Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches

Short-Term Effects of High-Frequency Chest Compression and Positive Expiratory Pressure in Patients With Cystic Fibrosis

Abstract BACKGROUND: Cystic fibrosis patients require daily airway clearance therapies. The primary objective of this study was to compare the short-term efficacy of high-frequency chest compression and positive expiratory pressure mask on expectorated sputum, pulmonary function, and oxygen saturation in patients with CF hospitalized for an acute pulmonary exacerbation. METHODS: A controlled randomized cross-over trial with 24 hours between treatments was used. Thirty-four CF patients (26 ± 6.5 years) were included in the study. Before and 30 minutes after each treatment were recorded: pulmonary function testing, oxygen saturation, and perceived dyspnea. Preference for the two devices was assessed. RESULTS: No statistically significant difference between high-frequency chest compression and positive expiratory pressure mask was found in sputum production and in lung function testing. A reduction in SpO(2) was found after positive expiratory pressure mask (98 ± 1.0% versus 97 ± 1.2%; P < 0.001). Both treatments induced a statistically significant increase in Borg scale for dyspnea without differences between them. Patients reported greater satisfaction with positive expiratory pressure mask than with high-frequency chest compression (P < 0.001). CONCLUSION: High-frequency chest compression and positive expiratory pressure mask have comparable short-term effects on expectorated sputum and lung function. Although positive expiratory pressure mask was associated with a lower SpO(2), it was better tolerated than high-frequency chest compression

Three-Dimensional Radiographic Evaluation of the Malar Bone Engagement Available for Ideal Zygomatic Implant Placement

Zygomatic implant rehabilitation is a challenging procedure that requires an accurate prosthetic and implant plan. The aim of this study was to evaluate the malar bone available for three-dimensional zygomatic implant placement on the possible trajectories exhibiting optimal occlusal emergence. After a preliminary analysis on 30 computed tomography (CT) scans of dentate patients to identify the ideal implant emergencies, we used 80 CT scans of edentulous patients to create two sagittal planes representing the possible trajectories of the anterior and posterior zygomatic implants. These planes were rotated clockwise on the ideal emergence points and three different hypothetical implant trajectories per zygoma were drawn for each slice. Then, the engageable malar bone and intra- and extra-sinus paths were measured. It was possible to identify the ideal implant emergences via anatomical landmarks with a high predictability. Significant differences were evident between males and females, between implants featuring anterior and those featuring posterior emergences, and between the different trajectories. The use of internal trajectories provided better bone engagement but required a higher intra-sinus path. A significant association was found between higher intra-sinus paths and lower crestal bone heights

Arachidonic acid and docosahexaenoic acid metabolites in the airways of adults with cystic fibrosis: effect of docosahexaenoic acid supplementation.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by genetic mutations in CF transmembrane conductance regulator (CFTR) protein. Several reports have indicated the presence of specific fatty acid alterations in CF patients, most notably decreased levels of plasmatic and tissue docosahexaenoic acid (DHA), the precursor of Specialized Pro-resolving Mediators (SPMs). We hypothesized that DHA supplementation could restore the production of DHA-derived products and possibly contribute to a better control of the chronic pulmonary inflammation observed in CF subjects. Sputum samples from 15 CF and 10 Chronic Obstructive Pulmonary Disease (COPD) subjects were collected and analyzed by LC/MS/MS and blood fatty acid were profiled by gas chromatography upon lipid extraction and transmethylation. As compared to COPD patients, CF subjects showed increased concentrations of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and 15-hydroxyeicosatetraenoic acid (15-HETE), while the concentrations of DHA metabolites were not different in the two groups. After DHA supplementation, not only DHA/AA ratio and highly unsaturated fatty acid (HUFA) index were significantly increased (p &lt; 0.05), but CF subjects showed a tendency toward a decrease in LTB4 and PGE2 and an increase in 17-hydroxy-docosahexaenoic acid (17OH-DHA) levels, together with a significantly reduction in 15-HETE. At the end of the washout period, LTB4, PGE2, 15-HETE, and 17OH-DHA tended to recover baseline values. As compared to baseline, 15-HETE/17OH-DHA ratio significantly changed after supplementation (p &lt; 0.01). Our results showed that in CF patients an impairment in fatty acid metabolism, characterized by increase in AA metabolites and decrease in DHA, was partially corrected by DHA supplementation

dose administration maneuvers and patient care in tobramycin dry powder inhalation therapy

Abstract The purpose of this work was to study a new dry powder inhaler (DPI) of tobramycin capable to simplify the dose administration maneuvers to maximize the cystic fibrosis (CF) patient care in antibiotic inhalation therapy. For the purpose, tobramycin/sodium stearate powder (TobraPS) having a high drug content, was produced by spray drying, characterized and the aerodynamic behavior was investigated in vitro using different RS01 DPI inhalers. The aerosols produced with 28, 56 or 112 mg of tobramycin in TobraPS powder using capsules size #3, #2 or #0 showed that there was quasi linear relationship between the amount loaded in the device and the FPD. An in vivo study in healthy human volunteers showed that 3–6 inhalation acts were requested by the volunteers to inhale 120 mg of TobraPS powder loaded in a size #0 capsule aerosolized with a prototype RS01 device, according to their capability to inhale. The amount of powder emitted at 4 kPa pressure drop at constant air flow well correlated with the in vivo emission at dynamic flow, when the same volume of air passed through the device. The novel approach for the administration of 112 mg of tobramycin in one capsule could improve the convenience and adherence of the CF patient to the antibiotic therapy

Airway clearance therapy in cystic fibrosis patients.

Abstract Cystic fibrosis (CF) is the most common life-shortening inherited disease affecting Caucasian people. In CF, the major feature of lung disease is the retention of mucus due to impaired clearance of abnormally viscous airway secretions. Airway clearance techniques (ACTs) may significantly improve mucociliary clearance and gas exchange, thereby being of clinical benefit in reducing pulmonary complications in CF patients. ACTs include conventional chest physiotherapy, active cycle of breathing techniques, autogenic drainage, positive expiratory pressure and high-frequency chest compression. In order to suit the needs of patients, families and care-givers, ACTs need to be individually and continuously adapted

Mepolizumab in the treatment of severe eosinophilic asthma

IL-5 is crucial in the pathogenesis and evolution of eosinophilic asthma. Mepolizumab is a high-affinity humanized monoclonal antibody of the IgG1/k subtype that inhibits the binding of IL-5 to its receptor expressed on eosinophils, thereby inducing significant reduction in eosinophil circulation, as well as asthma exacerbations and corticosteroid treatment. This review deals with the currently available studies of mepolizumab in the treatment of patients with severe eosinophilic asthma

Asthma phenotypes and endotypes in childhood

Asthma is a very heterogeneous disease and since early childhood many classifications have been proposed according to phenotype and endotype. The phenotype includes the clinical features of asthma such as age of onset, triggers, comorbidities, response to treatment and evolution over time. The endotype is more difficult to define, includes the underlying immunopathological mechanisms of the disease and requires reliable biomarkers. A deep knowledge of phenotype and endotype of the patient may guide a tailored therapeutic approach. In this review the main phenotypes and endotypes of asthma acknowledged in children will be discussed

What is the role of Achromobacter species in patients with cystic fibrosis?

In recent years, advances in diagnosis and treatment have significantly modified the short-and long-term prognosis of cystic fibrosis (CF) patients. However, as in the past, the most important health problem that has significantly reduced the quality of life in CF patients is the progressive deterioration of lung structure and function. In recent years, Achromobacter species have emerged with increasing incidence in the respiratory secretions of CF subjects. The significance of this detection remains debated. In this review article, the characteristics of these pathogens, the importance of their presence in CF patients, and possible antibiotic treatment of treatments for colonization and infection are discussed. Literature analysis shows that Achromobacter species, mainly A. xylosoxidans, are pathogens with intrinsic characteristics that favour persistent lung colonization and several virulence factors and secretion systems that significantly interfere with respiratory cell survival. However, although it seems undebatable that Achromobacter species detection is a marker of CF severity, the role of these pathogens as a cause of lung structure and functional deterioration is not definitively established. Nonetheless, there is general agreement about the need for antibi otic therapy to eradicate these pathogens when they are detected in CF patients. Unfortunately, eradication is difficult, and no standard treatment is recommended by scientific societies. New possibilities are potentially offered by some recently developed drugs, such as cefiderocol, but further studies on the dosage, treatment duration and efficacy and safety of this new antibiotic in CF patients of different ages are urgently needed