The impact of chest computed tomography and chest radiography on clinical management of cystic fibrosis lung disease.

BACKGROUND: Recent standards of care mention chest radiography (CR) but not chest computed tomography (CT) in routine annual follow-up of children with cystic fibrosis (CF). To minimise radiation risk, CT or CR should only be performed if they impact clinical decision making. We investigated whether in addition to a wide range of commonly used clinical parameters, chest CT and/or CR in routine follow-up of CF patients influence clinical decisions. METHODS: 36 web based clinical vignettes (i.e. case simulations) were designed using clinical data from patients aged 8-18 years, randomly selected from two CF centres in The Netherlands. In a randomized cross-over design, clinicians assessed eight vignettes and suggested therapeutic/diagnostic management on two occasions, with a ten-week interval. Radiological information (CT or CR) was included at only one of the two assessments, in random order. Any differences in management could be attributed to information from CT or CR, and were compared by McNemar analysis. RESULTS: 44 European and Australian clinicians completed a total of 143 CT vignette pairs and 167 CR vignette pairs. CT was associated with a significant increase in antifungal treatment (Risk Ratio (RR) 2.8 (1.3-6.0, p = .02)), bronchoscopies (RR 1.6 (1.1-2.5, p = .04)), mycobacterial cultures (RR 1.3 (1.0-1.5, p = .02)), and 'need for hospitalization' (i.e. intravenous antibiotics and/or bronchoscopy) (RR 1.4 (1.0-1.9, p = .03)). CR led to a significant increase in inhaled antibiotics only (RR 1.3 (1.0-1.6, p = .04)). CONCLUSIONS: CT but not CR, at routine biennial follow-up was associated with several changes in treatment and/or diagnostic testing, including the need for hospitalization.

HLA-G expression and regulation during Pseudomonas aeruginosa infection in cystic fibrosis patients.

BACKGROUND: Deregulated immune response fails to control biofilm-forming bacteria, as Pseudomonas aeruginosa, in the lungs of cystic fibrosis (CF) patients. HLA-G is an immune-modulatory molecule involved in respiratory diseases and infections. MATERIALS & METHODS: HLA-G mRNA and protein were analyzed in plasma and exhaled breath condensate from CF patients undergoing intravenous antibiotic treatment, CF cell line and murine model. RESULTS: Therapy normalizes HLA-G plasmatic in CF patients suggesting a systemic anti-inflammatory role while in CF airway system, higher expression of HLA-G is associated with P. aeruginosa infection. CF cell line and murine model expressed higher HLA-G molecules in the presence of P. aeruginosa. CONCLUSION: Plasmatic and lung HLA-G expression suggest a role in reducing systemic inflammation and supporting P. aeruginosa infection.

Neutrophil elastase-mediated increase in airway temperature during inflammation.

BACKGROUND: How elevated temperature is generated during airway infections represents a hitherto unresolved physiological question. We hypothesized that innate immune defence mechanisms would increase luminal airway temperature during pulmonary infection. METHODS: We determined the temperature in the exhaled air of cystic fibrosis (CF) patients. To further test our hypothesis, a pouch inflammatory model using neutrophil elastase-deficient mice was employed. Next, the impact of temperature changes on the dominant CF pathogen Pseudomonas aeruginosa growth was tested by plating method and RNAseq. RESULTS: Here we show a temperature of ~38°C in neutrophil-dominated mucus plugs of chronically infected CF patients and implicate neutrophil elastase:α1-proteinase inhibitor complex formation as a relevant mechanism for the local temperature rise. Gene expression of the main pathogen in CF, P. aeruginosa, under anaerobic conditions at 38°C vs 30°C revealed increased virulence traits and characteristic cell wall changes. CONCLUSION: Neutrophil elastase mediates increase in airway temperature, which may contribute to P. aeruginosa selection during the course of chronic infection in CF.

Bronchiectases at early chest computed tomography in children with cystic fibrosis are associated with increased risk of subsequent pulmonary exacerbations and chronic pseudomonas infection.

BACKGROUND: Children with cystic fibrosis (CF) are often Pseudomonas aeruginosa (PsA) free and exhibit normal spirometry between the ages of 5 and 7. It is reported that computed tomography (CT) is more sensitive than FEV1 as an instrument in the identification of pulmonary disease. It is not known whether CF-CT scores in childhood may be used to highlight children at risk of developing severe disease. AIMS: 1 - To assess the number of respiratory exacerbations (RTEs) during a follow-up period of 6 years and their correlation with the CF-CT scores in young CF children. 2 - To assess whether PsA-negative CF children with high chest CF-CT scores are more likely to develop chronic PsA lung infection. METHODS: 68 chest CT performed in patients without chronic PsA infection were scored. All patients (median age 7.8 years) had at least 4 clinical, functional and microbiologic assessments/year in the subsequent 6 years. RTE was defined as hospitalization and IV antibiotic treatment for respiratory symptoms. RESULTS: 86.8% patients had <3 RTEs in the 6 year follow-up period. The number of RTEs in the 6 years subsequent to the CT scan was correlated to the bronchiectasis CT score (BCTS) (r = 0.612; p < 0.001) and to FEV1 at baseline (r = -0.495, p<0.001). A BCTS ≥ 17.5 identified patients with >3 RTEs during follow-up (sensitivity: 100%, specificity: 85%), while FEV1 did not. Only BCTS was significant in a logistic multivariate model (RR 1.15). BCTS was significantly lower and FEV1 higher in patients who did not develop chronic PsA infection by the end of the study. CONCLUSION: In CF children free from chronic PsA, both CT scores and FEV1 values demonstrate significant correlation with disease severity in the subsequent 6 years but CT score has higher predictive value in the identification of patients at risk.

Totally implantable central venous access ports in patients with cystic fibrosis: a multicenter prospective cohort study.

PURPOSE: The aim of this study was to assess the incidence of late onset complications of totally implantable venous access devices (TIVAD) in patients with cystic fibrosis (CF) and to investigate possible associations between the rate of complications and different policies of TIVAD management. METHODS: A multicenter prospective cohort study was performed in 11 Italian CF Centers. Patients with CF and a TIVAD were recruited and followed-up. RESULTS: The study commenced on May 2008 and ended on September 2010. Eighty subjects were studied (77.5% women--mean age 27.2 years). Eighteen late complications of ports were observed (22.5%; incidence 0.96 per 1000 days of observation): three lumen occlusions, seven catheter-related infections , three port-related venous thrombosis, in addition to five other complications. A statistically significant association was found between the onset of catheter-related infection and the presence of CF-related diabetes (CFRD) (P=.0064) CONCLUSIONS: Our data suggest that TIVADs represent a safe and effective device for the intermittent IV administration of drugs in people with CF. However, people with CFRD have a higher risk of developing TIVAD-related infection.

Whole blood fatty acid analysis with micromethod in cystic fibrosis and pulmonary disease.

OBJECTIVES: To assess fatty acid (FA) profiles in whole blood of 90 cystic fibrosis patients (CF) and 30 control subjects (C) and to correlate FA changes to the severity of respiratory disease. METHODS: Whole blood FA were assessed by GC with a micromethod-based analysis. RESULTS: Saturated and monounsaturated FA are higher, whereas polyunsaturated FA are lower in CF versus C with reduction of total n-6 FA, 22:5n-3 and 22:6n-3 (DHA). The product of linoleic acid (LA) x DHA, proposed as a marker for the disease, is 30% lower in CF than in C. Correlations with the severity of the respiratory disease are present for different FA and for the LA x DHA product. There is a reduction of Delta5 desaturase activity in CF, greater in severe disease, suggesting a basic metabolic alteration. CONCLUSIONS: The micromethod-based analysis of blood FA facilitates the assessment of the FA status while confirming alterations of FA profiles already reported in specific blood compartments of CF.

Efficacy and tolerability of Creon for Children in infants and toddlers with pancreatic exocrine insufficiency caused by cystic fibrosis: an open-label, single-arm, multicenter study.

OBJECTIVES: To evaluate the efficacy and safety of a pancreatic enzyme preparation specifically developed for infants and small children with cystic fibrosis (CF). METHODS: Twelve patients with CF younger than 24 months with pancreatic exocrine insufficiency and a coefficient of fat absorption (CFA) less than 70% were treated with Creon for Children (Solvay Pharmaceuticals GmbH, Hannover, Germany) minimicrospheres for 8 weeks. The primary end point was the mean change from baseline in the CFA after 2 weeks of treatment, based on 72-hour fat balance assessments. RESULTS: Two weeks' treatment with Creon for Children resulted in a significant increase in the mean CFA from 58.0% at baseline to 84.7% (P=0.0013) in the full analysis sample. There was a significant reduction of mean stool fat (from 13.3 to 5.3 g/d; P=0.001) and mean fecal energy loss (from 238.5 to 137.9 kJ/d; P=0.018) at 2 weeks. Dietary fat intake did not change, whereas an improvement was observed in stool frequency and characteristics. Patient weight and height increased over 8 weeks of treatment. No serious adverse event was reported. CONCLUSIONS: Creon for Children was well tolerated and significantly decreased fat malabsorption in infants with pancreatic exocrine insufficiency due to CF.

Preliminary evidence for cell membrane amelioration in children with cystic fibrosis by 5-MTHF and vitamin B12 supplementation: a single arm trial.

BACKGROUND: Cystic fibrosis (CF) is one of the most common fatal autosomal recessive disorders in the Caucasian population caused by mutations of gene for the cystic fibrosis transmembrane conductance regulator (CFTR). New experimental therapeutic strategies for CF propose a diet supplementation to affect the plasma membrane fluidity and to modulate amplified inflammatory response. The objective of this study was to evaluate the efficacy of 5-methyltetrahydrofolate (5-MTHF) and vitamin B12 supplementation for ameliorating cell plasma membrane features in pediatric patients with cystic fibrosis. METHODOLOGY AND PRINCIPAL FINDINGS: A single arm trial was conducted from April 2004 to March 2006 in an Italian CF care centre. 31 children with CF aged from 3 to 8 years old were enrolled. Exclusion criteria were diabetes, chronic infections of the airways and regular antibiotics intake. Children with CF were supplemented for 24 weeks with 5-methyltetrahydrofolate (5-MTHF, 7.5 mg /day) and vitamin B12 (0.5 mg/day). Red blood cells (RBCs) were used to investigate plasma membrane, since RBCs share lipid, protein composition and organization with other cell types. We evaluated RBCs membrane lipid composition, membrane protein oxidative damage, cation content, cation transport pathways, plasma and RBCs folate levels and plasma homocysteine levels at baseline and after 24 weeks of 5-MTHF and vitamin B12 supplementation. In CF children, 5-MTHF and vitamin B12 supplementation (i) increased plasma and RBC folate levels; (ii) decreased plasma homocysteine levels; (iii) modified RBC membrane phospholipid fatty acid composition; (iv) increased RBC K(+) content; (v) reduced RBC membrane oxidative damage and HSP70 membrane association. CONCLUSION AND SIGNIFICANCE: 5-MTHF and vitamin B12 supplementation might ameliorate RBC membrane features of children with CF. TRIAL REGISTRATION: ClinicalTrials.gov NCT00730509.

Biomarkers of neutrophilic inflammation in exhaled air of cystic fibrosis children with bacterial airway infections.

Leukotriene B(4) (LTB(4)) and interleukin-8 (IL-8) are inflammatory mediators involved in the neutrophil response to pulmonary bacterial colonization in cystic fibrosis (CF). The aim of this study was to investigate whether the LTB(4) and IL-8 levels in exhaled breath condensate (EBC) could be related to the type of bacterial colonization in CF patients. The pH level in EBC was analyzed as an estimate of airway acidification. Forty children were evaluated: 10 CF patients with P. aeruginosa, 10 CF patients with S. aureus, 10 not colonized CF patients, and 10 healthy children. LTB(4) and IL-8 in EBC were analyzed by specific enzyme immunoassay kits (EIA). The pH of EBC was measured with a pH-meter after deareation by bubbling with argon. Exhaled LTB(4) was higher in CF children with P. aeruginosa compared to those with S. aureus (P < 0.01), not colonized (P < 0.001), and healthy children (P < 0.01). Exhaled IL-8 was elevated in CF patients colonized by P. aeruginosa compared with other subgroups (vs. not colonized, P < 0.05; vs. healthy children, P < 0.001). IL-8 levels were higher in CF children with S. aureus than in healthy children (P < 0.05). There was an increase in IL-8 levels in not colonized CF patients compared with healthy children (P < 0.05). EBC pH was higher in healthy children compared to CF patients not colonized (P < 0.05). Our data suggest that EBC is suitable for evaluating neutrophil inflammatory mediators (LTB(4), IL-8, and pH) involved in the response to pulmonary bacterial colonization in CF children.