Efficacy and tolerability of a new nasal spray formulation containing hyaluronate and tobramycin in cystic fibrosis patients with bacterial rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis is common in cystic fibrosis (CF), as CFTR defects equally affect the airway and sinonasal mucosa. However, therapeutic strategies for CF-associated chronic rhinosinusitis lag behind current approaches for pulmonary disease. OBJECTIVE: To assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF. METHODS: In a double-blind controlled study, 27 patients with an established diagnosis of CF and a documented nasal infection with Pseudomonas aeruginosa and/or Staphylococcus aureus [22 males (81%), median age of 15 years (range 5-26 yrs)], were randomized to receive the nasal spray formulation containing hyaluronate and tobramycin (N=14) or hyaluronate alone (N=13) for 14 days. Efficacy and local tolerability of the treatments were assessed by ear, nose and throat (ENT) examination and related symptoms. RESULTS: The formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain). The treatment was well tolerated without relevant side effects. CONCLUSIONS: The present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF. TRIAL REGISTRATION NUMBER: EudraCT 2007-003628-39.

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.

BACKGROUND: Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis. METHODS: We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3-6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551. FINDINGS: We screened 540 patients and enrolled 171 (mean age 13·8 years, SD 5·9, range 5-30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16·3% in the alendronate group (n=65) versus 3·1% in the placebo group (n=63; p=0·0010). 19 of 57 young people (33·3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events. INTERPRETATION: Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density. FUNDING: Telethon Foundation (Italy).

Early antibiotic treatment for Pseudomonas aeruginosa eradication in patients with cystic fibrosis: a randomised multicentre study comparing two different protocols.

BACKGROUND: Pseudomonas aeruginosa chronic pulmonary infection is an unfavourable event in cystic fibrosis. Bacterial clearance is possible with an early antibiotic treatment upon pathogen isolation. Currently, no best practice exists for early treatment. The efficacy of two different regimens against initial P. aeruginosa infection was assessed. METHODS: In a randomised, open-label, parallel-group study involving 13 centres, the superiority of inhaled tobramycin/oral ciprofloxacin compared with inhaled colistin/oral ciprofloxacin (reference treatment) over 28 days was evaluated. Patients were eligible if they were older than 1 year with first or new P. aeruginosa isolation. Treatments were assigned equally by centralised balanced randomisation, stratified by age and forced expiratory volume in 1 s values. The participants and those giving the intervention were not masked to arm assignments. The primary endpoint was P. aeruginosa eradication, defined as three successive negative cultures in 6 months. Analysis was by intention to treat. This trial was registered with EudraCT, number 2008-006502-42. RESULTS: 105 patients were assigned to inhaled colistin/oral ciprofloxacin (arm A) and 118 to inhaled tobramycin/oral ciprofloxacin (arm B). All patients were analysed. P. aeruginosa was eradicated in 66 (62.8%) patients in arm A and in 77 (65.2%) in arm B (OR 0.90, 95% CI 0.52 to 1.55, p=0.81). Following treatment, an increase in Stenotrophomonas maltophilia was noted (OR 3.97, 95% CI 2.27 to 6.94, p=0.001) with no differences between the two arms (OR 0.89, 95% CI 0.44 to 1.78, p=0.88). CONCLUSIONS: No superiority of treatment under study was demonstrated in comparison to the reference treatment. Early eradication treatment was associated with an increase in S maltophilia.

Borderline sweat test: Utility and limits of genetic analysis for the diagnosis of cystic fibrosis.

OBJECTIVE: The sweat test remains the gold standard for the diagnosis of Cystic Fibrosis (CF) even despite the availability of molecular analysis of Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR). We investigated the relationship between CFTR mutation analysis and sweat chloride concentration in a cohort of subjects with borderline sweat test values, in order to identify misdiagnosis of CF. DESIGN AND METHODS: In the period between March 2006 and February 2008 we performed 773 sweat tests in individuals referred for suspect CF. Ninety-one subjects had chloride values in the border-line range. Clinicians required CFTR gene complete scanning on 66 of them. RESULTS: The mean value of sweat chloride in the DNA negative subjects was lower than in those with at least one CFTR mutation. Our data indicate that 39 mEq/l is the best sensitivity trade off for the sweat test with respect to genotype. CONCLUSIONS: To optimise diagnostic accuracy of reference intervals, it may be useful to modify from 30 to 39 mEq/l the threshold for sweat chloride electrolytes.

Benefits of breastfeeding in cystic fibrosis: a single-centre follow-up survey.

AIM: To study the effect of breastfeeding (BF) on growth, lung function and number of infections during the first 3 years of life in children with cystic fibrosis (CF). MATERIAL AND METHODS: One hundred forty-six CF patients, 5-18 years old, were recruited at their annual care visit. Information about infant feeding, psychosocial and socioeconomic conditions and smoking exposure was obtained by interviews. Anthropometric parameters at 1 year of age and the number of infections and hospitalisations during the first 3 years of life were obtained from clinical charts. Anthropometrics and pulmonary function parameters were obtained at enrollment. RESULTS: In CF patients, particularly those with pancreatic insufficiency, the prevalence of BF was lower than the general Italian population. After multivariate analysis patients with prolonged BF showed higher values of CED expiratory volume in 1 sec (FEV-1) (p = 0.001) and a lower number of infections during the first 3 years of life (p = 0.098). CONCLUSION: Prolonged BF is beneficial in children with CF and may protect them against decline of pulmonary function. Particular attention should be paid to promote BF in infants with CF.

Dietary and circulating polyunsaturated fatty acids in cystic fibrosis: are they related to clinical outcomes?

OBJECTIVE: To assess the relationship between dietary intakes, plasma phospholipid (PL) fatty acid profile and clinical parameters in children with cystic fibrosis (CF) in comparison to healthy controls. PATIENTS AND METHODS: A cross-sectional survey including 37 patients with CF (ages 8.0 +/- 2.9 yrs) and a reference group of 68 healthy children (ages 8.0 +/- 0.7 yrs) was carried out by means of a food-frequency questionnaire. At enrollment, all subjects underwent blood sampling for plasma PL fatty acids (FA). In CF patients, pulmonary function tests (forced expiratory volume in 1 second and forced vital capacity), anthropometric measurements and the Shwachman score were also determined. RESULTS: In CF patients, mean z score for weight and height (-0.35 +/- 1.16 and -0.28 +/- 0.99) were lower than controls (0.83 +/- 1.73 and 0.55 +/- 1.11, respectively). Patients with CF showed higher energy intakes (110 +/- 43 kcal/d) compared with controls (75 +/- 22 kcal/d; P < 0.0001), with higher intake of total (saturated and monounsaturated) fats and lower intake of polyunsaturated FA (3.9 +/- 1.0% of total macronutrient intake vs 4.3 +/- 1.2%, P = 0.05). In CF patients, plasma and PL levels of linoleic and docosahexaenoic acids were lower, whereas those of arachidonic acid were similar compared with controls. The Shwachman score showed significant positive associations with plasma PL levels of arachidonic acid and total n-6 long-chain FA (r = 0.32, P = 0.05, and r = 0.35, P = 0.03, respectively). CONCLUSIONS: The data give suggestions that fat intake and CF-associated biomechanisms are bound in a vicious circle, concurring to create the clinical and biochemical picture of CF. The quantity and quality of fat supplementation in CF need careful attention to balance the fat supply with polyunsaturated FA.

BMD and body composition in children and young patients affected by cystic fibrosis.

UNLABELLED: Longer survival in cystic fibrosis has led to more bone complications. One hundred thirty-six young patients were studied for 12-24 months. Low BMD was found in 66%. Fat mass and lean mass were also reduced. Impaired pulmonary function and total steroid dose had the greatest negative influence on bone. INTRODUCTION: Low BMD is reported as a frequent complication in adult patients affected by cystic fibrosis (CF), but the available data are less consistent for younger patients. MATERIALS AND METHODS: This study was designed to evaluate BMD longitudinally over 12-24 months in a sample of 136 young patients (3-24 years of age) and to investigate its major determinants. BMC and body composition were also evaluated. RESULTS: BMD (expressed as Z score) of spine and of total body was reduced in 66% of patients. The prevalence of low BMD was the same in children, adolescents, and young adults. The main determinants of BMD were forced expiratory volume in 1 s (FEV1; as an index of pulmonary function), puberty, platelet count (as an index of portal hypertension), and cumulative steroid dose. Changes of FEV1 over time influenced BMD changes. Bone mass, fat mass (FM) and fat-free (lean) mass (FFM) were reduced in CF patients at both total body and subregions (trunk, limbs). Lean mass influenced BMD of total body and lower limbs, whereas fat mass (and BMI) influenced spine BMD. FEV1 also influenced FFM. CONCLUSIONS: Low BMD was present in a significant proportion of CF patients, independent of sex and age. BMD depended on pulmonary function, steroid dose, and presence of advanced liver disease. Pulmonary function and puberty were the main stimuli for the increase of BMD over time. CF also altered body composition, and FFM was influenced by pulmonary function.

Dysregulated interleukin-8 secretion and NF-kappaB activity in human cystic fibrosis nasal epithelial cells.

BACKGROUND: It is not clear whether cystic fibrosis (CF) airway inflammation is a consequence of bacterial infection or is intrinsically dysregulated. The aim of this study was to investigate IL-8 secretion and NF-kappaB activity in primary respiratory epithelial cells cultured from nasal polyps obtained from CF and non-CF subjects. METHODS: NF-kappaB activity was studied by electrophoretic mobility-shift and quantitative colorimetric assays in nuclear extracts. Immunoreactive IL-8 levels were assessed by ELISA in cell culture supernatants. Both parameters were studied at baseline and following challenge with Pseudomonas aeruginosa or stimulation with pro-inflammatory cytokines. RESULTS: Under basal conditions, CF cells presented a significant higher activity of NF-kappaB than non-CF cells (P=0.0004). P. aeruginosa challenge and IL-1beta/H2O2 co-stimulation caused four and two fold induction of NF-kappaB activity in non-CF and CF cells, respectively. IL-8 levels in unstimulated CF cells were significantly higher than in non-CF cells (P=0.0025). Upon incubation with P. aeruginosa and IL-1beta/H2O2, non-CF cells produced 6.3 times more IL-8 than unstimulated cells, whereas IL-8 secretion increased only of 1.4 times in CF cells. CONCLUSIONS: CF respiratory epithelial cells exhibit a basal dysregulated production of IL-8 that partially correlates to enhanced NF-kappaB activity. Our data corroborate the hypothesis of a basal exaggerated inflammatory response in the CF respiratory epithelium.

Paranasal mucoceles in children with cystic fibrosis.

Sinus mucocele is rare in the paediatric age, and so far no prevalence data have been reported in children with Cystic Fibrosis (CF). Moreover, safety and efficacy of endoscopic management of sinus mucoceles has been widely proven but only in the adult population. The aim of our study was to evaluate the prevalence of this complication and the efficacy of endoscopic sinus surgery in CF patients during the initial years of life. Among the 242 CF patients born in the period between 1990 and 2001 and in regular follow up at our CF Centre, 90 patients with possible symptoms of chronic upper airways disease (CUAD) underwent a comprehensive ENT examination including rhinofibroscopy. In selected cases a CT scan of the paranasal sinuses was also performed. CUAD was diagnosed in 55/90 because of the consistent presence of nasal obstruction, combined with at least two other nasal symptoms such as chronic nasal discharge, snoring, epiphora. Diagnosis of mucoceles (five maxillary bilateral mucoceles, one maxillary unilateral, three maxillary and etmoidal mucoceles) was done by means of CT scan in 9/15 who performed the examination. Median age at the diagnosis was 4+/-0.5 years, ranging from 0.5+/-7 years, showing a prevalence of 16.4% (9/55) among patients with symptoms. Endoscopic sinus surgery was performed in all the cases. The follow-up period ranged from 3 months to 6 years with no recurrence observed. Sinus mucocele in CF population is less unusual than expected and a high degree of suspicion is needed. Endoscopic sinus surgery seems to be a safe and efficient treatment of this complication also in a paediatric population at a high risk as for the CF patients.

Cytokine levels in sputum of cystic fibrosis patients before and after antibiotic therapy.

It is not known whether cytokine levels in sputum may be used as outcome measures after parenteral antibiotic therapy in cystic fibrosis (CF) patients. Here, we assessed the effects of antibiotic therapy on cytokine levels in sputum and serum obtained from young CF patients. Thirty-two CF patients (14 females; mean age, 18.6 years; range, 11.4-35.7 years), consecutively admitted at the CF Center of Milan for parenteral antibiotic therapy during pulmonary exacerbation, were enrolled in the study. Before and after 21 days (range, 5-41) of intravenous antibiotic treatment, all patients underwent routine laboratory determinations (including white blood cell (WBC) count and C-reactive protein (CRP)), a chest X-ray, pulmonary function tests (forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) as % predicted), and sputum cultures. Interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha levels in serum and sputum samples were determined by means of immunometric assays. After therapy, FEV1 and FVC significantly improved (median increase of 7.5% and 8.5% predicted, respectively), while CRP and WBC count were significantly decreased (median values from 14 to 5.5 mg/dl and from 8,350 to 7,400 n/mm3, respectively). While levels of IL-6 and IL-10 in sputum were generally undetectable, IL-8 and TNF-alpha were always measurable, and IL-8 levels significantly decreased after antibiotic treatment (median values from 7,165 to 5,415 pg/ml). Following antibiotic therapy, IL-8 and TNF-alpha levels in sputum were inversely related with both FEV(1) and FVC. In conclusion, TNF-alpha and IL-8 levels in sputum of young CF patients with pulmonary exacerbation were always detectable and may be useful, noninvasive outcome measures to assess response to therapy in CF patients.

Effects of liver transplantation on the nutritional status of patients with cystic fibrosis.

The long-term effects of liver transplantation on nutritional status, body composition and pulmonary function in patients with liver disease associated with cystic fibrosis (CF) are poorly defined. We studied 15 patients with CF-associated biliary cirrhosis and severe portal hypertension. Seven underwent liver transplantation (age: 14.8 +/- 6.2 years), and eight were treated conservatively (age: 15.9 +/- 6.7 years). All patients were evaluated at baseline and thereafter yearly for a median duration of 5 years. During follow-up, transplanted patients gained weight and showed a significant increment in body mass index (P < 0.004), whereas patients without transplantation remained stable (P = 0.063). Baseline bone mineral content (dual energy X-ray absorptiometry scan) was lower than normal in all patients (more in transplanted patients) and increased in transplanted patients (P < 0.05), but not in patients without transplantation. In both groups percent body fat did not change, whereas fat free mass increased only in the transplant group (P = 0.06) (P < 0.03 versus nontransplanted patients). Only in transplanted patients' plasma concentrations of vitamin E and A increased (P < 0.05 versus nontransplanted patients). Forced espiratory volume in 1 s and forced vital capacity showed similar deterioration in transplanted and in nontransplanted patients. Liver transplantation is associated with long-term beneficial effects on the nutritional status of CF patients and seems to favor bone mineralization.

Fcgamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis.

It has been suggested that genes other than CFTR could modulate the severity of lung disease in cystic fibrosis (CF). Neutrophil Fcgamma receptor II (FcgammaRII) is involved in host defense against microorganisms and in inflammatory response. We evaluated the association between genetic variability of this gene and both airway infection with Pseudomonas aeruginosa and severity of lung disease in patients with CF. We studied 167 Italian unrelated patients with CF and 50 control subjects. The distribution of FcgammaRIIA genotypes in CF patients was compared with that in control subjects and the different genotypes were related with the presence or absence of P. aeruginosa infection and markers of disease severity in CF patients. The distribution of FcgammaRIIA genotypes was not significantly different between CF patients and controls. We observed that in CF patients with the same CFTR genotype (DeltaF508/DeltaF508), those carrying the R allele of FcgammaRIIA had an increased risk of acquiring chronic P. aeruginosa infection (P=0.042, R.R.: 4.38; 95% CI: 1.17/22.4). Moreover, the frequency of R/R genotype in patients with chronic P. aeruginosa infection seems to be higher than that of control subjects and patients without chronic infection. The observation that CF patients carrying the R allele of FcgammaRIIA are at higher risk of acquiring chronic P. aeruginosa infection suggests that the FcgammaRII loci genetic variation is contributing to this infection susceptibility.

Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome.

Incidence of liver disease (LD) associated with cystic fibrosis (CF) and its clinical characterization still is unsettled. We have assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, we enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis. Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed esophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes. In conclusion, LD is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although LD does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation.