CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed

Biodegradable microparticles designed to efficiently reach and act on cystic fibrosis mucus barrier.

Cystic fibrosis (CF) is a progressive genetic disease caused by mutations in the gene that produces the CF transmembrane conductance regulator (CFTR) protein. The malfunction of the CFTR protein causes a thick buildup of mucus in the lungs that clogs the airways and traps bacteria, thus leading to infections, extensive lung damage and respiratory failure. Micro-delivery systems are currently being investigated as an efficient way to cross the viscous and complex architecture of the CF mucus. In this study, we produced synthetic and natural microparticles (MPs) based on poly(dl‑lactide‑co‑glycolide) (PLGA) or gellan gum through tailored water/oil emulsion procedures. Morphological and physico-chemical characterizations were carried out on both classes of MPs showing particles having diameters within suitable ranges to reach the CF airways. In vitro biocompatibility tests were also performed on both MPs using a human lung cancer cell line (A549) demonstrating that treatment with MPs induces no cytotoxic effects. Both classes of MPs were loaded with a mucolytic agent (N‑acetyl cysteine, NAC) and their release kinetics evaluated using high performance liquid chromatography (HPLC). The analysis pointed out that the amount of NAC released from MPs resulted in a dose-dependent increment, with a rapid release kinetic to satisfy the requirement for inducing an early mucus degradation. Finally, mucolytic action of NAC-loaded MPs was evaluated in an artificial sputum model through its rheological analysis obtaining the lowest viscosity profile after the addition of drug-loaded MPs. Taken together, gained results allowed us to select suitable MPs as potential drug targeting platforms having a mucolytic action for CF treatment

Polyphenolic Extract from Tarocco (<i>Citrus sinensis</i> L. Osbeck) Clone “Lempso” Exerts Anti-Inflammatory and Antioxidant Effects via NF-kB and Nrf-2 Activation in Murine Macrophages

Citrus fruits are often employed as ingredients for functional drinks. Among Citrus, the variety, &#8220;Lempso&#8222;, a typical hybrid of the Calabria region (Southern Italy), has been reported to possess superior antioxidant activity when compared to other common Citrus varieties. For these reasons, the aim of this study is to investigate in vitro the nutraceutical value of the Tarocco clone, &#8220;Lempso&#8222;, highlighting its anti-inflammatory and antioxidant potential. A post-column 2,2&#8242;-diphenyl-1-picrylhydrazyl (DPPH&#8226;) radical scavenging assay for the screening of antioxidant compounds in these complex matrices was developed. Subsequently, polyphenolic extract was tested on a murine macrophage cell line under inflammatory conditions. The extract resulted was able to significantly inhibit nitric oxide (NO) and cytokine release and inducible nitric oxide synthase (iNOS) and cycloxygenase-2 (COX-2) expression. The inhibition of these pro-inflammatory factors was associated to Nuclear factor-kB (NF-kB) inhibition. Our results also indicate an anti-oxidant potential of the extract as evidenced by the inhibition of reactive oxygen species (ROS) release and by the activation of the nuclear factor E2-related factor-2 (Nrf-2) pathway in macrophages. The obtained results highlight the anti-inflammatory and antioxidant potential of Lempso extract and its potential use, as a new ingredient for the formulation of functional beverages with high nutraceutical value, providing health benefits to consumers

SARS-CoV-2 infection in cystic fibrosis: A multicentre prospective study with a control group, Italy, February-July 2020.

ObjectiveTo describe the symptoms and clinical course of SARS-CoV-2 infection in patients with cystic fibrosis (CF).MethodsWe carried out a prospective multicentre cohort study based on 32 CF centres and 6597 patients. Centres were contacted to collect baseline and follow-up data of patients who reported symptoms suggestive of COVID-19 or who had contact with a positive/suspected case between the end of February and July 2020. Symptoms and clinical course of the infection were compared between patients who tested positive by molecular testing (cases) and those who tested negative (controls).ResultsThirty patients were reported from the centres, 16 of them tested positive and 14 tested negative. No differences in symptoms and outcome of the disease were observed between groups. Fever, cough, asthenia and dyspnea were the most frequently reported symptoms. Eight cases (50%) were hospitalized but none required ICU admission. Two adults with a history of lung transplant required non-invasive ventilation, none required ICU admission and all patients fully recovered without short-term sequelae.ConclusionsThe course of SARS-CoV-2 in our patients was relatively favorable. However, COVID-19 should not be considered a mild disease in CF patients, particularly for those with severely impaired respiratory function and organ transplant

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.

Summary 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 fi brosis. Methods We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fi brosis and low bone mineral density, from ten cystic fi brosis regional centres in Italy. The fi rst phase was an open-label, 12-month observational study of the eff ect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the effi cacy 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-totreat 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, fi ve 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 diff er signifi cantly for other adverse events. Interpretation Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fi brosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and eff ectively increase bone mineral density. Funding Telethon Foundation (Italy)

The prognostic role of Gender-Age-Physiology system in idiopathic pulmonary fibrosis patients treated with pirfenidone

GAP system have proven to be an easy tool for predicting disease stages and survival in IPF patients

The prognostic role of Gender-Age-Physiology system in idiopathic pulmonary fibrosis patients treated with pirfenidone

GAP system have proven to be an easy tool for predicting disease stages and survival in IPF patients