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Abstract: Background: The role of nasal potential difference (NPD) measurement as a diagnostic test for cystic fibrosis (CF) is a subject of global controversy because of the lack of validation studies, clear reference values, and standardized protocols for diagnostic NPD. Methods: To determine diagnostic NPD frequency, protocols, interpretation, and rater agreement, we surveyed the 18 NPD centres of the European Cystic Fibrosis Society Diagnostic Network Working Group. Results: Fifteen centres reported performing 373 diagnostic NPDs in 2012. Most use the CFF–TDN–SOP (67%) and the chloride-free+isoproterenol response of the side with the largest response (47%) as diagnostic criteria and use centre-specific reference ranges. Rater agreement for five NPD tracings – in general – was good, but poor in tracings with different responses between the two nostrils. Conclusions: NPD is frequently used as a diagnostic and research tool for CF. Performance is highly standardized, centre-specific reference ranges are established, and rater agreement – in general – is good. Centre-independent diagnostic criteria and reference ranges must be defined by multicentre validation studies to improve standardized interpretation for diagnostic use. [Copyright &y& Elsevier]

Patients with cystic fibrosis (CF) are at risk to develop CF related diabetes (CFRD) and subsequently even diabetic neuro- and/or vasculopathy. We sought to determine if there are typical signs of diabetes-related retinal alterations present in CF patients with preserved and impaired glycemic control. During routine annual examination CF patients were offered an additional 7-day period of real time continuous glucose monitoring (rtCGM) and an ophthalmological examination including retinal optical coherence tomography (OCT). Patients were categorized according to the glycemic control, i.e. the results of an oral glucose tolerance test (OGTT) and rtCGM were taken into consideration. OCT data was analyzed by our previously published visual analysis software generating dedicated and spatially resolved deviation maps for visualization and quantification of differences in total retinal thickness and thickness of retinal nerve fiber layer (RNFL) as well as ganglion cell layer (GCL) in comparison to age-matched healthy controls and patients with either type 1 or type 2 diabetes mellitus. Results of the rtCGM and/or OGTT enabled discrimination between patients with normal glycemic control (CFNG; n = 6), with abnormal glycemic control (CFAG; n = 6) and overt CFRD (n = 4). OCT data indicates gradually increasing retinal thinning in all 3 groups, depending on the degree of glucose metabolism disorder compared to healthy controls. At the foveal region total retinal thickness and GCL thickness were significantly thinner in CFRD patients compared to CFNG patients (total retinal thickness: 260.4 µm (239.3–270.8) vs. 275.4 µm (254.3–289.5); GCL: 11.82 µm (11.16–15.25) vs. 17.30 µm (13.95–19.82); each p < 0.05). Although we investigated a rather small number of patients, we obtained evidence that intraretinal neurodegenerative changes occur in each of our subgroups (CFNG, CFAG, CFRD). Beyond this, our results favor the detrimental role of additional diabetes, as the deviations from healthy controls were most pronounced in the CFRD group and are similar to those seen in patients suffering from type 1 or type 2 diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients suffering from melanoma or metastatic cutaneous squamous cell carcinoma profit from immune checkpoint blockade as a therapy. Pneumonitis is a rare but potentially fatal immune-related adverse event, and even more subclinical damage is most likely to occur. The sensitive marker lung clearance index, integrated into pulmonary function testing, was used to detect possible early pulmonary impairment. As slightly impaired lung function could be observed, we recommend the sensitive marker lung clearance index as a diagnostic method that should be implemented into the clinical routine follow-ups during immune checkpoint therapy in order to enable possible further recommendations. Background: Immune checkpoint blockade (ICB) has presented a breakthrough in the treatment of malignant tumors and increased the overall survival of patients with various tumor entities. ICB may also cause immune-related adverse events, such as pneumonitis or interstitial lung disease. The lung clearance index (LCI) is a multiple-breath washout technique offering information on lung pathology in addition to conventional spirometry. It measures the degree of pulmonary ventilation inhomogeneity and allows early detection of pulmonary damage, especially that to peripheral airways. Methods: This cross-sectional study compared the lung function of patients with melanoma or metastatic cutaneous squamous cell carcinoma who received programmed cell death 1 (PD-1) and cytotoxic T-Lymphocyte-associated Protein 4 (CTLA-4) antibodies, alone or in combination, to age- and sex-matched controls. Lung function was assessed using spirometry, according to American Thoracic Society and European Respiratory Society standards, the LCI, and a diffusion capacity of carbon monoxide (DLCO) measurement. Results: Sixty-one screened patients and thirty-eight screened controls led to nineteen successfully included pairs. The LCI in the ICB-treated patients was 8.41 ± 1.15 (mean ± SD), which was 0.32 higher compared to 8.07 ± 1.17 in the control group, but the difference was not significant (p = 0.452). The patients receiving their ICB therapy for under five months showed a significantly lower LCI (7.98 ± 0.77) compared to the ICB patients undergoing therapy for over five months (9.63 ± 1.22) at the point of testing (p = 0.014). Spirometric analysis revealed that the forced expiratory volume between 25 and 75% of the forced vital capacity (FEF25–75%) in the ICB-treated patients was significantly reduced (p = 0.047) compared to the control group. DLCO (%predicted and adjusted for hemoglobin) was 94.4 ± 19.7 in the ICB patients and 93.4 ± 21.7 in the control group (p = 0.734). Conclusions: The patients undergoing ICB therapy showed slightly impaired lung function compared to the controls. Longer periods of ICB treatment led to deterioration of the LCI, which may be a sign of a subclinical inflammatory process. The LCI is feasible and may be easily integrated into the clinical daily routine and could contribute to early detection of pulmonary (auto-)inflammation. [ABSTRACT FROM AUTHOR]

Childhood interstitial lung disease (chILD) is a collective term for a group of rare lung disorders of heterogeneous origin. Surfactant dysfunction disorders are a cause of chILD with onset during the neonatal period and infancy. Clinical signs of tachypnea and hypoxemia are nonspecific and usually caused by common conditions like lower respiratory tract infections. We report on a fullterm male newborn who was readmitted to the hospital at 7 days of age with marked tachypnea and poor feeding during the respiratory syncytial virus season. After exclusion of infection and other, more common congenital disorders, chILD was diagnosed using chest computed tomography and genetic analysis. A likely pathogenic heterozygous variant of SFTPC (c.163C>T, L55F) was detected by whole exome sequencing. The patient received supplemental oxygen and noninvasive respiratory support and was treated with intravenous methylprednisolone pulses and hydroxychloroquine. Despite the treatment, his respiratory situation deteriorated continuously, leading to several hospitalizations and continuous escalation of noninvasive ventilatory support. At 6 months of age, the patient was listed for lung transplant and transplanted successfully aged 7 months. [ABSTRACT FROM AUTHOR]

Aim: Chronic conditions can influence the situation of healthy siblings of affected children. We investigated the opinion of the affected child about the situation of their healthy sibling and the sibling relationship. Methods: We performed a semi‐structured interview with epilepsy or asthma patients aged 6–18 years and asked them to draw a picture: "Epilepsy/Asthma, my siblings and me." Results: Of the 58 children with epilepsy, 67%, and of the 40 children with asthma, 60% thought that their siblings were worried about the condition. Among other aspects, they addressed helplessness during a seizure. Of the children with epilepsy, 83% and of those with asthma, 95% assumed that their siblings were not disadvantaged because of the participant's condition. Of the patients with epilepsy, 91% and of those with asthma, 93% thought that the sibling relationship would not be different without the condition. Of the participants with epilepsy, 86% and of those with asthma, 93% drew a picture; 30% with epilepsy and 14% with asthma visualised an interaction with their siblings in context of a seizure or episode of dyspnoea. Conclusion: According to the affected children, the condition worries their siblings but does not affect the siblings' lives or the sibling relationship. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Pulmonary retransplantation remains controversial due to the increased morbidity and mortality compared with primary lung transplantation. So far, only few data about paediatric retransplantation are available. We retrospectively analysed our experience with retransplantations in children. Methods: Since 1994, seven pulmonary retransplantations in children were performed at our institution. We analysed pretransplant characteristics, operative parameters as well as the post-transplant outcome of these recipients and compared them to 29 patients who underwent primary lung transplantation during the same period. Results: Indications for retransplantation were bronchiolitis obliterans syndrome in six patients and primary graft failure in one patient. Pretransplant characteristics, perioperative morbidity and mortality were similar in both groups. Hospital mortality was 2/7 (29%) after retransplantation and 6/29 (21%) after primary transplantation (p =0.64). Actuarial 3-year survival was 71% and 60% after redo and primary transplantation, respectively (p =0.50). Development of bronchiolitis obliterans syndrome did not differ between both groups (p =0.99). Conclusions: In our small cohort of paediatric patients, pulmonary retransplantation was associated with an acceptable long-term outcome comparable to primary pulmonary transplantation. This differs from currently available data. However, further long-term studies including more patients and longer follow-up intervals are required. [ABSTRACT FROM AUTHOR]

Mueller C, Hansen G, Ballmann M, Schwerk N, Simon AR, Goerler H, Strueber M. Size reduction of donor organs in pediatric lung transplantation. Pediatr Transplantation 2010:14: 364–368. © 2009 John Wiley & Sons A/S. Lobar transplantation and peripheral segmental resection allow downsizing of larger lungs for use in smaller recipients, particularly with regard to pediatric patients on the high urgency waiting list. We studied the safety and outcome of these techniques in children. All pediatric patients who underwent reduced size LTx between January 2000 and March 2009 were retrospectively reviewed and compared with pediatric patients who underwent full size LTx during the same period. Patient characteristics, intra-operative variables, and post-operative morbidity and mortality were compared. Among 28 primary LTxs, 16 (57%) were performed in reduced size technique. Preoperatively, there was a trend toward a higher rate of mechanical ventilation and a higher capillary pCO2 in the reduced size group. Surgical procedures tended to be longer in that group. Post-operative complications, survival and functional parameters were comparable between both groups. Our study demonstrates that reduced size LTx in children is a reliable therapeutic option that provides results comparable to full size LTx. This technique might help to reduce waiting list mortality by expanding the donor pool in pediatric LTx. [ABSTRACT FROM AUTHOR]

Background: Pediatric lung transplantation (LTx) remains a challenge for a highly selected group of patients. The requirements for immunosuppressive therapy and the associated risks must be weighed against the long-term prognosis of this operation. Therefore, we retrospectively analyzed our experience after 53 lung and heart–lung transplantations (HLTx) in children. Methods: All pediatric patients <18 years of age who underwent LTx (n = 37) and HLTx (n = 16) at our institution were included in this study. We analyzed indications for transplantation, survival rates and causes of death. Herein we assess pediatric-specific challenges in comparison to adults. Results: Thirty-day mortality was 13.2%. Kaplan–Meier survival rates at 1, 3, 5 and 10 years were 69%, 64%, 44% and 39%, respectively. Main indications for transplantation were cystic fibrosis and congenital heart disease with Eisenmenger syndrome. Other diagnoses were retransplantation, primary pulmonary hypertension and pulmonary fibrosis. The main causes of death were infection and chronic graft failure. Reduced-size transplantation was performed in 42% of double-lung transplantation (DLTx) patients without negatively impacting survival. Six patients received pulmonary retransplantation, 1 of whom died early. Conclusions: Pediatric transplantation is a feasible therapeutic option when undertaken by an experienced team. It should be offered to the small patient population suffering from end-stage pulmonary disease. The limited number of pediatric donor organs can be overcome by using reduced-size organs. However, the management of pediatric-specific complications and therapeutic requirements is essential for positive long-term results after LTx in these patients. [Copyright &y& Elsevier]

Abstract: This report describes the first biosynthetic analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) in freshly excised human rectal biopsies. Expression of functional CFTR was assessed by intestinal current measurement (ICM) prior to biosynthetic studies. Several structural features of CFTR are found to be comparable to those established in CFTR-expressing cell lines. Interestingly, maturation of CFTR increases substantially in tissue incubated at 26 °C. Our data provide a solid basis for future studies on the characterisation of CFTR in pathological cases. [Copyright &y& Elsevier]

Background: In adults with rheumatic diseases pulmonary complications are relevant contributors to morbidity and mortality. In these patients diffusion capacity for CO (DLCO) is an established method to detect early pulmonary impairment. Pilot studies using DLCO indicate that early functional pulmonary impairment is present even in children with rheumatic disease albeit not detectable by spirometry and without clinical signs of pulmonary disease. Since the lung clearance index (LCI) is also a non-invasive, feasible and established method to detect early functional pulmonary impairment especially in children and because it requires less cooperation (tidal breathing), we compared LCI versus DLCO (forced breathing and breath-holding manoeuvre) in children with rheumatic diseases. Findings: Nineteen patients (age 9–17 years) with rheumatic disease and no clinical signs of pulmonary disease successfully completed LCI and DLCO during annual check-up. In 2 patients LCI and DLCO were within physiological limits. By contrast, elevated LCI combined with physiological results for DLCO were seen in 8 patients and in 9 patients both, the LCI and DLCO indicate early functional pulmonary changes. Overall, LCI was more sensitive than DLCO to detect early functional pulmonary impairment (p = 0.0128). Conclusions: Our findings suggest that early functional pulmonary impairment is already present in children with rheumatic diseases. LCI is a very feasible and non-invasive alternative for detection of early functional pulmonary impairment in children. It is more sensitive and less cooperation dependent than DLCO. Therefore, we suggest to integrate LCI in routine follow-up of rheumatic diseases in children. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF; OMIM 219700) is a rare genetic disorder caused by a chloride channel defect, resulting in lung disease, pancreas insufficiency and liver impairment. Altered L-arginine (Arg)/nitric oxide (NO) metabolism has been observed in CF patients' lungs and in connection with malnutrition. The aim of the present study was to investigate markers of the Arg/NO pathway in the plasma and urine of CF patients and to identify possible risk factors, especially associated with malnutrition. We measured the major NO metabolites nitrite and nitrate, Arg, a semi-essential amino acid and NO precursor, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) in plasma and urine samples of 70 pediatric CF patients and 78 age-matched healthy controls. Biomarkers were determined by gas chromatography–mass spectrometry and high-performance liquid chromatography. We observed higher plasma Arg (90.3 vs. 75.6 µM, p < 0.0001), ADMA (0.62 vs. 0.57 µM, p = 0.03), Arg/ADMA ratio (148 vs. 135, p = 0.01), nitrite (2.07 vs. 1.95 µM, p = 0.03) and nitrate (43.3 vs. 33.1 µM, p < 0.001) concentrations, as well as higher urinary DMA (57.9 vs. 40.7 µM/mM creatinine, p < 0.001) and nitrate (159 vs. 115 µM/mM creatinine, p = 0.001) excretion rates in the CF patients compared to healthy controls. CF patients with pancreatic sufficiency showed plasma concentrations of the biomarkers comparable to those of healthy controls. Malnourished CF patients had lower Arg/ADMA ratios (p = 0.02), indicating a higher NO synthesis capacity in sufficiently nourished CF patients. We conclude that NO production, protein-arginine dimethylation, and ADMA metabolism is increased in pediatric CF patients. Pancreas and liver function influence Arg/NO metabolism. Good nutritional status is associated with higher NO synthesis capacity and lower protein-arginine dimethylation. [ABSTRACT FROM AUTHOR]

Balanced composition of a well-functioning pulmonary surfactant is crucial and essential for normal breathing. Here, we explored whether the composition of lipids recovered by broncho-alveolar lavage (BAL) in children with cystic fibrosis (CF) differ from children with protracted bacterial bronchitis (PBB) and controls. We wanted to differentiate, if alterations are primarily caused by the disease process or secondary due to an increased amount of cell-membrane lipids derived from inflammatory cells. Comprehensive lipidomics profiles of BAL fluid from children diagnosed with CF, PBB and controls were generated by electrospray ionization tandem mass spectrometry analysis. BAL cell differential and numbers were examined. 55 children (37 patients with CF, 8 children with PBB and 10 controls) were included in this study. Results showed comparable total quantities of lipids in all groups. Phospholipids were the major lipid fraction and similar in all groups, whereas the fractions of cholesteryl esters were less and of free cholesterol were increased in children with CF. Among the phospholipids, patients with CF had higher proportion of the non-surfactant membrane-lipids in the classes phosphatidylethanolamine based plasmalogens (PE P), phosphatidylethanolmine (PE) and phosphatidylserine (PS), but a lower proportion of phosphatidylcholine (PC) compared to healthy controls. No such changes were identified in the BAL fluid of children diagnosed with PBB. No differences were observed for the surfactant lipids dipalmitoyl-phosphatidylcholin (PC 32:0) and phosphatidylglycerol (PG). In CF patients with neutrophilic airway inflammation the lipid composition for surfactant phospholipid components were unchanged, whereas alteration in lipid profile were characteristic for those found in membranes of inflammatory cells. We suspect that the changes in CF were caused by the prolonged inflammation in contrast to a relatively short standing process in PBB. • Patients with cystic fibrosis have different lipidomics in the broncho alevolar lavage fluid compared to PBB and healthy controls • Lipidomics of the BAL fluid from patients with CF show increased lipids derived from cell-membranes • The amount of surfactant lipids between CF, PBB patients and healthy controls is comparable [ABSTRACT FROM AUTHOR]

Background: Staphylococcus aureus is an important pathogen in cystic fibrosis (CF). However, it is not clear which factors are associated with worse lung function in patients with persistent S. aureus airway cultures. Our main hypothesis was that patients with high S. aureus density in their respiratory specimens would more likely experience worsening of their lung disease than patients with low bacterial loads. Methods: Therefore, we conducted an observational prospective longitudinal multi-center study and assessed the association between lung function and S. aureus bacterial density in respiratory samples, co-infection with other CF-pathogens, nasal S. aureus carriage, clinical status, antibiotic therapy, IL-6- and IgG-levels against S. aureus virulence factors. Results: 195 patients from 17 centers were followed; each patient had an average of 7 visits. Data were analyzed using descriptive statistics and generalized linear mixed models. Our main hypothesis was only supported for patients providing throat specimens indicating that patients with higher density experienced a steeper lung function decline (p<0.001). Patients with exacerbations (n = 60), S. aureus small-colony variants (SCVs, n = 84) and co-infection with Stenotrophomonas maltophilia (n = 44) had worse lung function (p = 0.0068; p = 0.0011; p = 0.0103). Patients with SCVs were older (p = 0.0066) and more often treated with trimethoprim/sulfamethoxazole (p = 0.0078). IL-6 levels positively correlated with decreased lung function (p<0.001), S. aureus density in sputa (p = 0.0016), SCVs (p = 0.0209), exacerbations (p = 0.0041) and co-infections with S. maltophilia (p = 0.0195) or A. fumigatus (p = 0.0496). Conclusions: In CF-patients with chronic S. aureus cultures, independent risk factors for worse lung function are high bacterial density in throat cultures, exacerbations, elevated IL-6 levels, presence of S. aureus SCVs and co-infection with S. maltophilia. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance. Methods: In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4. Results: A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%. Conclusion: In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher. [ABSTRACT FROM AUTHOR]

Abstract: Background: An annual oral glucose tolerance test (OGTT) has become part of standard care in cystic fibrosis (CF) to screen for CF-related diabetes (CFRD). The objective of this study was to determine predictors for future CFRD derived from an OGTT. Methods: Data were collected from 2001 to 2009 during a longitudinal prospective study on “Early Diagnosis of Diabetes Mellitus in CF Patients, trial number NCT00662714”. The 1093 patients included in the analysis had at least two valid OGTTs each and no CFRD at the first glucose challenge. Normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and CFRD were defined using WHO criteria. In a subsample of 521 patients, the NGT group was further divided into patients with a 1-hour glucose level >11.1mmol/l (indeterminate glucose tolerance — INDET) and those with a lower level (no-INDET). Logistic regression analysis was used to identify predictors from the first OGTT for future diabetes. Results: Compared with NGT (n=838), IFG (n=70; odds ratio [OR], 95% confidence interval: 2.92, 1.60–5.33) and IGT without IFG (n=155, OR 2.37, 1.48–3.79) were both significant and independent risk factors for future CFRD. Patients with IGT and IFG (n=30) had the highest risk (OR 5.30, 2.32–12.10). In the subsample analysis, INDET (n=116) was associated with a significantly increased risk for future CFRD compared with no-INDET (n=269; OR 2.81, 1.43–5.51). Conclusions: In this large study, IFT, IGT, and INDET were all predictors of future CFRD. The OGTT in patients with CF should include a 1-hour post-challenge value. [Copyright &y& Elsevier]

Background: Long-term exercise interventions have been shown to improve vital capacity in cystic fibrosis (CF). Yet, no data are available indicating positive effects of long-term exercise training on FEV1. Methods: 39 Swiss patients with CF were randomly divided into strength training (ST, n=12), endurance training (AT, n=17) and controls (CONCH, n=10), and also compared with age-matched Swiss (n=35) and German (n=701) CF registry data. A partially supervised training of 3×30min/week for 6months took place with measurements at baseline and after 3, 6, 12 and 24months. Primary outcome was FEV1 at 6months. Results: FEV1 increased significantly in both training groups compared with CONCH (AT:+5.8±0.95, ST:+7.4±2.5, CONCH:−11.5±2.7% predicted, p<0.001) and both registry groups at 6months. At 24months, changes in favour of the training groups persisted marginally compared with CONCH, but not compared with registry data. Conclusions: A partially supervised training over 6months improved FEV1 but effects were basically gone 18months off training. Regular long-term training should be promoted as essential part of treatment in CF. [ABSTRACT FROM AUTHOR]

Background: Published estimates on age-dependent frequency of diabetes in cystic fibrosis (CF) vary widely, and are based mostly on older data. However, CF treatment and prevention of comorbidities changed over recent years. In many studies, definition of cystic fibrosis-related diabetes (CFRD) is not in line with current guideline recommendations. Therefore, we evaluated age-dependent occurrence of glucose abnormalities and associated risk factors in CF patients who participated in a multicenter screening program using oral glucose tolerance tests (OGTT). Methods: Between 2001 and 2010, 43 specialized CF centers from Germany and Austria serially performed 5,179 standardized OGTTs in 1,658 clinically stable, non-pregnant CF patients with no prior steroid medication or lung transplantation. Age-dependent occurrence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, one (DGT) or two consecutive (CFRD) diabetic OGTTs was analyzed, using Kaplan Meier curves. Cox proportional-hazards models were created to elucidate the influence of sex or underweight. Results: At baseline/last OGTT, median age was 15.9 years/18.2 years and 30.6%/31.8% of patients were underweight. 25% of patients showed IFG at age 14.3 years; IGT at age 16.3 years; IFG+IGT combined at age 17.7 years. DGT was observed in 25% of patients at age 22.6 years; CFRD at age 34.5 years. Females had a 3.54 [95% CI 1.23–10.18] times higher risk for CFRD; risk for DGT was 2.21 [1.22–3.98] times higher. Underweight was a risk factor for IGT (HR [95% CI]: 1.38 [1.11–1.71]) and IFG+IGT (1.43 [1.11–1.83]), and in males also for DGT (1.49 [1.09–2.04]). Conclusions/Significance: If confirmation of diabetes by a second test is required, as recommended in current guidelines, age at CFRD diagnosis was higher compared to most previous studies. However, known risk factors for glucose abnormalities in CF were confirmed. Confirmation of diabetic OGT by a repeat test is important for a consistent diagnosis of CFRD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Volumetric capnography reflecting the course of CO2-exhalation is used to assess ventilation inhomogeneity. Calculation of the slope of expiratory phase 3 and the capnographic index (KPIv) from expirograms allows quantification of extent and severity of small airway impairment. However, technical limitations have hampered more widespread use of this technique. Using expiratory molar mass–volume-curves sampled with a handheld ultrasonic flow sensor during tidal breathing is a novel approach to extract similar information from expirograms in a simpler manner possibly qualifying as a screening tool for clinical routine. The aim of the present study was to evaluate calculation of the KPIv based on molar mass–volume-curves sampled with an ultrasonic flow sensor in patients with CF and controls by assessing feasibility, reproducibility and comparability with the Lung Clearance Index (LCI) derived from multiple breath washout (MBW) used as the reference method. Methods: Measurements were performed in patients with CF and healthy controls during a single test occasion using the EasyOne Pro, MBW Module (ndd Medical Technologies, Switzerland). Results: Capnography and MBW were performed in 87/96 patients with CF and 38/42 controls, with a success rate of 90.6% for capnography. Mean age (range) was 12.1 (4–25) years. Mean (SD) KPIv was 6.94 (3.08) in CF and 5.10 (2.06) in controls (p=0.001). Mean LCI (SD) was 8.0 (1.4) in CF and 6.2 (0.4) in controls (p=<0.001) and correlated significantly with the KPIv (p=<0.001). Conclusion: Calculation of the KPIv based on molar mass–volume-curves is feasible. KPIv is significantly different between patients with CF and controls and correlates with the LCI. However, individual data revealed a relevant overlap between patients and controls requiring further evaluation, before this method can be recommended for clinical use. [Copyright &y& Elsevier]

The opportunistic bacterium Pseudomonas aeruginosa is a major nosocomial pathogen causing both devastating acute and chronic persistent infections. During the course of an infection, P. aeruginosa rapidly adapts to the specific conditions within the host. In the present study, we aimed at the identification of genes that are highly expressed during biofilm infections such as in chronically infected lungs of patients with cystic fibrosis ( CF), burn wounds and subcutaneous mouse tumours. We found a common subset of differentially regulated genes in all three in vivo habitats and evaluated whether their inactivation impacts on the bacterial capability to form biofilms in vitro and to establish biofilm-associated infections in a murine model. Additive effects on biofilm formation and host colonization were discovered by the combined inactivation of several highly expressed genes. However, even combined inactivation was not sufficient to abolish the establishment of an infection completely. These findings can be interpreted as evidence that either redundant traits encode functions that are essential for in vivo survival and chronic biofilm infections and/or bacterial adaptation is considerably achieved independently of transcription levels. Supplemental screens, will have to be applied in order to identify the minimal set of key genes essential for the establishment of chronic infectious diseases. [ABSTRACT FROM AUTHOR]

Background: The state of oligomerization of surfactant associated protein-A (SP-A) monomers differs between individuals. This likely affects SP-A's functional properties and could thereby influence clinical status in patients with lung diseases. In this study we focus on SP-A structure in cystic fibrosis (CF) compared to both healthy subjects and disease controls. Methods: SP-A composition and function were assessed in both bronchoalveolar lavage (BAL) fluid and serum of 46 CF patients with mild disease, 25 patients with chronic bronchitis and 22 healthy subjects by gel chromatography and a functional agglutination assay. Relation of SP-A agglutination ability to disease severity of the subjects was explored. Results: SP-A was present in seven major oligomeric forms with the majority of SP-A being structurally organized as complex oligomeric forms. More complex oligomeric forms were associated with better SP-A function with regard to its agglutination ability. These forms were more frequently observed in BAL than in serum, but there were no differences between disease groups. In CF patients, more complex forms of SP-A were associated with better lung function. Conclusions: Organizational structure of SP-A affects its functional activity and is linked to disease severity in CF. [ABSTRACT FROM AUTHOR]

Background/Aims: Knowledge about the abundance and distribution of CFTR protein glycoforms in native lung tissue is scarce. For upcoming studies with correctors and potentiators for CFTR it is important to get more information about mutant CFTR protein biochemistry. Target for novel treatment is the most afflicted organ in cystic fibrosis (CF), the lung. Methods: Lung tissue sampled from patients with CF and non-CF donors prior to lung transplantation was examined for CFTR-immunoreactive signals by immunoblot. Quantitation of the immunoreactive signals was carried out by densitometry. Results: The complexglycosylated and mannose-rich CFTR isoforms were present in all non-CF specimens, whereas no or only the immature CFTR isoform was visible in CF samples. Whereas some complexglycosylated CFTR was often present in rectal biopsies of F508del homozygous subjects, no mature CFTR was detectable in CF lungs at the stage of terminal respiratory insufficiency. Conclusion: Immunoblot analysis of CFTR in lung tissue is feasible, but in context of the upcoming studies of CFTR correctors and potentiators rectal biopsies seem to be a more appropriate choice because of their safe and repeatable excision. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50,100 and 200 mg) or matching placebo. Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. Conclusions In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. [ABSTRACT FROM AUTHOR]

Abstract: The major cystic fibrosis mutation F508del has been classified by experiments in animal and cell culture models as a temperature-sensitive mutant defective in protein folding, processing and trafficking, but literature data on F508del CFTR maturation and function in human tissue are inconsistent. In the present study the molecular pathology of F508del CFTR was characterized in freshly excised rectal mucosa by bioelectric measurement of the basic defect and CFTR protein analysis by metabolic labelling or immunoblot. The majority of investigated F508del homozygous subjects expressed low amounts of complex-glycosylated mature F508del CFTR and low residual F508del CFTR-mediated chloride secretory activity in the rectal mucosa. The finding that some F508del CFTR escapes the ER quality control in vivo substantiates the hope that the defective processing and trafficking of F508del CFTR can be corrected by pharmacological agents. [Copyright &y& Elsevier]

Benden C, Faro A, Worley S, Arrigain S, Aurora P, Ballmann M, Boyer D, Conrad C, Eichler I, Elidemir O, Goldfarb S, Mallory GB, Mogayzel PJ, Parakininkas D, Solomon M, Visner G, Sweet SC, Danziger-Isakov LA. Minimal acute rejection in pediatric lung transplantation – Does it matter?. Pediatr Transplantation 2010: 14:534–539. © 2010 John Wiley & Sons A/S. In adult lung transplantation, a single minimal AR episode is a significant predictor of BOS independent of other factors. However, the significance of single minimal AR episodes in children is unknown. A retrospective, multi-center analysis was performed to determine whether isolated single AR episodes are associated with an increased BOS risk in children. Risk factors for BOS, death, or re-transplantation, and a combined outcome of BOS, death, or re-transplantation were assessed. Original data included 577 patients (<21 yr of age). A total of 383 subjects were eligible for the study. Fifteen percent of patients developed BOS, and 13% of patients either died or underwent re-transplant within one-yr post-transplant. In the multivariable survival model for time to BOS, there was no significant risk to developing BOS after a single minimal AR (A1) episode (HR 1.7, 95% CI 0.64–4.8; p = 0.28). Even after a second minimal AR episode, no significant risk for BOS was appreciated. However, a single episode of mild AR (A2) was associated with twice the risk of BOS within one-yr post-transplant. In this select cohort, a single minimal AR episode was not associated with an increased risk for BOS within one yr following lung transplantation, in contrast to previous reports in adults. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ganciclovir together are superior in preventing CMV viremia than ganciclovir alone. Methods: A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models. Results: Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus (p < 0.05). In multivariable models, patients who did not receive CMVIG as part of their prophylaxis were 3 times more likely to develop CMV infection (hazard ratio, 3.4; 95% confidence interval, 1.2–9.5) independent of CMV serostatus. However, CMVIG administration was not associated with decreased risk of episodes of CMV disease. Receipt of CMVIG was not associated with decreased risks of post-transplant morbidities (acute rejection, respiratory viral infection or early bronchiolitis obliterans) or morbidity within the first year after pediatric lung transplantation. Conclusion: The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation. [Copyright &y& Elsevier]

Abstract: There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families. [Copyright &y& Elsevier]

Background: Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized. Methods: A retrospective, multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models. Results: Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p < 0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio [HR] 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age >15 years were associated with PFI (p < 0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8). Conclusions: Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization. [Copyright &y& Elsevier]

Background: In a cross-sectional analysis of cystic fibrosis (CF) patients with mild lung disease, reduced surfactant activity was correlated to increased neutrophilic airway inflammation, but not to lung function. So far, longitudinal measurements of surfactant function in CF patients are lacking and it remains unclear how these alterations relate to the progression of airway inflammation as well as decline in pulmonary function over time. Methods: As part of the BEAT trial, a longitudinal study to assess the course of airway inflammation in CF, we studied lung function, surfactant function and endobronchial inflammation using bronchoalveolar lavage fluid from 20 CF patients with normal pulmonary function (median FEV1 94% of predicted) at three times over a three year period. Results: There was a progressive loss of surfactant function, assessed as minimal surface tension. The decline in surfactant function was negatively correlated to an increase in neutrophilic inflammation and a decrease in lung function, assessed by FEV1, MEF75/25%VC, and MEF25%VC. The concentrations of the surfactant specific proteins A, C and D did not change, whereas SP-B increased during this time period. Conclusion: Our findings suggest a link between loss of surfactant function driven by progressive airway inflammation and loss of small airway function in CF patients with limited lung disease. [ABSTRACT FROM AUTHOR]

Alterations in the L-arginine (Arg)/nitric oxide (NO) pathway have been reported in cystic fibrosis (CF; OMIM 219700) as the result of various factors including systemic and local inflammatory activity in the airways. The aim of the present study was to evaluate the Arg/NO metabolism in pediatric CF patients with special emphasis on lung impairment and antibiotic treatment. Seventy CF patients and 78 healthy controls were included in the study. CF patients (43% male, median age 11.8 years) showed moderately impaired lung functions (FEV1 90.5 ± 19.1% (mean ± SD); 21 (30%) had a chronic Pseudomonas aeruginosa (PSA) infection, and 24 (33%) had an acute exacerbation). Plasma, urinary, and sputum concentrations of the main Arg/NO metabolites, nitrate, nitrite, Arg, homoarginine (hArg), and asymmetric dimethylarginine (ADMA) were determined in pediatric CF patients and in healthy age-matched controls. Clinical parameters in CF patients included lung function and infection with PSA. Additionally, the Arg/NO pathway in sputum samples of five CF patients was analyzed before and after routine antibiotic therapy. CF patients with low fractionally exhaled NO (FENO) showed lower plasma Arg and nitrate concentrations. During acute exacerbation, sputum Arg and hArg levels were high and dropped after antibiotic treatment: Arg: pre-antibiotics: 4.14 nmol/25 mg sputum vs. post-antibiotics: 2.33 nmol/25 mg sputum, p = 0.008; hArg: pre-antibiotics: 0.042 nmol/25 mg sputum vs. post-antibiotics: 0.029 nmol/25 mg sputum, p = 0.035. The activated Arg/NO metabolism in stable CF patients may be a result of chronic inflammation. PSA infection did not play a major role regarding these differences. Exacerbation increased and antibiotic therapy decreased sputum Arg concentrations. [ABSTRACT FROM AUTHOR]

Abstract: Ex vivo biochemical analysis of rectal biopsies of a carrier of the mild 2789+5 G-A CFTR frameshift splice site mutation revealed mutant truncated CFTR of expected size and an imbalance of more core-glycosylated and less mature full-length CFTR. This first immunoblot analysis of a non-F508del CFTR mutant protein derived from human tissue demonstrates that splice site mutations should not only be investigated at the mRNA, but also at the protein level to properly interpret the associations between genotype, molecular pathology and disease. [Copyright &y& Elsevier]

We present a 14-year-old boy who suffered from progressive biventricular cardiac failure and secondary pulmonary artery hypertension associated with the rarely seen Alström syndrome. The boy underwent successful heart–lung transplantation. We conclude from this report that heart–lung transplantation in patients with Alström syndrome is a viable therapeutic option in select cases. [Copyright &y& Elsevier]