Early and sustained improvements of lung clearance index from two to sixteen weeks of elexacaftor/tezacaftor/ivacaftor therapy in patients with cystic fibrosis-a real world study.

Since the introduction of CFTR modulator therapies, longitudinal real-life data of lung clearance index (LCI) during treatment is scarce. In this single-centre, post-approval setting, we report data of 51 patients with different stages of lung disease, age 2-52 years with repeated measurements of forced expiratory volume as a percentage of the predicted value (ppFEV1) and LCI after 2, 4, and 16 weeks of CFTR modulator treatment and at baseline. In 25 patients during elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) treatment, significant improvements of LCI (median -1.4) and ppFEV1 (median +8.3%) were observed after only 2 weeks, and were maintained after 4 and 16 weeks of treatment (LCI: -2.0, -2.2; ppFEV1: +7.2%, +11.8%). We observed a significant correlation between LCI improvement at week 16 and lower baseline LCI. In 26 younger and healthier patients receiving lumacaftor/ivacaftor (LUM/IVA) treatment, no significant changes of LCI and ppFEV1 occured. With ELX/TEZ/IVA, our data shows rapid, significant improvements of LCI and ppFEV1 already after 2 weeks. Early LCI measurements can help to assess the patient's response to this high-cost therapy.

Malignancies in patients with cystic fibrosis: a case series.

BACKGROUND: Previous reports have shown an increased number of colorectal cancers in patients with cystic fibrosis. We assessed the database of our cystic fibrosis center to identify patients with all kinds of cancer retrospectively. All patients visiting the Cystic Fibrosis Centre Innsbruck between 1995 and 2019 were included. CASE PRESENTATION: Among 229 patients with cystic fibrosis treated at the Cystic Fibrosis Centre in Innsbruck between 1995 and 2019, 11 subjects were diagnosed with a malignant disease. The median age at diagnosis was 25.2 years (mean 24.3 years). There were four gynecological malignancies (cervical intraepithelial neoplasia and cervical cancer), two hematological malignancies (acute lymphocytic leukemia), one gastrointestinal malignancy (peritoneal mesothelioma), and four malignancies from other origins (malignant melanoma, neuroblastoma, adrenocortical carcinoma, and thyroid cancer). One malignancy occurred after lung transplantation. There was a strong preponderance of females, with 10 of the 11 cases occurring in women. Six deaths were attributed to cancer. CONCLUSIONS: Most diagnoses were made below 30 years of age, and half of the subjects died from the malignant disease. Awareness of a possible malignancy is needed in patients with atypical symptoms. Regular screenings for cancer should also be considered, not only for gastrointestinal tumors.

Arm muscle area for the longitudinal assessment of nutritional status in paediatric patients with cystic fibrosis - A single centre experience.

BACKGROUND: In cystic fibrosis, adequate nutrition contributes to good long-term prognosis. A body mass index (BMI) at or above the 50th percentile for age and sex in all children has been recommended. As researchers have described a depletion of fat-free mass despite normal BMI, longitudinal studies using more sensitive nutritional parameters are warranted. We evaluated anthropometric measurements in an attempt to identify early indicators of deteriorating nutritional status in our paediatric cohort. METHODS: We analysed datasets from children and adolescents between 2 and 17.9 years with at least two entries for triceps skinfold thickness and upper arm circumference in our patient database between January 1995 and December 2018. Arm muscle area (AMA) was calculated, and all values were expressed as z-scores from CDC growth charts. RESULTS: A total of 4,862 encounters from 161 paediatric patients (78 girls) were available, representing a median number of 28 visits during a median follow-up of 8.1 years per patient. Linear mixed effects models revealed relatively stable courses for weight, height, BMI and skinfold thickness up to adulthood. AMA was the only parameter which declined slightly (r = -0.036), particularly in boys. Kaplan-Meier-analyses showed that AMA was the earliest parameter to decrease below -1 z-score between 6 and 18 years. CONCLUSIONS: The present data suggest that compared with weight or BMI, AMA could serve as an earlier indicator of a deteriorating nutritional status. The benefit of assessing skinfold thickness and arm circumference routinely and calculating AMA from these measurements should be evaluated in large, prospective, multi-centre studies.

Reference Values Matter: Fewer Patients With Malnutrition Using American Compared to More Recent German Growth Charts.

ABSTRACT: Reference values are important for patient care as well as for comparisons between different centers or countries. We investigated two anthropometric reference datasets, the US Centers for Disease Control (CDC) growth charts and the German Health Interview and Examination Survey for Children and Adolescents Study (KiGGS) percentiles, which were established in Germany between 2003 and 2006. A smaller proportion of children with cystic fibrosis had decreased z scores <-2 with CDC (5.0% for weight and 3.0% for height) compared to KiGGS (7.4% for weight and 6.3% for height) values (P < 0.0001). Median z scores were higher using the CDC reference data. Thus, the choice of growth reference is important, may influence clinical management and must be considered when comparing the outcomes of different institutions.

Lung clearance index to detect the efficacy of Aztreonam lysine inhalation in patients with cystic fibrosis and near normal spirometry - A single-centre feasibility study.

Comparing the efficacy of inhaled antibiotics can be difficult in small groups of patients with cystic fibrosis and mild lung disease. In a feasibility study we compared Aztreonam lysine for inhalation solution (AZLI; Cayston®) to standard inhaled antibiotic therapy in patients with cystic fibrosis and near normal spirometry. To detect treatment responses we used both lung clearance index (LCI) and forced expiratory volume in one second (FEV1). At baseline, median FEV1 was 87% pred. and median LCI was 8.6 (upper limit of normal: 7.0). After 4 weeks, LCI improved by -0.36 after AZLI and deteriorated by +0.12 after tobramycin treatment (p = 0.039). No significant differences between treatments (p = 0.195) were observed using FEV1. These results suggest that lung clearance index can be used to detect treatment induced changes in subjects with mild lung disease.

Fecal Calprotectin in Cystic Fibrosis and Its Relation to Disease Parameters: A Longitudinal Analysis for 12 Years.

OBJECTIVES: Fecal calprotectin (FC) is a marker of inflammation in the intestinal tract. We assessed FC levels longitudinally in patients with cystic fibrosis (CF) and evaluated the relation between FC results and relevant markers of disease. METHODS: Calprotectin was measured in fecal samples starting in 2003 and values were stored in the center's patient database. In this retrospective analysis, we searched for associations of FC concentrations with disease severity and progression. Linear mixed effects models were used to model the logarithm of FC levels. RESULTS: A total of 171 patients (0-61 years) had 2434 FC measurements between 2003 and 2015, with a total observation period of 1686 patient-years. Median (interquartile range) FC concentrations were 60.9 (75.9) µg/g and 61% of the samples showed elevated FC concentrations (>50 µg/g). Despite some statistically significant effects, there was no clinically relevant association among FC and sex, age, forced expiratory volume in 1 second z score, or body mass index z score. Pancreatic insufficiency (ie, fecal elastase <100 µg/g stool) was associated with considerably higher FC values compared to normal pancreatic function (median FC 68 vs 29 µg/g, P < 0.0001). F508del homozygous subjects showed a trend to higher FC values than heterozygous patients (median 71 vs 62 µg/g, P = 0.173). In addition, a significant association with increasing serum C-reactive protein concentrations (P < 0.0001) was observed. CONCLUSIONS: FC was elevated in two-thirds of stool specimens. Increased FC was more common in patients with pancreatic insufficiency. Whether increased FC reflects intestinal inflammation in patients with CF remains to be determined.

Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role?

To assess whether long-term inhalation with hypertonic saline is able to halt the progression of mild CF lung disease, we analysed longitudinal data of lung clearance index (LCI) and spirometry. A total of 34 patients with mild lung disease (FEV1 ≥ 70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease.

Evaluating patient experience in a cystic fibrosis centre using a disease-specific patient satisfaction questionnaire.

UNLABELLED: Medical care for persons with chronic diseases like cystic fibrosis (CF) is provided by multi-professional teams. We assessed the patients' perspective of care by reporting the results of two consecutive patient satisfaction surveys performed within a 2-year interval at our CF centre. The newly developed, disease-specific questionnaire for parents and adults had 104 items with up to 6 response categories each. For data analysis, responses were dichotomized into a problem score with 0 % as the ideal result. Adolescents were surveyed using a different questionnaire. Seventy-six and 89 respondents, respectively, took part in the 2009 and 2011 surveys (response rates: 72 to 84 %). In 2009, the ideal problem score of 0 % was reported for 18 and 20 % of all items in adults and parents, respectively. Thirteen items had a problem score >30 %. After the whole team had implemented quality improvement measures, the 2011 survey showed a >10 % decrease in problem scores for 11 and 21 % of items in the adults and parents groups, respectively. Adolescents also reported better experiences in 2011 than in 2009. CONCLUSION: Exploring the patients' perspectives aids to identify strengths and weaknesses and helps to provide patient-centred care, which is important for persons with chronic illness.

Cystic fibrosis (CF) care through the patients' eyes - a nationwide survey on experience and satisfaction with services using a disease-specific questionnaire.

UNLABELLED: The patients' perspective is an important aspect of quality management. A newly developed disease-specific questionnaire was used to assess the patients' experiences with care provided in specialised cystic fibrosis (CF) care centres. METHODS: 90 CF centres in Germany were invited to participate. Centre staff collected patient consent forms and sent the patients' addresses to the study centre. The questionnaires for adults and parents had 100 and 104 items respectively, with 3-6 response categories each. Items were dichotomised into "problem scores" (PS), indicating the presence or absence (PS 0%) of a reported problem. RESULTS: 56 CF centres took part in the survey and recruited 1642 adults with CF and 1205 parents. The response rates were 74% in each group, with 1221 completed questionnaires from adults and 891 from parents. Participants reported good experiences with care. Factor analysis revealed 10 factors covering 70 items. Participants reported the best results for the factors "Physiotherapists" (PS 6%) and "Physician-Patient Relationship" (PS 9%). Factors with the highest problem scores were inpatient and outpatient "Facilities, Hygiene and Services". CF centres received reports of their own results and mean problem scores of all participating institutions. The problem scores differed considerably between CF centres. CONCLUSIONS: The nation-wide CF-specific patient experience survey identified specific shortcomings which were mainly related to communication, centre organisation, and facilities. Centre staff can use the results to improve the quality of care. We suggest that patients' views should become an integral component of efforts to promote patient-centred care.

Patient experience in cystic fibrosis care: Development of a disease-specific questionnaire.

OBJECTIVES: The aim of this study was to develop valid and reliable disease-specific questionnaires for adult patients with cystic fibrosis and for parents of minors with cystic fibrosis for assessing patient experience with cystic fibrosis care. METHODS: The pilot versions of the questionnaires were developed based on a literature review, interviews with health professionals and focus groups. A postal survey with two reminders was conducted in 56 German cystic fibrosis centres recruiting 2874 participants. Psychometric evaluation was done via exploratory factor analysis and reliability and regression analysis. The questionnaires' ability to differentiate between subgroups and between cystic fibrosis centres was evaluated. RESULTS: Response rates were 74% for both adult patients and parents. Ten factors were extracted for both the adult and the parents' models (Cronbach's alpha between 0.6 and 0.9), explaining 50% and 48% of the variance, respectively. The factors organisation & access and the doctor-patient/parent-interaction had the highest relevance for a good overall care experience. The questionnaires were able to distinguish between different cystic fibrosis centres. DISCUSSION: The questionnaires are well suited for use in internal and external quality management of cystic fibrosis care due to their good psychometric properties, the ability to differentiate between centres and its practicability.

Tracking Lung Clearance Index and chest CT in mild cystic fibrosis lung disease over a period of three years.

INTRODUCTION: Lung disease remains the main cause of morbidity and mortality in patients with Cystic Fibrosis (CF). To detect lung disease before clinical symptoms become apparent, sensitive tools are essential. Spirometry is used for monitoring, but the FEV1 remains frequently normal throughout childhood. The Lung Clearance Index (LCI) calculated from Multiple Breath Washout (MBW) was introduced at the CF centre Innsbruck in 2007 for assessing ventilation inhomogeneity in patients with mild lung disease. We hypothesized that LCIs in 2007 are of prognostic value for the presence or absence of structural lung changes in later years. METHODS: Between 2007 and 2010 MBW, spirometry and ultra-low-dose HR-CT were prospectively tracked in 36 patients (6-53 years) with a mean FEV1 ≥ 80% predicted in 2007. RESULTS: At study start the majority of patients had abnormal CT scores and LCI results. While CT and spirometry remained largely stable throughout the study, LCI results slightly improved but still correlated with CT scores in 2010. LCI results in 2007 correlated with CT scores in 2010 while FEV1 did not. In 86% the LCI value in 2007 was indicative for the presence or absence of structural lung changes in 2010. CONCLUSION: The LCI is a sensitive tool for detecting and tracking pulmonary changes. Extended structural changes are unlikely if the LCI is normal. The LCI has the potential to be used for monitoring the progression of early CF lung disease and assessing the effect of treatment in both clinical care and research settings.

Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease.

It is widely accepted that CF lung disease starts before clinical symptoms become apparent or spirometry deteriorates. Computed chest tomography (CT) is the reference method for identifying structural changes in CF; however, radiation exposure limits its use as a monitoring tool. It has been suggested that the Lung Clearance Index (LCI) measured by Multiple Breath Washout (MBW) for assessing ventilation inhomogeneity is a more sensitive surrogate marker than spirometry allowing non-invasive monitoring of CF lung disease. The aim of this study was to prospectively investigate the diagnostic accuracy of the LCI in comparison to CT in CF patients with early lung disease and normal FEV(1) (>80% pred.). MBW and ultra-low-dose CT were performed in 34 patients (6-26 years). LCI was abnormal in 76.5% subjects. LCI and CT correlated significantly in 82.3%. LCI was related to presence and extent of structural lung changes observed on CT with a sensitivity of 88%. Diagnostic accuracy of the LCI for detecting CF lung disease in patients with normal FEV(1) was good when compared to CT. Results indicate that structural changes are unlikely if a normal LCI is measured. We speculate that serial measurements of the LCI for assessing ventilation inhomogeneity may help to identify early structural lung disease and help to reduce the individual cumulative radiation dose. The LCI may be a suitable surrogate marker for monitoring progression of CF lung disease and effect of treatment in both, clinical care and research settings.

Add-on salmeterol compared to double dose fluticasone in pediatric asthma: a double-blind, randomized trial (VIAPAED).

RATIONALE: In asthmatic children whose symptoms are uncontrolled on standard doses of inhaled corticosteroids (ICS), guidelines recommend to either increase the ICS dose or to add further controller medication, e.g. a long acting ss2-agonist (LABA). The aim of this study was to compare the efficacy and safety of doubling the dose of ICS (fluticasone proprionate FP 200 microg twice daily) with adding a long-acting beta-2 agonist to the ICS (SFC, salmeterol 50 microg/ FP 100 microg twice daily) in children with uncontrolled asthma. METHODS: Children between 4 and 16 years of age were eligible for this multicenter, randomized, double blind, double dummy, parallel-group study. During a 14-day run-in phase, all children inhaled FP 100 microg b.i.d. Patients with persistent symptoms on > or =7 of 14 days were randomized to 8 weeks treatment with a Diskus(R) containing either SFC 50 microg/100 microg b.i.d. or FP 200 microg b.i.d.. The primary endpoint was the mean change in morning (a.m.) PEF from baseline. The initial statistical hypothesis of non-inferiority of SFC vs. FP was confirmed in an adaptive interim analysis, so that the study was terminated prematurely. RESULTS: 441 patients from 39 centers entered the run-in phase, and 64% of these were randomized to treatment (N = 138 to SFC and N = 145 to FP). After 8 weeks, patients on SFC had significantly better results for primary and secondary endpoints: The mean increase in morning PEF was 30.4 +/- 34.1 L/min in the SFC group and 16.7 +/- 35.8 L/min in the fluticasone group, and the mean (95% CI) improvement from baseline a.m. PEF in the ITT group was significantly larger after SFC (+8.6 L/min, CI: [1.3; infinity]). Patients in the SFC group experienced 8.7% (CI: [1.2;16.3]) more days without asthma symptoms and 8.0% (CI: [0.6;15.3]) more days without salbutamol than patients receiving FP. Good asthma control was achieved for a longer period in the SFC (3.4 +/- 2.7 weeks) group than in the FP group (2.7 +/- 2.7, P = 0.02). Both treatments were generally well tolerated. Asthma exacerbations were recorded in 3 and 6 and SAEs in 2 and 1 patients from the SFC and FP groups, respectively. CONCLUSIONS: In children with persistent asthma inadequately controlled on low dose ICS alone, adding a long acting beta-2-agonist to ICS in a single inhaler was more effective than doubling the ICS dose. These results support recommendations of adding LABA to low-dose ICS as the preferred controller option for children older than 4 years with symptomatic asthma.

Once-weekly azithromycin in cystic fibrosis with chronic Pseudomonas aeruginosa infection.

BACKGROUND: Data on the effects of long-term treatment with azithromycin (AZM) on inflammatory markers in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa are scarce. So far there is no pharmacokinetic and clinical data on once-weekly dosage of AZM in CF patients. METHODS: In a randomised double-blind, placebo-controlled trial, patients received AZM or placebo 1 per week for 8 weeks (AZM dosage--20-29 kg: 500 mg, 30-39 kg: 750 mg, 40-49 kg: 1000 mg and > or = 50 kg: 1250 mg) after a course of intravenous antipseudomonal antibiotics. Pulmonary function tests, the serum markers LPS-binding protein (LBP), interleukin-8 (IL-8), CRP, P. aeruginosa alginate in sputum samples and quality of life scores were evaluated. RESULTS: Thirty-eight patients (21 AZM/17 placebo) (mean age: 23.7 years; mean FEV(1): 62% of predicted) were recruited. After treatment (mean dose of 21.2 mg/kg body weight once a week) pulmonary function declined in both groups compared to baseline (i.e. after cessation of i.v. antibiotics). The AZM group was significantly better for mean changes in serum CRP (AZM: +0.9 mg/l, placebo: +21.6 mg/l, p=0.019), lipopolysaccharide binding protein in serum, LBP (AZM: +0.9 microg/ml, placebo: +7.0 microg/ml, p=0.015), serum interleukin-8 (AZM: -3.1 pg/ml, placebo: +2.9 pg/ml, p=0.001) and alginate in sputum (AZM: +85 microg/ml, placebo: +353 microg/ml, p=0.048). Quality of life was significantly better after AZM and there was no increase in treatment-related adverse events. CONCLUSION: Once-weekly azithromycin ameliorated inflammatory reactions and improved quality of life. A decline of pulmonary function after cessation of i.v. antibiotics could not be prevented.

Parental knowledge and behaviour to prevent environmental P. aeruginosa acquisition in their children with CF.

BACKGROUND: Chronic infection with Pseudomonas aeruginosa (PA) is associated with an accelerated decline of lung function in patients with cystic fibrosis (CF). Precautions to avoid contact with PA from the environment have been recommended by caregivers and are being carried out by many families with CF children. The present study was conducted to portray the spectrum of hygienic measures and to evaluate the restrictions and impact caused by these measures. SUBJECTS AND METHODS: In a multi-centre survey, parents of children below 13 years of age responded to mailed questionnaires. The items covered parental knowledge of PA, information provided by caregivers, the parents' feelings and thoughts about PA infection, and measures taken in daily life to prevent a possible contact with PA in the environment. RESULTS: 130 parents from 10 CF centres responded to the questionnaire (63% response rate). 76% of the respective children had always been PA negative. Most parents displayed erroneous beliefs regarding PA infection (mean: 3.5 correct replies to 9 questions). Families performed a mean of 11 different hygienic measures, e.g. they prevented their child from being the first person to use the bathroom in the morning (72%) or from bathing in gravel pits and standing water (52%). The majority of parents felt markedly (44%) or somewhat (44%) stressed that their child might acquire PA, and many parents felt markedly (16%) or somewhat (43%) restricted and stressed by the hygienic measures. Less stressed parents tended to have more knowledge and undertook fewer measures. CONCLUSION: When informing and teaching parents on the nature of PA infection, caregivers should provide clear recommendations on reasonable actions to be taken. Also, physicians should anticipate and adequately respond to parental fears and misconceptions.