the amount of once-daily tobramycin courses.Conclusion. Clinically not significant reduction of eCCL occurred in a minority of CF patients. However, chronic tubular dysfunction was not present in patients with CF repeatedly treated with tobramycin in the once-daily dosing scheme.

Background There is only sparse data on the use of non-invasive ventilation (NIV) in acute respiratory failure (ARF) in infants and children. For this setting we investigated feasibility and efficacy of NIV and aimed to identify early predictors for treatment failure. Patients and Methods Retrospective chart review was performed for all patients treated with NIV for ARF from 2003 to 2010 on an 8-bed pediatric intensive care unit of a tertiary university hospital. Results Seventy-four patients were treated with NIV. One patient did not tolerate mask ventilation and needed immediate invasive ventilation. Intubation rate of the remaining patients was 23% and mortality 15%. Institution of NIV led to significant improvement of both respiratory and heart rate in all patients within the first hour and to further stabilization within the next 8–10 hr. In patients with NIV success blood gases improved significantly 1–2 hr after starting NIV. Multivariate analysis identified low pH after 1–2 hr to be an individual risk factor for NIV failure. Other factors tested were age, underlying disease, acute respiratory insufficiency versus post-extubation failure (PEF), and 1–2 hr after starting NIV oxygen saturation, respiratory rate, PCO2, and FiO2. Patients with PEF tended to show better outcomes compared to those with acute respiratory insufficiency. Conclusion NIV can be effective in infants and children with ARF. Low pH 1–2 hr after start of NIV is associated with NIV failure. It may therefore be useful in the decision to continue or stop mask ventilation. Pediatr. Pulmonol. 2011; 46:1114–1120. © 2011 Wiley Periodicals, Inc.

Advanced stages of Duchenne muscular dystrophy (DMD) result in severe lung volume decline and are associated with high respiratory morbidity and mortality. The aim of this study was to investigate whether lung volume decline in subjects with DMD is associated with ventilation inhomogeneity measured with the multiple-breath washout technique.This cross-sectional study of lung function included 45 subjects with DMD and 16 healthy controls using multiple-breath washout, spirometry, and cough peak flow.Subjects with DMD exhibited an elevated lung clearance index (> 7.0) defined as the cumulative exhaled volume divided by the functional residual capacity to lower the sulfur hexafluoride concentration below 2.5% compared with controls (8.16 ± 2.55 vs 6.23 ± 0.46, P < .001). Lung clearance index elevation was negatively correlated with vital capacity (% predicted: r = -0.79, P < .001) and cough peak flow (L/min: r = -0.41, P = .005). Furthermore, dead-space ventilation (dead-space-to-tidal-volume ratio) and functional residual capacity showed a positive correlation with lung clearance index elevation (r = 0.81 and 0.48, P < .001). An FVC of < 24% predicted lung clearance index elevation with a sensitivity of 96% and a specificity of 80%.Moderate-to-severe lung volume decline in subjects with DMD is associated with ventilation inhomogeneity. Lung clearance index elevation may be the result of altered ventilation geometry or retention of airway secretions in the infection-free DMD subject. OA embargo

BackgroundTo describe a simple quantitative immunofluorescence assay (IFA) for the detection of specific Stenotrophomonas maltophilia antibodies in serum of CF patients.MethodsA total of 100 sera (64 CF patients and 36 healthy subjects) were collected over a period of 2years at the University Hospital Essen, Germany. Sputum culture status classified CF patients into groups. Serologic response was determined after Pseudomonas aeruginosa absorption by indirect IFA to Sm whole cell.ResultsCF patients with “chronic S. maltophilia” showed significantly higher S. maltophilia antibody levels compared with healthy individuals (P1:120 titre was established to differentiate “CF chronic S. maltophilia” from the other groups. For “CF chronic S. maltophilia”, the IFA showed sensitivity and specificity values of 70.7% and 84.7%, respectively.ConclusionOur data demonstrated that quantitative IFA is a simple serological assay for the detection of specific S. maltophilia antibodies, which could be useful as a diagnostic tool for monitoring immune response of CF patients to S. maltophilia.

Background In cystic fibrosis (CF) patients, the absence or dysfunction of the chloride channel CF transmembrane conductance regulator (CFTR) results in reduced chloride ion transport in respiratory epithelial cells. Moli1901 stimulates an alternative chloride channel and may thus compensate for the CFTR deficiency in the airway epithelium of CF patients. Methods A phase II, placebo-controlled, double-blinded, single-center, multiple (5 consecutive days), rising-dose (daily dose, 0.5, 1.5, or 2.5 mg of Moli1901) study was conducted to investigate the safety and tolerability of multiple doses of aerosolized inhaled Moli1901 in 24 patients with CF and stable lung disease. Results Moli1901 was well tolerated in all but one CF patient, in whom a transient significant decrease in FEV 1 developed following inhalation, which resolved spontaneously, and in a second patient in whom transient throat numbness developed during drug inhalation. A significant improvement of FEV 1 was observed in the group receiving treatment with 2.5 mg/d Moli1901 compared to the group receiving placebo (p = 0.01 [Wilcoxon test]). Moli1901 was not detected in the plasma of the highest dose group. Conclusions The inhalation of Moli1901 up to a total cumulative dose of 12.5 mg appears to be safe in adult patients with CF. In addition, Moli1901 had a sustained beneficial effect on pulmonary function, which supports further studies of its efficacy in CF patients.

complications and when symptoms of sleep disordered breathing are present; a minority of the CPNG request consultation in these two situations (14.3% and 35.7%). While both groups request routine pulmonary function tests, 95.5% of Respirologists use maximal inspiratory and expiratory pressures to assess respiratory muscle strength, whereas 81.8% of CPNG members additionally use peak cough flow. Assessment for sleep disordered breathing is requested by both groups when pulmonary function is abnormal or patients are symptomatic. Respirologists favor polysomnography, whereas CPNG members use overnight pulse oximetry. Nocturnal noninvasive ventilation and lung volume recruitment are used in a minority of patients by both groups. Conclusions/Reflections: Respirologists and CPNG members provide similar respiratory management of DMD patients, but differ in their timing of initial respiratory consultation and choice of diagnostic tests for pulmonary function and sleep-disordered breathing. Opportunities exist for standardization of respiratory care practices for childhood DMD amongst care providers.