Gratiana Steinkamp

Placebo-controlled, double-blind, randomized study of aerosolized tobramycin for early treatment of Pseudomonas aeruginosa colonization in cystic fibrosis

In chronic Pseudomonas aeruginosa pulmonary infection of patients with cystic fibrosis (CF), antibiotic therapy generally fails to eradicate the bacterial pathogen. The mucoid bacterial phenotype, high sputum production by the host, and low airway levels of antibiotics seem to be responsible for the observed decrease in antibiotic efficacy. We hypothesized that early antibiotic treatment by inhalation in CF patients may be able to prevent or at least delay airway infection. In a prospective placebo‐controlled, double‐blind, randomized multicenter study, 22 CF patients received either 80 mg b.i.d. of aerosolized tobramycin or placebo for a period of 12 months shortly after the onset of P. aeruginosa pulmonary colonization.

Improvement of nutritional status and lung function after long-term nocturnal gastrostomy feedings in cystic fibrosis

We investigated weight gain and clinical course of 14 patients with cystic fibrosis (CF), aged 7 to 23 years, who received long-term nocturnal supplemental feedings by means of percutaneous endoscopic gastrostomies (PEGs). The patients (nine female, five male) were moderately malnourished; the weight-for-height value was 77.8% (SD 6.4%) of the predicted value. Lung function tests revealed severe airway obstruction; mean vital capacity was 46.1% (SD 14.4%), and mean forced expiratory volume in 1 second (FEV1) was 30.8% (SD 12.3%) of predicted value. A nonelemental formula providing 35% of total energy from fat was used for nocturnal feedings. The patients received 800 to 1500 kcal per night by slow intragastric infusions. Enteric-coated pancreatic microsphere preparations were taken orally just before bedtime. After 1 year of supplemental feedings, body weight had increased by 6.0 kg (SD 3.6 kg) and weight-for-height value by 9.0% (SD 6.1%) of predicted compared with baseline values. Lung function also improved significantly: vital capacity increased by 8.2% (SD6.3%) and FEV1 by 3.9% (SD 4.2%) of predicted values (p < 0.01). The total duration of nocturnal feedings was 364 months, or 26 months per patient. Nine of the fourteen patients continue to use the PEG, three patients had the PEG tube removed, and two patients have died 21 and 23 months after PEG insertion. We conclude that nocturnal PEG feedings of malnourished patients with CF improve nutritional status and lung function without major side effects.

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)

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 µg twice daily) with adding a long‐acting beta‐2 agonist to the ICS (SFC, salmeterol 50 µg/ FP 100 µg twice daily) in children with uncontrolled 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.

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.

Fibrosing Alveolitis in Childhood A Long-Term Follow-up

ABSTRACT. A retrospective analysis of 14 pediatric cases with fibrosing alveolitis, proved by lung biopsy, was carried out. The children were initially 6‐16 years old (mean: 9.8 years) and were observed for 2 to 7 years. Symptoms had been present prior to diagnosis for 1 to 156 weeks (median: 11 weeks). The most prominent clinical findings were dyspnoea (100%), dry cough (91 %), tachypnoea (85%), and weight loss (70%). Open (n=9) or transbronchial (n=5) lung biopsy specimens had predominantly cellular appearances in 8 children (group A) and showed predominantly fibrotic changes in 6 cases (group B). Lung function tests revealed a marked ventilatory impairment in all children. Mean vital capacity was 44% (SD 16%), and total lung capacity 58% (SD 14%) of the predicted normal values. Specific lung compliance was significantly lower in children with fibrotic changes (mean: 0.016 vs. 0.030 ml/cmH2O/ml in patients of group A, p<0.05). Results from 200 lung function measurements were evaluated during the follow‐up. Corticoisteroid treatment improved vital capacity in all children after 6 and 12 months of treatment to 64% and 62% of the predicted normal, respectively. Deterioration of pulmonary function was observed in 7 children when prednisone was tapered to below 10 mg per day. Only 4 children had a normal vital capacity at their last visit to the clinic. We conclude that children with fibrosing alveolitis experience severe alterations in lung function, and that the overall outlook is quite unfavorable.

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.

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.

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 centers 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) &mgr;g/g and 61% of the samples showed elevated FC concentrations (>50 &mgr;g/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 &mgr;g/g stool) was associated with considerably higher FC values compared to normal pancreatic function (median FC 68 vs 29 &mgr;g/g, P < 0.0001). F508del homozygous subjects showed a trend to higher FC values than heterozygous patients (median 71 vs 62 &mgr;g/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.