Contamination of hypertonic saline solutions in use by cystic fibrosis patients in Israel

BackgroundTreatment of cystic fibrosis (CF) patients with inhaled hypertonic saline (HS) solutions is safe, beneficial and reduces exacerbation rates. We studied contamination of solutions used by Israeli CF patients for prolonged periods.MethodsThe study addressed whether daily opening of previously unopened solutions caused contamination, survival of 6 CF-associated bacteria in artificially inoculated solutions, in-use contamination of solutions and patterns of their use by patients.ResultsRepeated opening did not contaminate solutions and survival of indicator bacteria was variable. Mycobacterium abscessus survived in 3% HS solution for 6 weeks and Burkholderia cenocepacia and Pseudomonas aeruginosa were longer. In 30/76 (39.5%) of used solutions 49 contaminants were found, none being common CF-associated pathogens.ConclusionsMost CF-related bacteria survived to some degree in HS. Approximately 40% of solutions used by patients were contaminated by organisms of uncertain significance. Our findings highlight the potential risk posed by contamination of HS solutions and support recommendations to use sterile unit-dose formulations.     

Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation

BackgroundIvacaftor is used to treat patients with CF and a G551D gating mutation; the KONNECTION study assessed the efficacy and safety of ivacaftor in patients with CF and a non-G551D gating mutation.MethodsPatients with CF ≥6 -years- old with non-G551D gating mutations received ivacaftor 150 mg q12h or placebo for 8 weeks in this 2-part, double-blind crossover study (Part 1) with a 16-week open-label extension (Part 2). The primary efficacy outcome was absolute change in FEV₁ through 8 and 24 weeks of ivacaftor treatment; secondary outcomes were changes in BMI, sweat chloride, and CFQ-R and safety through 8 and 24 weeks of treatment.ResultsEight weeks of ivacaftor resulted in significant improvements in percent predicted FEV₁, BMI, sweat chloride, and CFQ-R scores that were maintained through 24 weeks. Ivacaftor was generally well tolerated.ConclusionsIvacaftor was efficacious in a group of patients with CF who had selected non-G551D gating mutations.     

Annual Review Clinic improves care in children with cystic fibrosis

BackgroundIt is unclear whether annual multidisciplinary reviews in cystic fibrosis (CF) patients should be conducted in dedicated annual review (AR) clinics or during continuous assessments throughout the year. Our aim was to assess the effect of introducing an AR clinic.MethodsA retrospective written and electronic record review of CF patients was carried out for 2007 (no AR Clinic) and 2010 (established AR Clinic) calendar years. An internet-based satisfaction survey was distributed to families attending the AR clinic.ResultsIn total, 123 children (mean age 9.5 years, range 1.32–18.8 years) and 141 children (8.3 years, 1.1–18.3 years) were included in 2007 and 2010 respectively. There was a significant increase in multidisciplinary reviews (documented annual review 28% vs 85%, P < 0.001; dietary assessment 46% vs 92%, P < 0.001) and investigations (OGTT 2% vs 74%, P < 0.001; abdominal ultrasound 35% vs 85%, P < 0.001) conducted after the introduction of AR clinic. The majority of the families surveyed (85%) were satisfied or very satisfied with the AR clinic.ConclusionsCF AR clinic significantly improves the number of annual investigations and multidisciplinary reviews performed. Families were satisfied with this new process.     

Chronic Mycobacterium abscessus infection and lung function decline in cystic fibrosis

BackgroundAlthough nontuberculous mycobacteria (NTM) are recognized pathogens in cystic fibrosis (CF), associations with clinical outcomes remain unclear.MethodsMicrobiological data was obtained from 1216 CF patients over 8 years (481 ± 55 patients/year). Relationships to clinical outcomes were examined in the subset (n = 271, 203 ± 23 patients/year) with longitudinal data.ResultsFive hundred thirty-six of 4862 (11%) acid-fast bacilli (AFB) cultures grew NTM, with Mycobacterium abscessus (n = 298, 55.6%) and Mycobacterium avium complex (n = 190, 35.4%) most common. Associated bacterial cultures grew Stenotrophomonas or Aspergillus species more often when NTM were isolated (18.2% vs. 8.4% and 13.9% vs. 7.2%, respectively, p < 0.01). After controlling for confounders, patients with chronic M. abscessus infection had greater rates of lung function decline than those with no NTM infection (− 2.52 vs. − 1.64% predicted FEV₁/year, p < 0.05).ConclusionsNTM infection is common in CF and associated with particular pathogens. Chronic M. abscessus infection is associated with increased lung function decline.     

Treatment compliance in children and adults with Cystic Fibrosis

ObjectivesTo determine treatment compliance and how compliance was perceived by patients, parents and by a multidisciplinary team in Cystic Fibrosis (CF) patients. Also to analyse the relative importance given to each of the prescribed treatments, reasons for non-adherence and to investigate possible predictors of therapeutic compliance.Patients and methods34 CF patients (21 females), aged between 1.6 and 40.6 years, attending an outpatient CF clinic. Design: cross-sectional. A self-administered questionnaire was given to all patients whilst attending a programmed visit which was used to determine compliance to different treatments (physiotherapy, nutritional supplements, respiratory and digestive medications). Patients were subjectively classified as compliant or non-compliant by medical staff involved in their care.ResultsTreatment compliance was greater for digestive (88.2%) and respiratory medication (61.8%), compared to physiotherapy (41.2%) or nutritional supplements (59%). CF patients considered digestive medication indispensable (94.1%), compared to nutritional supplements (44.1%). Whilst 26.4% of CF patients considered that respiratory medications or nutritional supplements influenced little or nothing in their quality of life. Comparing age groups younger patients were found to be more compliant (10.4 vs. 20.5 years p = 0.008) and had less severe disease (Shwachman score 83.2 vs. 73.9 p = 0.048).ConclusionsCF patients had greater treatment adherence when prescribed digestive and respiratory medications, compared to physiotherapy or nutritional supplements. Therapeutic adherence was found to worsen with age and disease severity, however improved with treatments which were perceived by patients as more important or had a greater influence in their quality of life.     

Development of a quantitative immunofluorescence assay for detection of Stenotrophomonas maltophilia antibodies in patients with cystic fibrosis

BackgroundTo describe a simple quantitative immunofluorescence assay (IFA) for the detection of specific Stenotrophomonas maltophilia antibodies in serum of CF patients.MethodsA total of 100 sera (64 CF patients and 36 healthy subjects) were collected over a period of 2 years at the University Hospital Essen, Germany. Sputum culture status classified CF patients into groups. Serologic response was determined after Pseudomonas aeruginosa absorption by indirect IFA to Sm whole cell.ResultsCF patients with “chronic S. maltophilia” showed significantly higher S. maltophilia antibody levels compared with healthy individuals (P < 0.0001) and CF patients with “intermittent” (P = 0.0315) or “never S. maltophilia/P. aeruginosa” (P = 0.0002). A discriminant cut-off value of > 1:120 titre was established to differentiate “CF chronic S. maltophilia” from the other groups. For “CF chronic S. maltophilia”, the IFA showed sensitivity and specificity values of 70.7% and 84.7%, respectively.ConclusionOur data demonstrated that quantitative IFA is a simple serological assay for the detection of specific S. maltophilia antibodies, which could be useful as a diagnostic tool for monitoring immune response of CF patients to S. maltophilia.     

Levels of moderate–vigorous physical activity are low in Spanish children with cystic fibrosis: A comparison with healthy controls

BackgroundPhysical activity (PA) is recommended as part of the treatment regimen for cystic fibrosis (CF) although objective methods have been scarcely used to monitor achievement of PA guidelines.MethodsPA was measured by accelerometer in outpatient CF children (n = 47) and results were compared with those obtained in age- and gender-matched healthy controls (n = 39).Results2.1% of the outpatients fulfilled PA guidelines (i.e. ≥ 60 min·day^− 1 of moderate-to-vigorous PA (MVPA)) vs. 34.2% of controls. Overall, lower MVPA levels were observed in CF patients than controls despite the former undergoing more light or total PA. Peak oxygen uptake was also lower in the CF group than in controls (37.5 ± 7.8 vs. 43.5 ± 7.6 ml·kg^− 1·min^− 1, p = 0.002) and was correlated with MVPA and vigorous PA in the former.ConclusionsThese findings support a need to promote PA interventions (including MVPA) targeted at improving cardiorespiratory fitness in CF children.     

Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985–2005

IntroductionThe treatment of patients with CF has continued to evolve. We hypothesised that sputum microbiology may have changed as a result of this.MethodRetrospective analysis of sputum microbiology from adult CF patients (1985 to 2005) using the Royal Brompton Hospital CF database.ResultsColonisation with Pseudomonas aeruginosa or Staphylococcus aureus between 1985 and 2005 remained stable (77 to 82%, p = 0.159; 54 to 47%, p = 0.108; respectively). Haemophilus influenzae (48 to 6%; p < 0.001), Aspergillus species (18 to 9%; p = 0.002) and Burkholderia cepacia complex (9 to 4%; p = 0.041) prevalence decreased. Stenotrophomonas maltophilia and MRSA increased (1 to 4%, p = 0.02; 1 to 6%, p = 0.002, respectively).ConclusionP. aeruginosa colonisation has remained stable; there has been a decline in B. cepacia complex, H. influenzae and Aspergillus sp., and only a small increase in S. maltophilia and MRSA. Intensive antibiotic strategies have been employed, which, so far, have not resulted in clinically significant emergence of new pathogens.     

Dietary essential amino acids are highly anabolic in pediatric patients with cystic fibrosis

BackgroundCurrent nutritional approaches have been partially successful in Cystic Fibrosis (CF). Essential amino acids mixtures with high Leucine levels (EAA) have anabolic properties in catabolic conditions, however data in CF are lacking.MethodsOn two days according a randomized crossover design, 15 pediatric CF patients ingested 6.7 g EAA versus mixture of total amino acids as present in whey. Whole body protein and Arginine metabolism (as EAA lack Arginine) were assessed by stable isotope methodology.ResultsProtein synthesis (P < 0.05) but not protein breakdown was higher after EAA and 70% higher values for net anabolism (P < 0.001)were found both in patients with and without nutritional failure. Arginine turnover was lower (P < 0.001) and de novo Arginine synthesis tended lower (P = 0.09) after EAA. Nitric oxide synthesis was not different.ConclusionsCF patients are highly responsive to EAA intake independent of their nutritional status. Addition of Arginine to the EAA mixture may be warranted in CF.     

Prevalence of dyslipidemia in adults with cystic fibrosis

BackgroundA high fat calorie diet is advocated for patients with cystic fibrosis (CF) however the lipid profiles of individuals with CF, including those with CF-related diabetes (CFRD), are not well studied.MethodsWe conducted a retrospective review of adult CF patients attending St Michael's Hospital between January 2005 and December 2007.Results334 patients (77% pancreatic insufficient (PI)) were included in the study. Mean HDL cholesterol was significantly lower in males (p < 0.0001) with 44% of males having HDL cholesterol < 38.7 mg/dL(1 mmol/L). Pancreatic sufficient patients were more likely than PI subjects to have total cholesterol > 201 mg/dL(5.2 mmol/L) (p < 0.01). 5% of subjects had triglyceride concentrations > 195 mg/dL(2.2 mmol/L). Diabetes was diagnosed in 23% of subjects. Lipid profiles were similar between diabetics and non-diabetics. Total cholesterol and triglycerides both increased with increasing age and increasing BMI (p < 0.01).ConclusionDyslipidemia occurs in CF patients however no differences in lipid profiles were seen between those with diabetes and those without. Fasting lipids should be monitored in CF patients, particularly those with PS, older age, and high BMI. As survival in CF increases, the prevalence of dyslipidemia may increase resulting in clinically important complications.     

Mycobacterium avium and Mycobacterium abscessus complex target distinct cystic fibrosis patient subpopulations

BackgroundClinical observations suggest that Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABSC) may affect cystic fibrosis (CF) patients with different characteristics and risk factors, but this has never been demonstrated within a single prospective cohort.MethodsWe studied 50 MABSC-positive and 23 MAC-positive patients from a French prevalence study of non‐tuberculous mycobacteria (NTM) in CF. Risk factors specifically associated with MABSC and MAC were analyzed by nested case–control studies, with two NTM-negative controls matched by age, sex and center for each case.ResultsMAC-positive patients were significantly older than MABSC-positive patients (mean [SD] age, 23.1 [10.2] vs 17.4 [8.3] years, p = 0.013), and were also older at CF diagnosis (mean [SD] age, 12.9 [16.1] vs 3.1 [7.7] years, p = 0.015); they tended to be less frequent of the ΔF508/ΔF508 genotype (33.3 vs 61.1%, p = 0.17) and to use pancreatic extracts less frequently (82.4 vs 97.6%, p = 0.07). Risk factors identified by multivariate analysis were: i) in the MAC case–control study, an older age at CF diagnosis (p = 0.004); ii) in the MABSC case–control study, at least one course of intravenous antibiotics (p = 0.01) and more frequent isolation of Aspergillus (p = 0.03).ConclusionsMAC affects adult patients with a mild form of CF, whereas MABSC affects younger patients with more severe CF and more frequent intravenous antimicrobial treatment.     

Health related quality of life in cystic fibrosis: To work or not to work?

BackgroundThe present study investigated whether patients with CF who are studying or working report a better HRQoL in comparison to non-working/studying patients.Methods57 adult CF patients completed the Cystic Fibrosis Questionnaire—Revised, a CF-specific measure of HRQoL. Medical condition was quantified in terms of FEV1 % predicted, BMI, Pseudomonas aer. status, pancreatic status (PS), having an indwelling catheter device (PAC), CF Related Diabetes Mellitus and nutritional status.ResultsMean age was 26.7 years (SD 8.1), mean FEV1 % predicted was 65.09 (SD 22.18), mean BMI was 21.23 (SD 3.45). FEV1 % predicted was related to HRQoL domains Physical Functioning and General Health (r = 0.27 and 0.38 respectively, p < 0.05). A higher BMI was associated with better scores on Eating Disturbances (= fewer problems; r = 0.44, p < 0.01) and a better perception of Weight (r = 0.43, p < 0.01) and Body Image (r = 0.28, p < 0.05). Analysis of variance showed that specific domains of HRQoL were related to diabetes (Weight), taking caloric supplements (Body Image and Weight) and/or PAC (Physical Functioning, Treatment Burden, Role, Weight). Twenty-four patients worked/studied, these patients had a higher FEV1, and fewer had Pseudomonas aer. or a PAC or took high caloric supplements, compared to non-working/studying patients. After controlling for medical parameters, patients who were working/studying scored higher than non-working/studying patients on Physical Functioning, Role Functioning and Social Functioning.ConclusionsCF patients' HRQoL is related to medical status. The non-working/studying CF patients in this sample had greater disease severity and reported a lower quality of life than their working/studying peers, even after controlling for relevant medical parameters. The decision to stop work/study for CF patients is difficult and affects patients' personal, social and financial well-being.     

Molecular analysis of changes in Pseudomonas aeruginosa load during treatment of a pulmonary exacerbation in cystic fibrosis

BackgroundIntravenous antibiotics for pulmonary exacerbations (PEs) of cystic fibrosis (CF) usually target Pseudomonas aeruginosa. Insights into the CF lung microbiome have questioned this approach. We used RT-qPCR to determine whether intravenous antibiotics reduced P. aeruginosa numbers and whether this correlated with improved lung function. We also investigated antibiotic effects on other common respiratory pathogens in CF.MethodsSputa were collected from patients when stable and again during a PE. Sputa were expectorated into a RNA preservation buffer for RNA extraction and preparation of cDNA. qPCR was used to enumerate viable P. aeruginosa as well as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Burkholderia cepacia complex and Aspergillus fumigatus.ResultsFifteen CF patients were followed through 21 PEs. A complete set of serial sputum samples was unavailable for two patients (three separate PEs). P. aeruginosa numbers did not increase immediately prior to a PE, but numbers during intravenous antibiotic treatment were reduced ≥ 4-log in 6/18 and ≥ 1-log in 4/18 PEs. In 7/18 PEs, P. aeruginosa numbers changed very little with intravenous antibiotics and one patient demonstrated a ≥ 2-log increase in P. aeruginosa load. H. influenzae and S. pneumoniae were detected in ten and five PEs respectively, but with antibiotic treatment these bacteria rapidly became undetectable in 6/10 and 4/5 PEs, respectively. There was a negative correlation between P. aeruginosa numbers and FEV₁ during stable phase (r_s = 0.75, p < 0.05), and reductions in P. aeruginosa load with intravenous antibiotic treatment correlated with improved FEV₁ (r_s = 0.52, p < 0.05).ConclusionsExacerbations are not due to increased P. aeruginosa numbers in CF adults. However, lung function improvements correlate with reduced P. aeruginosa burden suggesting that current antibiotic treatment strategies remain appropriate in most patients. Improved understanding of PE characterised by unchanged P. aeruginosa numbers and minimal lung function improvement following treatment may allow better targeted therapies.     

Expression of the inflammatory regulator A20 correlates with lung function in patients with cystic fibrosis

BackgroundA20 and TAX1BP1 interact to negatively regulate NF-κB-driven inflammation. A20 expression is altered in F508del/F508del patients. Here we explore the effect of CFTR and CFTR genotype on A20 and TAX1BP1 expression. The relationship with lung function is also assessed.MethodsPrimary nasal epithelial cells (NECs) from CF patients (F508del/F508del, n = 7, R117H/F508del, n = 6) and controls (age-matched, n = 8), and 16HBE14o- cells were investigated. A20 and TAX1BP1 gene expression was determined by qPCR.ResultsSilencing of CFTR reduced basal A20 expression. Following LPS stimulation A20 and TAX1BP1 expression was induced in control NECs and reduced in CF NECs, broadly reflecting the CF genotype: F508del/F508del had lower expression than R117H/F508del. A20, but not TAX1BP1 expression, was proportional to FEV₁ in all CF patients (r = 0.968, p < 0.001).ConclusionsA20 expression is reduced in CF and is proportional to FEV₁. Pending confirmation in a larger study, A20 may prove a novel predictor of CF inflammation/disease severity.     

Pulmonary artery pressure in cystic fibrosis adults: Characteristics,clinical correlates and long-term follow-up

BackgroundWe examined pulmonary artery pressure (PAP) characteristics of CF adults, studied clinical correlates and long-term survival.MethodsComprehensive clinical data were collected and Doppler echocardiography was used to estimate PAP in 109 stable CF adults and 50 healthy controls.ResultsCF patients had lower day and night-time oxygen status, elevated CRP and BNP, and elevated PAP (27.7(13.2, 62.8) mmHg patients v 17.9(11.3, 30.9) mmHg controls, p < 0.001). Even patients with mild pulmonary disease had raised PAP. PAP measurements strongly correlated with arterial partial pressure of oxygen (PaO₂, r = − 0.673, p < 0.001), and FEV₁ percentage predicted (FEV₁%, r = − 0.642, p < 0.001) which were both independent predictors of PAP. At 10 year follow up PAP measurements were related to survival but FEV₁% and PaO₂ were both stronger predictors of death.ConclusionsPAP is raised in CF adults and correlates with pulmonary disease severity. Unlike PaO₂ and FEV₁%, it does not appear to be an independent prognostic marker.     

Serology as a diagnostic tool for predicting initialPseudomonas aeruginosa acquisition in childrenwith cystic fibrosis

RationalePseudomonas aeruginosa (Pa) serology could potentially be a useful adjunct to respiratory culture methods for the detection of initial or early Pa infection in patients with cystic fibrosis (CF).ObjectiveTo evaluate the utility of Pa serology to predict Pa isolation from respiratory (generally oropharyngeal) cultures in the subsequent 6 or 12 months among young children with CF from whom Pa had never been previously cultured. Pa serology was also evaluated in a group of healthy controls.MethodsChildren ≤ 12 years of age without prior isolation of Pa from respiratory cultures participating in the Early Pseudomonal Infection Control EPIC Observational Study (EPIC OBS) had annual serum samples for measurement of antibodies against alkaline protease, elastase and exotoxin A using a commercial kit; controls had a single serum sample. Logistic regression with generalized estimating equations was used to characterize associations between log₁₀ serum antibody titers and first isolation of Pa from a respiratory culture within the subsequent 6 or 12 months, with adjustment for sex and age. Receiver operating characteristic curves were used to optimize antibody titer cutpoints by age group. The diagnostic properties of each antibody were estimated using these optimized cutpoints.ResultsPa serology was evaluated in 582 children with CF (2084 serum samples) and 94 healthy controls. There was substantial overlap between serum antibody titers among controls, CF patients who did not acquire Pa (N = 261) and CF patients who did acquire Pa (N = 321). The maximum positive predictive value for first Pa positive culture within the ensuing 6 months was 76.2% and maximum negative predictive value was 72.1% for any antigen or combination of antigens; values were similar for 12 months.ConclusionsPa serology does not appear useful for predicting first Pa positive oropharyngeal culture among young CF patients.     

Reduced physical activity associated with work and transport in adults with cystic fibrosis

BackgroundHabitual physical activity (HPA) is believed to contribute to overall fitness in CF, however little is known about HPA patterns in adults.MethodsAdults with CF were recruited from a tertiary hospital outpatient clinic and were compared with controls without CF. HPA was measured as MET·minutes·week^? 1 using the long-form International Physical Activity Questionnaire. The relationship between HPA and lung function was explored.ResultsCF-group, n = 101 [45% females, mean(sd) age = 29(9), FEV1 % pred = 60(23)] and controls, n = 35 [69% females, age 32(10), FEV1 % pred = 101(130)]. Both groups reported similar levels of moderate and vigorous activities but the CF-group accumulated significantly less total HPA than controls, mean(sd) = 5309(6277) vs. 7808(5493), due to less HPA associated with work, 1887(4285) vs. 3707(5292) and transport 613(1018) vs. 1315(1123). Females with CF showed low to moderate correlations of HPA with lung function (R from 0.30 to 0.42, p < 0.05).ConclusionsAdults with CF accumulate less HPA than non-CF peers. Work and transportation form important targets through which physical activity may be accumulated to supplement prescribed exercise. In females with CF, declining physical activity seen in older adolescents carries into adulthood, which may have implications for wellbeing and outcome.     

Small macrophages are present in early childhood respiratory disease

BackgroundRecently, 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).MethodsMacrophage 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.ResultsSmall 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.ConclusionsIn 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.     

Blood basophils from cystic fibrosis patients with allergic bronchopulmonary aspergillosis are primed and hyper-responsive to stimulation by aspergillus allergens

IntroductionFifteen to sixty percent of cystic fibrosis patients harbor Aspergillus fumigatus (Af) in their airways (CF-AC) and some will develop allergic bronchopulmonary aspergillosis (CF-ABPA). Since basophils play a key role in allergy, we hypothesized that they would display alterations in CF-ABPA patients compared to CF-AC or patients without Af colonization (CF).MethodsUsing flow cytometry, we measured CD203c, CD63 and CD123 levels on basophils from CF-ABPA (N = 11), CF-AC (N = 14), and CF (N = 12) patients before and after ex vivo stimulation with Af allergens.ResultsBaseline CD203c was increased in basophils from CF-ABPA compared to CF-AC and CF patients. Af extract and recombinant Aspf1 stimulated basophils from CF-ABPA patients to markedly upregulate CD203c, along with modest upregulation of CD63 and a CD123 downward trend. Plasma TARC/CCL17 at baseline and post-stimulation cell supernatant histamine levels were similar in the three groups.ConclusionsIn CF-ABPA, blood basophils are primed and hyperresponsive to Af allergen stimulation.