R. Casciaro

Hyaluronic Acid Improves the Tolerability of Hypertonic Saline in the Chronic Treatment of Cystic Fibrosis Patients: A Multicenter, Randomized, Controlled Clinical Trial

UNLABELLED TRIAL DESIGN AND METHODS: Between December 2009 and July 2011, four cystic fibrosis (CF) centers in Italy participated in a randomized, double-blind, controlled clinical trial to test whether 7% hypertonic saline (HS) administered together with 0.1% hyaluronic acid (HA) was better tolerated by patients who previously did not tolerate HS well on its own. Participants were CF patients at least 8 years old, in clinically stable conditions, with forced expiratory volume in 1 sec (FEV1) at least 50% predicted. Forty patients were recruited and randomized to receive either HS or HS plus HA (5 mL to be inhaled over 15 min, twice daily for 28 days). Primary endpoints were cough, throat irritation, salty taste, and overall acceptability, as assessed by each patient on a semiquantitative scale on a diary card. Secondary endpoint was FEV1 change at the end of treatment. Patients were randomized into randomly permuted blocks. The first and last doses were administered in hospital. In between, patients were treated at home. Patients, all caregivers, and the statistician who conducted the analysis (different from the one who generated the random list) were blinded to group assignment. RESULTS Severity of cough, throat irritation, and saltiness were more severe in patients treated with HS alone, both after the first inhalation and over the entire treatment period. Overall pleasantness was rated higher by patients treated with the combination product. All differences were highly significant. There were no changes in FEV1 between the first and last administrations. Five patients did not complete the study. Four patients (two from each group) withdrew because of cough or throat irritation. One more patient from the HS group withdrew because of a respiratory exacerbation at week 3. CONCLUSIONS HS is currently a cornerstone in the treatment of CF patients. The addition of HA to HS reduces the prevalence and severity of cough, throat irritation, and saltiness and may improve compliance in patients who previously did not tolerate HS well on its own. Longer-term studies could further assess the benefit of chronic treatment.

Liver disease as risk factor for cystic fibrosis‐related diabetes development

Aim: To evaluate clinical and genetic factors, besides pancreatic insufficiency, associated with increased risk of cystic fibrosis‐related diabetes.

Catheter Lock and Systemic Infusion of Linezolid for Treatment of Persistent Broviac Catheter-Related Staphylococcal Bacteremia

The treatment of persistently positive blood cultures in the setting of indwelling central venous catheter (CVC)-related bacteremia may represent a difficult task when CVC removal is not feasible. In this setting, antibiotic lock has been demonstrated to be an effective option, both as a first-line

Slow-release insulin in cystic fibrosis patients with glucose intolerance: A randomized clinical trial

Minicucci L, Haupt M, Casciaro R, De Alessandri A, Bagnasco F, Lucidi V, Notarnicola S, Lorini R, Bertasi S, Raia V, Cialdella P, Haupt R. Slow‐release insulin in cystic fibrosis patients with glucose intolerance: a randomized clinical trial.

Role of nebulized amphotericin B in the management of allergic bronchopulmonary aspergillosis in cystic fibrosis: Case report and review of literature

Abstract Objectives: To review the data available in literature about nebulized amphotericin B (AMB) in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) and to report our experience in the use of this drug, with a particular therapeutic scheme. Case Report: We used nebulized liposomal amphotericin B (L-AMB) in a patient affected by CF, complicated by ABPA. The previous combined treatment with oral steroids and azoles had no respiratory benefit and caused relevant side effects. Amphotericin B has always been well tolerated and permitted a slight steroid tapering. We also observed benefits in pulmonary function and laboratory tests. Conclusions: Few data are available in literature about the use of nebulized AMB in CF and there are no RCTs evaluating antifungals in CF-ABPA. In our opinion, the reported case suggests that nebulized L-AMB could represent a possible strategy in ABPA management in CF patients.

Genotype–phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles

Background The effect of complex alleles in cystic fibrosis (CF) is poorly defined for the lack of functional studies. Objectives To describe the genotype–phenotype correlation and the results of either in vitro and ex vivo studies performed on nasal epithelial cells (NEC) in a cohort of patients with CF carrying cystic fibrosis transmembrane conductance regulator (CFTR) complex alleles. Methods We studied 70 homozygous, compound heterozygous or heterozygous for CFTR mutations: p.[Arg74Trp;Val201Met;Asp1270Asn], n=8; p.[Ile148Thr;Ile1023_Val1024del], n=5; p.[Arg117Leu;Leu997Phe], n=6; c.[1210-34TG[12];1210-12T[5];2930C>T], n=3; p.[Arg74Trp;Asp1270Asn], n=4; p.Asp1270Asn, n=2; p.Ile148Thr, n=6; p.Leu997Phe, n=36. In 39 patients, we analysed the CFTR gating activity on NEC in comparison with patients with CF (n=8) and carriers (n=4). Finally, we analysed in vitro the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele. Results The p.[Ile148Thr;Ile1023_Val1024del] caused severe CF in five compound heterozygous with a class I–II mutation. Their CFTR activity on NEC was comparable with patients with two class I–II mutations (mean 7.3% vs 6.9%). The p.[Arg74Trp;Asp1270Asn] and the p.Asp1270Asn have scarce functional effects, while p.[Arg74Trp;Val201Met;Asp1270Asn] caused mild CF in four of five subjects carrying a class I–II mutation in trans, or CFTR-related disorders (CFTR-RD) in three having in trans a class IV–V mutation. The p.[Arg74Trp;Val201Met;Asp1270Asn] causes significantly (p<0.001) higher CFTR activity compared with compound heterozygous for class I–II mutations. Furthermore, five of six compounds heterozygous with the p.[Arg117Leu;Leu997Phe] had mild CF, whereas the p.Leu997Phe, in trans with a class I–II CFTR mutation, caused CFTR-RD or a healthy status (CFTR activity: 21.3–36.9%). Finally, compounds heterozygous for the c.[1210-34TG[12];1210-12T[5];2930C>T] and a class I–II mutation had mild CF or CFTR-RD (gating activity: 18.5–19.0%). Conclusions The effect of complex alleles partially depends on the mutation in trans. Although larger studies are necessary, the CFTR activity on NEC is a rapid contributory tool to classify patients with CFTR dysfunction.

Multicentre chest computed tomography standardisation in children and adolescents with cystic fibrosis: The way forward

Progressive cystic fibrosis (CF) lung disease is the main cause of mortality in CF patients. CF lung disease starts in early childhood. With current standards of care, respiratory function remains largely normal in children and more sensitive outcome measures are needed to monitor early CF lung disease. Chest CT is currently the most sensitive imaging modality to monitor pulmonary structural changes in children and adolescents with CF. To quantify structural lung disease reliably among multiple centres, standardisation of chest CT protocols is needed. SCIFI CF (Standardised Chest Imaging Framework for Interventions and Personalised Medicine in CF) was founded to characterise chest CT image quality and radiation doses among 16 participating European CF centres in 10 different countries. We aimed to optimise CT protocols in children and adolescents among several CF centres. A large variety was found in CT protocols, image quality and radiation dose usage among the centres. However, the performance of all CT scanners was found to be very similar, when taking spatial resolution and radiation dose into account. We conclude that multicentre standardisation of chest CT in children and adolescents with CF can be achieved for future clinical trials. Multicentre chest CT standardisation is necessary and feasible to maximise image quality and reduce radiationhttp://ow.ly/ZfsaE

A polymorphism in the 5' UTR of the DEFB1 gene is associated with the lung phenotype in F508del homozygous Italian cystic fibrosis patients

Abstract Background: The identification of cystic fibrosis (CF) patients who are at greater risk of lung damage could be clinically valuable. Thus, we attempted to replicate previous findings and verify the possible association between three single nucleotide polymorphisms (SNPs c.–52G>A, c.–44C>G and c.–20G>A) in the 5’ untranslated region (5′ UTR) of the β defensin 1 (DEFB1) gene and the CF pulmonary phenotype. Methods: Genomic DNA from 92 Italian CF patients enrolled in different regional CF centres was extracted from peripheral blood and genotyped for DEFB1 SNPs using TaqMan® allele specific probes. In order to avoid genetic confounding causes that can account for CF phenotype variability, all patients were homozygous for the F508del CFTR mutation, and were then classified on the basis of clinical and functional data as mild lung phenotype (Mp, n=50) or severe lung phenotype patients (Sp, n=42). Results: For the c.–20G>A SNP, the frequency of the A allele, as well as the AA genotype, were significantly more frequent in Mp than in Sp patients, and thus this was associated with a protective effect against severe pulmonary disease (OR=0.48 and 0.28, respectively). The effect of the c.–20G>A A allele is consistent with a recessive model, and the protective effect against Sp is exerted only when it is present in homozygosis. For the other two SNPs, no differences were observed as allelic and genotypic frequency in the two subgroups of CF patients. Conclusions: Our results, although necessary to be confirmed in larger and multiethnic populations, reinforce DEFB1 as a candidate modifier gene of the CF pulmonary phenotype.

Inhaled hypertonic saline+hyaluronic acid in cystic fibrosis with asthma-like symptoms: a new therapeutic chance

The aim of the paper is to report the case of a boy affected by cystic fibrosis, with non-ABPA-related recurrent wheezing and frequent pulmonary exacerbation during childhood, who had been inhaling 7% NaCl+0.1% hyaluronic acid (HA) as a maintenance therapy. We reviewed patient database and, analysing a 7-year follow-up, considered pulmonary exacerbation, antibiotic and steroid courses, pulmonary function (forced expiratory volume in one second; FEV1) and microbiological data. After starting 7% NaCl+0.1% HA treatment, we observed a dramatic decrease of oral antibiotic need (0.55 courses/month during the pretreatment period against 0.10 courses/month in the treatment period), associated with a good initial recovery and a stability of FEV1. In our opinion this case could suggest an extended indication for inhaled 7% NaCl+0.1% HA use in CF, not only in patients who did not tolerate hypertonic saline, but also in patients with coexistent asthma-like symptoms.

A long-term follow-up of residual mass neuroblastoma in a patient with cystic fibrosis

Purpose To report a long-term follow-up of a young woman affected by cystic fibrosis (CF) with a residual retroperitoneal mass of neuroblastoma (NBL) after treatment. Case report We reviewed the patients database and analysed a 20-year follow-up by considering pulmonary exacerbation, nutritional condition, pulmonary function (forced expiratory volume in 1 s), microbiological data and residual retroperitoneal mass volume. We observed stable pulmonary and nutritional conditions. No variation was found in the residual retroperitoneal mass volume. Discussion We report this case of a patient with CF with previous NBL because such a long time of follow-up of a NBL with a stable retroperitoneal remaining tumour is uncommon and needs to be reported. Multidisciplinary management has been crucial in this case because of the presence of concomitant diseases and consequently, differential diagnosis challenges.