Journal of Cystic Fibrosis - Articles in Press

Risk factors for Mycobacterium abscessus infection in cystic fibrosis patients; a case–control study - Corrected Proof

2012-02-20

Abstract: Mycobacterium abscessus is a nontuberculous mycobacterium that is increasingly recognized as an opportunistic pathogen in cystic fibrosis (CF) patients. Factors that predispose CF patients to infection by this environmental bacterium remain unknown. In a case–control study of 22 CF patients with M. abscessus infection and 22 CF controls, we investigated risk factors for MAB infection as well as the positioning of MAB infection in relation to the other pathogens infecting CF patients. No clear risk factors were found; steroid treatment and CF related diabetes were equally common among cases and controls. M. abscessus disease affects CF patients of varying age, lung function and co-morbidities. Antimicrobial maintenance therapy did not prevent M. abscessus infection. A history of Stenotrophomonas maltophilia infection was significantly more frequent among cases than among controls and there may be a relation with Aspergillus fumigatus infection, or both may be signs of advanced lung damage that predisposes to MAB disease. The absence of clear risk factors and the omnipresence of MAB in the environment suggest that MAB infection in CF patients is a random event. Its symptoms and impact on lung function seem to warrant treatment.

The use of nebulised aztreonam lysine (AZLI) in aztreonam hypersensitive patients - Corrected Proof

P. Whitaker, C. Etherington, K. Williams, S. Conway, D. Peckham — 2012-02-20

Dear Editor, To date our experience with nebulised aztreonam lysine (AZLI) has been in patients with cystic fibrosis (CF) who have exhausted all other therapeutic options. These patients have advanced lung disease and required frequent courses of intravenous antibiotics. Unfortunately in patients with CF non-immediate hypersensitivity reactions to beta-lactam antibiotics are common. It has been reported that up to 20% of patients have multiple beta-lactam reactions . At the Regional Adult CF Unit in Leeds around 10% of patients have had a previous hypersensitivity reaction to aztreonam.

Acknowledgment of referees - Corrected Proof

2012-02-13

Comparison of antibiotic susceptibility patterns in Pseudomonas aeruginosa isolated from adult patients with cystic fibrosis (CF) with invasive Pseudomonas aeruginosa from non-CF patients - Corrected Proof

2012-02-13

The role of bacterial pathogens in CF pulmonary disease contributes greatly to the morbidity and mortality in patients with CF. CF patients have recurrent and chronic respiratory tract infections and most of their morbidity and mortality is due to such infections throughout their life . These infections are usually dominated by non-fermenting Gram-negative organisms (Burkholderia cenocepacia and Stenotrophomonas maltophilia), including Pseudomonas aeruginosa. P. aeruginosa is the single most important pathogen in this patient population. Recent advances in treatment, which include intensive physiotherapy and aggressive antibiotic treatment, have greatly improved the outlook for patients. However, with the improvement in survival rates in CF patients, a new range of pulmonary issues have arisen. These include the emergence of multi-drug resistant strains of P. aeruginosa and the appearance of organisms with increased virulence such as the Burkholderia cepacia complex (BCC).

Cystic fibrosis genetic counseling difficulties due to the identification of novel mutations in the CFTR gene - Corrected Proof

Myrto Poulou, Irini Fylaktou, Maria Fotoulaki, Emmanuel Kanavakis, Maria Tzetis — 2012-02-13

Abstract: Background: The Cystic Fibrosis database includes amongst the 1893 gene mutations and polymorphisms a lot of missense mutations, the disease status of which still remains unproven. In populations with high rates of CFTR mutation heterogeneity, molecular diagnosis is difficult often causing counseling difficulties especially in cases of rare and/or novel mutations.Methods: Approaches to counseling in cases of novel variants.Results: Thirty-seven novel variants (4 synonymous, 24 missense, 2 frameshift and 10 intronic substitutions) were identified and evaluated with the help of in silico tools.Conclusions: In a diagnostic environment the answers have to be given within a specific timeframe, the in silico tools in combination with the phenotype offer some help but their diagnostic value is limited and cannot be used in isolation for the determination of the severity of the mutation.

Retrospective analysis of stored dried blood spots from children with cystic fibrosis and matched controls to assess the performance of a proposed newborn screening protocol in Switzerland - Corrected Proof

2012-02-02

Abstract: Background: Newborn screening (NBS) for Cystic Fibrosis (CF) has been introduced in many countries, but there is no ideal protocol suitable for all countries. This retrospective study was conducted to evaluate whether the planned two step CF NBS with immunoreactive trypsinogen (IRT) and 7 CFTR mutations would have detected all clinically diagnosed children with CF in Switzerland.Methods: IRT was measured using AutoDELFIA Neonatal IRT-Kit in stored NBS cards.Results: Between 2006 and 2009, 66 children with CF were reported, 4 of which were excluded for various reasons (born in another country, NBS at 6months, no informed consent). 98% (61/62) had significantly higher IRT compared to matched control group. There was one false negative IRT result in an asymptomatic child with atypical CF (normal pancreatic function and sweat test).Conclusions: All children but one with atypical CF would have been detected with the planned two step protocol.

Ivacaftor potentiation of multiple CFTR channels with gating mutations - Corrected Proof

2012-02-01

Abstract: Background: The investigational CFTR potentiator ivacaftor (VX-770) increased CFTR channel activity and improved lung function in subjects with CF who have the G551D CFTR gating mutation. The aim of this in vitro study was to determine whether ivacaftor potentiates mutant CFTR with gating defects caused by other CFTR gating mutations.Methods: The effects of ivacaftor on CFTR channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid (FRT) cells expressing different CFTR gating mutations.Results: Ivacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations.Conclusion: These in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D.

A randomized placebo-controlled trial of miglustat in cystic fibrosis based on nasal potential difference - Corrected Proof

Anissa Leonard, Patrick Lebecque, Jasper Dingemanse, Teresinha Leal — 2012-01-27

Abstract: Background: Preclinical data suggest that miglustat could restore the function of the cystic fibrosis transmembrane conductance regulator gene in cystic fibrosis cells.Methods: Single-center, randomized, double-blind, placebo-controlled, crossover Phase II study in 11 patients (mean±SD age, 26.3±7.7years) homozygous for the F508del mutation received oral miglustat 200mgt.i.d. or placebo for two 8-day cycles separated by a 14-day washout period. The primary endpoint was the change in total chloride secretion (TCS) assessed by nasal potential difference.Results: No statistically significant changes in TCS, sweat chloride values or FEV1 were detected. Pharmacokinetic and safety were similar to those observed in patients with other diseases exposed to miglustat.Conclusions: There was no evidence of a treatment effect on any nasal potential difference variable. Further studies with miglustat need to adequately address criteria for assessment of nasal potential difference.

Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis - Corrected Proof

Sophia L. Markantonis, Anna Katelari, Eleni Pappa, Stavros Doudounakis — 2012-01-27

Abstract: Background: A high incidence of adverse skin reactions following long-term oral administration of voriconazole in children with cystic fibrosis and allergic bronchopulmonary aspergillosis (ABPA). The aim was to study the pharmacokinetics of voriconazole in these patients and to determine a possible association between drug levels and adverse effects.Methods: Multiple venous blood samples were collected for HPLC determination of voriconazole concentrations and routine blood tests. Adverse events were recorded.Results: No significant correlation was found between incidence of photosensitivity and voriconazole serum levels in 6 of 8 children with ABPA. 80% of patients had trough voriconazole concentrations<1000ng/mL and were highly variable.Conclusions: Long-term voriconazole therapy and greater sun exposure in Greece appear to play a major role in the occurrence of photosensitivity. Steady-state plasma drug concentrations were found to be highly variable and below the recommended therapeutic range in most patients, without any apparent negative influence on outcome.

Determining presence of lung disease in young children with cystic fibrosis: Lung clearance index, oxygen saturation and cough frequency - Corrected Proof

E.M. Bakker, J.C. van der Meijden, E.M. Nieuwhof, W.C.J. Hop, H.A.W.M. Tiddens — 2012-01-24

Abstract: Background: Accurate assessment of pulmonary status in young children with cystic fibrosis (CF) requires sensitive and objective monitoring techniques.Objectives: This study aimed to evaluate the feasibility of lung clearance index (LCI) calculated from multiple breath washout (MBW), home nocturnal pulse oximetry and home nocturnal cough recording in young children with CF, and determine whether these tests can distinguish CF patients from healthy controls.Methods: We performed a prospective cross-sectional study in 20 CF patients and 30 healthy children aged 0–4years. MBW was performed in awake and unsedated children at the outpatient clinic using a commercially available device. Measurements of nocturnal oxygen saturation and nocturnal cough were done at home using a pulse oximeter and an audiometer.Results: There was a significant difference in mean LCI between healthy children and CF patients (LCI 7.1 vs. 9.3, p<0.001). Nocturnal oxygen saturation was normal in both groups and did not significantly differ between the groups. Similarly, cough showed no differences between both groups. Cough varied widely between children and between nights. Success rates for saturation and cough measurements were 90% and were similar for CF patients and healthy children. Success rate for LCI was 75% for CF patients and 50% for healthy children.Conclusions: Measurements of LCI, nocturnal oxygen saturation and cough were feasible in young children; however LCI was the only variable that showed a significant difference between children with CF and healthy children.

Effect of acute exacerbations on skeletal muscle strength and physical activity in cystic fibrosis - Corrected Proof

2012-01-06

Abstract: Background: Skeletal muscle weakness is an important complication of chronic respiratory disease. The effect of acute exacerbations on strength in patients with cystic fibrosis is not known.Methods: Quadriceps (QMVC) and respiratory muscle strength were measured in patients at the time of acute admission, at discharge and one month later. Patients wore an activity monitor during admission and at one month. Convalescent values were compared to the stable clinic population.Results: Data were available for 13 acute admissions and 25 stable CF outpatients. Strength and other parameters including daily step count did not differ significantly between the stable and one month post-admission groups. At admission, QMVC was 16.7 (8.3)% lower than at convalescence, whereas inspiratory muscle strength did not change significantly. Reduction in QMVC did not correlate with activity levels or with markers of systemic inflammation.Conclusion: Further research is needed to identify the mechanisms responsible for the reduction in QMVC.

Feasibility of using pedometers to measure daily step counts in cystic fibrosis and an assessment of its responsiveness to changes in health state - Corrected Proof

2012-01-06

Abstract: Background: Evaluation of physical activity is integral to the assessment of daily physical function and a potential objective outcome measure for clinical trials. We evaluated the feasibility of using pedometers to measure physical activity in adolescents and adults with cystic fibrosis (CF) and assessed the responsiveness of its measurement to changes in health state.Methods: Participants were recruited through two CF clinics in Seattle, WA. Subjects were instructed to use their pedometer for at least one ill and two well periods (each lasting 7days). Step rate was calculated as steps per hour of use. Daily symptoms were also recorded using the CF Respiratory Symptom Diary (CFRSD). Generalized estimating equation linear regression was used to compare mean step rate between health states and by self-reported symptom category.Results: We enrolled 30 CF patients with a mean (±SD) age of 22 (±7) years and a mean forced expiratory volume in 1s (FEV1) of 57% (±25%) predicted. The mean period step rate increased from 397 (95% CI 324–497) steps/hour when ill to 534 (95% CI 413–654) steps/hour when well (p=0.015). Pedometer-recorded step rate also correlated with self-reported physical activity items on the CFRSD.Conclusion: Step rate measured with a pedometer correlates significantly with changes in health status and self-reported activity, and could be used as an outcome measure in CF.

Impact of IVS8-(TG)m(T)n on IRT and sweat chloride levels in newborns identified by California CF newborn screening - Corrected Proof

2012-01-03

Abstract: We examined the relation between the number of (TG) repeats at the (IVS8)-(TG)m(T)5 locus of the CFTR gene with neonatal serum immunoreactive trypsinogen (IRT) and sweat chloride (SC) concentrations in hypertrypsinogenemic infants with genotype ΔF508-9T/5T identified by California cystic fibrosis newborn screening. SC and IRT distributions increased with increasing (TG) repeats.

Six minute walk test Z score: Correlations with cystic fibrosis severity markers - Corrected Proof

2011-12-22

Abstract: Background: The six-minute-walk-test (6MWT) has been increasingly used in cystic fibrosis (CF) patients. However, few studies in children have correlated 6MWT with current parameters used to evaluate CF severity. Moreover, no study transformed the values of distance walked from meters into Z scores to avoid bias like age and gender, which are sources of 6MWT variability.Methods: A cross-sectional descriptive study was performed to analyze the correlations (Spearman) among forced expiratory volume in one second (FEV1), body mass index (BMI), chest radiography (CXR), chest tomography (CT), and 6MWT Z score (Z-6MWT). Clinically stable CF patients, aged 6–21years, were included.Results: 34 patients, 14F/20M, mean age 12.1±4.0years were studied. The mean Z-6MWT was −1.1±1.106. The following correlations versus Z-6MWT were found: FEV1 (r=0.59, r2=0.32, p=0.0002), BMI Z score (r=0.42, r2=0.17, p=0.013), CXR (r=0.34, r2=0.15, p=0.0472) and CT (r=−0.45, r2=0.23, p=0.0073).Conclusions: In conclusion there was a significant, but poor, correlation between the six minute walk test Z score and the cystic fibrosis severity markers currently in use.

Small macrophages are present in early childhood respiratory disease - Corrected Proof

2011-12-21

Abstract: Background: Recently, an established “small macrophage” phenotype has been observed in the sputum of patients with CF and COPD. However, little is known about the prevalence of this phenotype in the airways of young children. Since respiratory inflammation begins early in CF, we hypothesised that these small macrophages would be increased in paediatric CF bronchoalveolar lavage (BAL).Methods: Macrophage populations in CF and disease control BAL were assessed by multicolour flow cytometry. BAL inflammatory indices were collected as part of the AREST-CF programme.Results: Small macrophages were present in CF (n=35, mean 36±12% of BAL macrophages) but not significantly different to the respiratory disease controls (n=7, mean 40±21%). Number of small macrophages correlated significantly with number of BAL neutrophils (r=0.44, p<0.01) but not infection or IL-8.Conclusions: In paediatric patients small macrophages are not unique to CF, but their establishment as the dominant phenotype in adults may be due to chronicity of inflammation and infection.

Long-term non-invasive ventilation in cystic fibrosis — Experience over two decades - Corrected Proof

2011-12-19

Abstract: Background: Non-invasive ventilation (NIV) is accepted as a bridge to lung transplantation in cystic fibrosis (CF) but there is little evidence to support its use outside this setting.Methods: We reviewed the records of all patients with CF who received domiciliary NIV at our centre between 1991 and 2010.Results: Of 47 patients studied, 36% underwent lung transplantation, 28% died without transplantation and 30% remain alive on NIV. Median duration of NIV was 16months (range 2–90). Mean FEV1 fell by 212ml over the year before NIV but increased by 18ml in the following year (p<0.01). Individual response to NIV was associated with lower baseline and more rapid decline in FEV1. From 1991 to 2000, 70% underwent lung transplantation; from 2001 to 2010 only 27% were transplanted.Conclusions: NIV may slow or reverse the decline in lung function in advanced CF. NIV is increasingly used beyond a bridge to transplantation at our centre.

IL-17A as a regulator of neutrophil survival in nasal polyp disease of patients with and without cystic fibrosis - Corrected Proof

L. Derycke, N. Zhang, G. Holtappels, T. Dutré, C. Bachert — 2011-12-19

Abstract: Nasal polyps in adults are characterized by a chronic inflammation of the upper airways and by the preferential activation of Th2 cells. In contrast, IL-17 producing Th17 cells dominate the inflammation in nasal polyps of cystic fibrosis (CF) patients.Method: IL-17A, IL-5, IL-6, IL-8, IL-1β, ECP, MCP-1 and myeloperoxidase expression was determined in tissue homogenates of nasal polyps of non-CF and CF patients and controls. The cellular source of IL-17A was determined by immuno-histochemistry and FACS analysis. The functional role of IL-17A in the survival of neutrophils from CF and non-CF patients was tested.Results: A significant upregulation of IL-17A and myeloperoxidase could be observed in nasal polyps from CF-patients. The cellular sources of IL-17A in nasal polyps were mainly T-lymphocytes. IL-17A was able to modulate the survival of neutrophils in nasal polyps from non-CF patients; however the survival of neutrophils in CF patients was independent of IL-17A.Conclusion: The present study shows that IL-17A has an impact on neutrophil survival in adult nasal polyp disease, but not in nasal polyps from CF patients.

Patient indicators of a pulmonary exacerbation: Preliminary reports from school aged children map onto those of adults - Corrected Proof

J. Abbott, A. Holt, A.M. Morton, A. Hart, G. Milne, S.P. Wolfe, S.P. Conway — 2011-12-15

Abstract: Background: Despite the importance of identifying and managing a pulmonary exacerbation, and its use as an outcome measure in interventions, there is no standardised definition in cystic fibrosis. In achieving standardised criteria it is important to identify patient-reported indicators.Methods: Interviews were undertaken with 35 school aged children. They reported symptoms experienced during a pulmonary exacerbation in two ways: the first symptoms they become aware of, and how they recognised when they were improving. Interviews were taped, transcribed verbatim and the data analysed thematically.Results: For many children, the onset of an exacerbation was characterised by ‘cold’ symptoms, tiredness, and changes in cough. For those with moderate or severe disease, sleep disruption, activity induced breathlessness, changes in mood, sputum volume and lack of appetite were common. When describing improvement children focused initially on activities they were now able to perform accompanied by improvements in tiredness and cough. Those with moderate or severe disease also reported improvements in sleep and mood, breathlessness, sputum volume and colour.Conclusions: Child-reported indicators of a pulmonary exacerbation tend to map onto those reported by adults. These results provide the rationale for the development of a single scale for school age children and adults that could be sensitive to progressive stages of CF disease.

Increasing resistance of the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa (Psa) to antibiotics in cystic fibrosis (CF)—A cause for concern? - Corrected Proof

Abdul Ashish, Matthew Shaw, C. Winstanley, Martin J. Ledson, Martin J. Walshaw — 2011-12-07

Abstract: Background: Transmissible Pseudomonas aeruginosa (Psa) strains such as the Liverpool Epidemic Strain (LES) are now widespread throughout UK CF clinics: their susceptibility to antibiotics is therefore important. To study this, we compared antibiogram patterns of Psa strains in our CF clinic over 5years, looking at differences in resistance patterns between strains and changes to these over time.Methods: The antibiograms of sputum samples between 2004 and 2008 from patients attending our centre were included. We compared Psa isolate antibiotic resistance (to six anti-pseudomonal antibiotics) patterns for patients infected with LES with those infected with other Psa strains, both in the total population in 2004 (125 patients) and 2008 (166 patients) and also longitudinally from annual review samples 2004 to 2008 in matched and unmatched patient groups.Results: LES exhibited significantly more resistant isolates in 2004 (p<0.0001). There was an increase in antibiotic resistance in both LES and other Psa strains over time (p<0.001). Cox proportional hazards analysis of both unmatched (n=125) and matched (n=56) patients in 2004 revealed that LES infected patients were more likely to develop antibiotic resistant isolates over time (hazard ratio 8.1, p<0.001). Fewer LES isolates were classed as fully sensitive in both matched and unmatched groups at the end of study period (p<0.001).Conclusion: This study shows a worrying trend in antibiotic resistance in the Psa isolates amongst patients chronically infected with LES. This highlights the need to prevent cross infection through segregation and also the need to develop new strategies to treat these organisms.

Reduced levels of active GLP-1 in patients with cystic fibrosis with and without diabetes mellitus - Corrected Proof

Magnus Hillman, Leif Eriksson, Lena Mared, Karin Helgesson, Mona Landin-Olsson — 2011-12-05

Abstract: Glucagon like peptide 1 (GLP-1) is an incretin hormone released as a bioactive peptide from intestinal L-cells in response to eating. It acts on target cells and exerts several functions as stimulating insulin and inhibiting glucagon. It is quickly deactivated by the serine protease dipeptidyl peptidase IV (DPP-IV) as an important regulatory mechanism. GLP-1 analogues are used as antidiabetic drugs in patients with type 2 diabetes.We served patients with cystic fibrosis (CF, n=29), cystic fibrosis related diabetes (CFRD, n=19) and healthy controls (n=18) a standardized breakfast (23g protein, 25g fat and 76g carbohydrates) after an overnight fasting. Blood samples were collected before meal as well as 15, 30, 45 and 60min after the meal in tubes prefilled with a DPP-IV inhibitor. The aim of the study was to compare levels of GLP-1 in patients with CF, CFRD and in healthy controls.We found that active GLP-1 was significantly decreased in patients with CF and CFRD compared to in healthy controls (p<0.01). However, levels in patients with CFRD tended to be lower but were not significantly lower than in patients with CF without diabetes (p=0.06). Total GLP-1 did not differ between the groups, which points to that the inactive form of GLP-1 is more pronounced in CF patients. The endogenous insulin production (measured by C-peptide) was significantly lower in patients with CFRD as expected. However, levels in non-diabetic CF patients did not differ from the controls.We suggest that the decreased levels of GLP-1 could affect the progression toward CFRD and that more studies need to be performed in order to evaluate a possible treatment with GLP-1 analogues in CF-patients.

Antimicrobial activity of fosfomycin and tobramycin in combination against cystic fibrosis pathogens under aerobic and anaerobic conditions - Corrected Proof

Gerard McCaughey, Matt McKevitt, J. Stuart Elborn, Michael M. Tunney — 2011-12-05

Abstract: Background: There is a need for new antibiotics or combination of antibiotics that possess activity against increasingly resistant cystic fibrosis (CF) respiratory pathogens such as Pseudomonas aeruginosa and MRSA.Methods: The antimicrobial activity of a novel 4:1 (w/w) fosfomycin:tobramycin (F:T) combination against CF respiratory pathogens under both aerobic and anaerobic conditions was determined by MIC, time-kill and biofilm studies, and compared with activity of fosfomycin and tobramycin, individually.Results: F:T and fosfomycin had excellent activity against P. aeruginosa and were more active than tobramycin against P. aeruginosa under anaerobic conditions with lower MIC50, MIC90 and geometric mean values. F:T (p<0.001) and fosfomycin (p<0.001) MICs for P. aeruginosa were significantly lower under anaerobic conditions with tobramycin MICs significantly higher (p<0.001). F:T and fosfomycin also had high activity against MRSA with both being more active than tobramycin. In time–kill studies, F:T was rapidly bactericidal against all 15 P. aeruginosa and 3/5 MRSA isolates tested. F:T also demonstrated bactericidal activity against P. aeruginosa grown in biofilm under both aerobic and anaerobic conditions.Conclusions: F:T has promising in vitro antimicrobial activity against MRSA and P. aeruginosa with greater activity under anaerobic conditions similar to those found in the CF lung.

Sinonasal persistence of Pseudomonas aeruginosa after lung transplantation - Corrected Proof

2011-12-02

ABSTRACT: We report on two CF patients who received double lung transplantation (LTX) due to Pseudomonas aeruginosa related pulmonary destruction. Prior to LTX we detected P. aeruginosa in nasal lavages (NL) and sputum cultures from both patients. Donor lungs of patient 1 became colonized within four weeks with P. aeruginosa identical in genotype with isolates from his pre-transplant sputum cultures and pre- and post-transplant NL.In contrast, patient 2 remained P. aeruginosa free in lower airway samples (bronchial lavage/sputum) for now up to 30months, despite persistent detection of P. aeruginosa that was identical in genotype with pre-transplant NL and sputum isolates in NL and even in throat swabs. For prevention of pulmonary re-colonization patient 2 has continuously inhaled Colomycin 1MIU once daily during the preceding more than 36 months with the novel Pari Sinus™ nebulizer, which in scintigraphic studies was shown to deliver vibrating aerosols into paranasal sinuses, additional to bronchial antibiotic inhalation.Discussion: Pulmonary colonization of transplanted donor lungs with identical clones previously colonizing the explanted lungs has been described previously and the upper airways were postulated as reservoir for descending colonization. However, this remained speculative, as upper airway sampling which does not belong to current standards, was not performed in these studies.Our report demonstrates persistence of identical P. aeruginosa genotypes in CF upper airways prior to and after LTX underlining risks of descending colonization of transplanted lungs with P. aeruginosa, which increases risks of graft dysfunction. Therefore, we recommend regular assessment of sinonasal colonization prior to and after LTX. Sinonasal inhalation with antimicrobials should be investigated in prospective trials.

Comparative bone status assessment by dual energy X-ray absorptiometry, peripheral quantitative computed tomography and quantitative ultrasound in adolescents and young adults with cystic fibrosis - Corrected Proof

2011-11-28

Abstract: Purpose: Quantitative ultrasound bone sonometry (QUS) might be a promising screening method for cystic fibrosis (CF)-related bone disease, given its absence of radiation exposure, portability of the equipment and low cost.The value of axial transmission forearm QUS in detecting osteopenia in CF was therefore studied.Methods: We investigated the application of QUS in the evaluation of bone status in a group of 64 adolescents (>12years) and young adults (<40years) with CF in a comparison with a dual X-ray absorptiometry (DXA) of the whole body and peripheral quantitative computed tomography (pQCT) of the radius at 4% and 66% sites.Results: Mean (SD) Z-scores of speed of sound (SOS), whole body bone mineral content (BMC), radial trabecular bone mineral density (BMD), and radial cortical BMD were respectively −0.31 (0.78), −0.09 (1.28), 0.10 (1.16) and −0.62 (2.88). The pQCT determined bone geometry values (cortical bone area and cortical thickness) were more depressed than the BMD data. QUS had a sensitivity and specificity of respectively 0% and 96% for diagnosing osteopenia (based on a whole body BMC Z-score<−2).Conclusions: QUS cannot replace DXA, but can screen out patients with normal bone mass. Further and larger studies are needed to examine if QUS may reflect other aspects than bone mass, or if it is possible to improve its sensitivity by supplementing the SOS results with clinical risk factors.

A fat lot of good: Balance and trends in fat intake in children with cystic fibrosis - Corrected Proof

C. Smith, A. Winn, P. Seddon, S. Ranganathan — 2011-11-28

Abstract: Background: The fundamental nutritional treatment of a high fat diet for cystic fibrosis (CF) is established and essentially unchanged in the last 25years. However, recent concerns have emerged regarding the potential risks of such a diet. We investigated the diets of children with CF to determine the source of energy, energy imbalance, and changing trends of fat intake.Method: In a prospective longitudinal study over 8years at a single paediatric CF clinic three-day food diaries that included supplementary nutrition (SN) either as enteral feeds or oral nutritional supplements (ONS), were analysed annually. Influence of year on percent energy by type (fat, carbohydrate and protein) and on fat component: saturated (SFA); monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) was examined.Results: 136 food diaries were analysed in 27 children (age range 1–18years). 51 (37%) food diaries included SN (enteral feeds n=15 and ONS n=36). Mean energy intake was 1726Kcals (oral diet alone) and 2245Kcals (including SN). Percent energy from macronutrients did not change significantly over time (protein p=0.06; carbohydrate p=0.44; fat p=0.07) and remained within recommended levels. Mean caloric contribution from fat was 38.7% from oral diet alone and 37.8% including SN. Percent energy derived from SFA remained statistically unchanged (SFA p=0.57) but fell from MUFA (p=0.05) and PUFA (p=0.004). Mean SFA consistently contributed >134% (mean 158%) of reference nutrient intake and mean PUFA intake <100% (92%).Conclusion: Macronutrient intakes did not change significantly in our population of CF children, but there was a consistent imbalance of fat-sources with over-dependence on saturated fats which, in the context of increased survival in CF may potentially increase risk of cardiovascular disease. Further studies are needed to confirm our findings, investigate consequences of fat imbalance and guide clearer advice regarding appropriate proportions of sources of fat for CF patients.

Diabetes mellitus and survival in cystic fibrosis patients after lung transplantation - Corrected Proof

2011-11-23

Abstract: Background: Diabetes mellitus (DM) is common in CF and associated with more severe disease. It is unclear whether DM influences outcome of lung transplantation (LTx).Methods: One hundred twenty-three CF patients evaluated for LTx at our centre were included. Survival was calculated.Results: Patients with and without DM did not differ with regard to gender, age, FEV1 and BMI prior to LTx. Eighty patients (65%) had a diagnosis of DM before and 13 (11%) only after LTx. Recipients with DM had a significantly higher 1- and 5-year survival (89% and 71%) than those without (71% and 51%). In the multivariate Cox-regression analysis, DM had no impact on LTx-survival.Conclusions: One- and five-year survival rates after LTx tend to be better in CF recipients with DM compared to those without DM. No impact of DM on the development of BOS was found.

Qualitative analysis of parent experiences with achieving cystic fibrosis nutrition recommendations - Corrected Proof

2011-11-23

Abstract: Background: A combined behavior–nutrition approach is recommended for children with CF with growth deficits. The present study aimed to use a qualitative approach to 1) understand families' experiences using behavior–nutrition intervention strategies and 2) identify the challenges with CF management families experienced during the developmental transition between toddlerhood and early school-age.Methods: Eight families (mean age of children=8.2years) participated in a semistructured interview. Themes were independently identified by three coders, confirmed via consensus, and compared to a reliability coder.Results: Parents discussed behavior and nutrition strategies, ongoing challenges with nutrition and behavior, new challenges, and protective factors. Challenges included transition to school, transfer of treatment responsibility, picky eating, and parental stress.Conclusions: Ongoing assessment and recommendations to address parent stress and child behavior are warranted. Providing families with anticipatory guidance can better prepare families for challenging developmental transitions including starting school and the transfer of treatment responsibility.

Comparing age of cystic fibrosis diagnosis and treatment initiation after newborn screening with two common strategies - Corrected Proof

Don B. Sanders, Huichuan J. Lai, Michael J. Rock, Philip M. Farrell — 2011-11-21

Abstract: Background: Newborn screening (NBS) for CF has become widespread, although there are multiple strategies. Little is known about outcomes such as age of diagnosis after different NBS methods.Methods: We used the U.S. Cystic Fibrosis Foundation Patient Registry to identify infants with CF born between 2001 and 2008 in states that utilized NBS. We compared ages at diagnosis, genotyping, sweat test, and first visit to a CF Centre between states that used serial immunoreactive trypsinogen (IRT/IRT) levels and states that used IRT and DNA analysis (IRT/DNA).Results: We identified 1288 infants with CF. Compared to infants born in IRT/IRT states, infants born in IRT/DNA states were younger at the time of diagnosis (median 2.3weeks versus 4.0weeks in IRT/IRT states, p<0.001), genotyping (0.7weeks versus 5.3weeks, p<0.001), and initial CF Centre visit (5.9weeks versus 7.7weeks, p=0.008).Conclusions: Although there is room to improve outcomes with both strategies, infants born in IRT/DNA states have treatment initiated at a younger age than infants born in IRT/IRT states.

Employment and work disability in adults with cystic fibrosis - Corrected Proof

2011-11-21

Abstract: Background: As a result of prolonged survival, more patients with cystic fibrosis (CF) participate in the labour force. The aim of this study was to evaluate their education, occupation levels and risk factors for work disability.Method: 207 patients answered a self-administered questionnaire about their educational level and work status. Independently, medical records were reviewed for illness severity indicators.Results: 39 patients (19%) were students, 117 (57%) were in the labour force, 13 (6%) were seeking employment and 38 (18%) were inactive. CF patients had a higher educational level and were more likely to hold skilled jobs and to work part time than the general population. FEV1 and educational level were the strongest predictive factors of disability.Conclusion: Many CF patients have access to professional life. Their higher educational levels improve the chances of attaining employment, which highlights the need for career counselling. Working part time helps to maintain employment despite declining health.

Effect of dornase alfa on inflammation and lung function: Potential role in the early treatment of cystic fibrosis - Corrected Proof

Michael W. Konstan, Felix Ratjen — 2011-11-17

Abstract: Dornase alfa has been shown to reduce markers of inflammation and neutrophil-associated metalloproteinases in cystic fibrosis (CF), suggesting a potential benefit from use of this therapy early in the disease. However, observational studies indicate that dornase alfa is often reserved for “sicker” patients. A 2-year, early intervention study of dornase alfa in CF patients with early lung disease demonstrated significant improvements in lung function and risk of exacerbation compared to placebo. A more recent analysis, using the database of the large observational Epidemiologic Study of Cystic Fibrosis (ESCF), found that initiation of dornase alfa has the potential to alter the course of CF by decreasing the rate of lung function decline in children and adults. These encouraging results, possibly linked to indirect effects on inflammation, suggest a greater role for dornase alfa therapy in the early treatment of CF, where it may help preserve lung function and potentially extend survival.

Inflammatory and growth factor response to continuous and intermittent exercise in youth with cystic fibrosis - Corrected Proof

2011-11-09

Abstract: Background: Children with cystic fibrosis (CF) tend to suffer from chronic systemic inflammation and may have impaired growth associated with muscle catabolism. Therefore, investigating which type of exercise can elicit an anabolic response with minimal inflammation is of clinical value.Methods: Twelve children with CF (mean±SD; age: 14.7±2.3years, predicted FEV1: 90.0±21.6%) and biological age-matched controls (age: 13.9±2.1years) completed moderate-intensity, continuous exercise (MICE) and high-intensity, intermittent exercise (HIIE) on separate days. During each exercise, blood was drawn at various time points and analyzed for immune cells, inflammatory cytokines, and growth mediators.Results: At rest, children with CF had higher concentrations of neutrophils and IL-6 compared with controls. In children with CF, HIIE did not affect immune cell subsets or cytokines: TNF-α, IL-6, and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). All immune cell subsets and IL-6 increased significantly with MICE in both groups. Growth hormone (GH) increased with both types of exercise, with a greater change from rest during MICE.Conclusions: HIIE was a sufficient stimulus to increase GH in children with CF, without affecting systemic inflammation.

A novel neutrophil derived inflammatory biomarker of pulmonary exacerbation in cystic fibrosis - Corrected Proof

2011-10-31

Abstract: Background: The focus of this study was to characterize a novel biomarker for cystic fibrosis (CF) that could reflect exacerbations of the disease and could be useful for therapeutic stratification of patients, or for testing of potential drug treatments. This study focused exclusively on a protein complex containing alpha-1 antitrypsin and CD16b (AAT:CD16b) which is released into the bloodstream from membranes of pro-inflammatory primed neutrophils.Methods: Neutrophil membrane expression and extracellular levels of AAT and CD16b were quantified by flow cytometry, Western blot analysis and by 2D-PAGE. Interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha) and AAT:CD16b complex were quantified in CF plasma (n=38), samples post antibiotic treatment for 14days (n=10), chronic obstructive pulmonary disease (n=10), AAT deficient (n=10) and healthy control (n=14) plasma samples by ELISA.Results: Cell priming with IL-8 and TNF-alpha caused release of the AAT:CD16b complex from the neutrophil cell membrane. Circulating plasma levels of IL-8, TNF-alpha and AAT:CD16b complex were significantly higher in patients with CF than in the other patient groups or healthy controls (P<0.05). Antibiotic treatment of pulmonary exacerbation in patients with CF led to decreased plasma protein concentrations of AAT:CD16b complex with a significant correlation with improved FEV1 (r=0.81, P=0.003).Conclusion: The results of this study have shown that levels of AAT:CD16b complex present in plasma correlate to the inflammatory status of patients. The AAT:CD16b biomarker may become a useful addition to the clinical diagnosis of exacerbations in CF.

CT of the paranasal sinuses is not a valid indicator for sinus surgery in CF patients - Corrected Proof

2011-10-24

Abstract: Background: No guidelines comprise when or to what extent sinus surgery should be done in patients with cystic fibrosis (CF) or how a CT scan of the paranasal sinuses should influence the decision. Symptoms of rhinosinusitis and/or eradication of pathogenic bacteria from the sinuses are reasons for sinus surgery.Methods: In this observational cross sectional study, 55 CF cases had their preoperative CT scans scored according to the Lund Mackay- and the Nair-system. Correlations between the CT scans, symptoms, surgical findings and cultures obtained during sinus surgery were made.Results: There was no significant correlation between the CT score and detection of pus, pathogenic bacteria or symptoms. Pus and pathogenic bacteria were found in several cases without sinus opacification on the CT scan. Non pathogenic and sterile cultures were also found in sinuses with opacification.Conclusions: A CT scan is not a valid criterion for sinus surgery in CF patients.

Ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy - Corrected Proof

2011-10-13

Abstract: Background: Cystic fibrosis (CF) lung disease is characterized by perpetuated neutrophilic inflammation with progressive tissue destruction. Neutrophils represent the major cellular fraction in CF airway fluids and are known to form neutrophil extracellular traps (NETs) upon stimulation. Large amounts of extracellular DNA-NETs are present in CF airway fluids. However, the structural contribution of NETs to the matrix composition of CF airway fluid remains poorly understood. We hypothesized that CF airway fluids consist of distinct DNA-NETs that are associated to subcellular structures.Methodology/principal findings: We employed atomic force microcopy (AFM) and scanning electron microcopy to ultrastructurally characterize the nature of CF sputum and the role of NETs within the extracellular CF sputum matrix. These studies demonstrate that CF sputum is predominantly composed of a high-density meshwork of NETs and NETosis-derived material. Treatment of CF sputum with different DNases degraded CF NETs and efficiently liquefied the mucous-like structure of CF sputum. Quantitative analysis of AFM results showed the presence of three globular fractions within CF sputum and the larger two ones featured characteristics of neutrophil ectosomes.Conclusions/significance: These studies suggest that excessive NET formation represents the major factor underlying the gel-like structure of CF sputum and provide evidence that CF-NETs contain ectosome-like structures that could represent targets for future therapeutic approaches.