Cystic Fibrosis Patients Research Articles

Leukocyte telomere length and attrition in association with disease severity in cystic fibrosis patients.

Cystic fibrosis (CF) is characterized by chronic airway inflammation and premature aging. The link with leukocyte telomere length (LTL) as a marker of biological aging is unclear. We studied disease severity and LTL in 168 CF patients of which 85 patients had a second retrospective LTL assessment. A higher FEV1 was associated with longer LTL, with a stronger effect in men (5.08% longer LTL) compared to women (0.41% longer LTL). A higher FEV1/FVC ratio was associated with 7.05% (P=0.017) longer LTL in men. CF asthma, as defined by the treatment with inhaled corticosteroids, was associated with -6.65% shorter LTL (P=0.028). Men homozygous for the ΔF508 genotype showed a -10.48% (P=0.026) shorter LTL compared to heterozygotes. A genotype-specific non-linear association between LTL shortening and chronological age was observed. Stronger age-related LTL shortening was observed in patients homozygous for the ΔF508 genotype (P-interaction= 0.044). This work showed that disease severity in CF patients negatively influences LTL, with slightly more pronounced effects in men. The homozygous genotype for ΔF508 may play a role in LTL attrition in CF patients. Understanding factors in CF patients that accelerate biological aging provides insights into mechanisms that can extend the overall life quality in CF-diseased.

Self-care capacity of adult cystic fibrosis patients during transition/transfer between services

To analyze the knowledge, abilities, and emotional state of cystic fibrosis patients during a specific follow-up period and compare this with the recall they had of the transition (planned and gradual shift from the pediatric unit) / transfer (direct change skipping the steps recommended by the guidelines) to a specialized cystic fibrosis adult unit. Prospective cross-sectional study with cystic fibrosis adult patients under follow-up in a specialist consultation. Group 1 were patients who transitioned and Group 2 were transferred patients. The following information was collected: sociodemographic variables, degree of knowledge, skills, and emotional state using a survey designed for this purpose (as part of the internal consistency validation process). Participants also completed the emotional subscale of Cystic Fibrosis Questionnaire-Revised. Inter-group comparisons were made for the transition/transfer, at the follow-up, and during the evolution. Thirty-five patients were analyzed; 65.8% male; mean age 31.9 years (SD =10.1). At the transition, Group 1 (n=19; 54.3%) had greater knowledge about their medication and reduced ability to manage appointments and making decisions in comparison to Group 2 at transfer. At follow-up, Group 1 made a better report on their emotional state and significantly improved their ability to manage appointments, communication, and decision-making. Patients who were moved to an adult cystic fibrosis unit through transition were more knowledgeable about their medications. However, those who were transferred managed their appointments and decision-making better, but felt sadder.

Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria metabolism functions radically differently compared with more naïve strains. Whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a convergent shift in metabolic function(s) linked with the persistence phenotype during Pseudomonas aeruginosa colonization in the airways of people with cystic fibrosis. We show that clinically relevant mutations in the key metabolic enzyme, pyruvate dehydrogenase, lead to a host-specialized metabolism together with a lower virulence and immune response recruitment. These changes in infection phenotype are mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate, respectively. Our results show how metabolic adaptations directly impinge on persistence and pathogenicity in this organism.

Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy.

Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators offer significant improvements, but approximately 10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimized for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial. Air-liquid interface cultures of primary human bronchial epithelial cells (HBEC) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalized human lung epithelial cell line mimicking Class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay (PLA) for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies. rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a Class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalization assay. The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.

Variability in Disease Severity Among Cystic Fibrosis Patients carrying Residual Function Variants: Data from the European Cystic Fibrosis Society Patient Registry

BackgroundCystic Fibrosis (CF) variants that exhibit residual function (RF) of the CF transmembrane conductance regulator (CFTR) are considered to have a milder disease, however, the spectrum of CF phenotype within the different RF variants has not been extensively investigated.AimTo characterise the spectrum of CF disease severity in people with CF (pwCF) carrying different RF variants, using the European CF Society Patient Registry (ECFSPR) data.MethodsA retrospective cross-sectional and longitudinal cohort study included data from the ECFSPR during 2008–2016. Demographic and clinical characteristics of pwCF carrying different RF variants were compared to pwCF homozygous for F508del. Among RF, a distinction was made between pwCF carrying class IV or class V variants and pwCF carrying specific RF variants.ResultsOut of 56 701 pwCF in the ECFSPR, 6192 carried RF variants and 22 766 were homozygous for F508del. Class IV/F508del variants were associated with a milder course compared to class V/F508del, both were milder than pwCF homozygous for F508del. FEV1pp declined already in childhood in all groups. For adults, the hazard ratio of death for class V/F508delversusClass IV/F508del was 2.14 (0.99–4.63, p=0.052). PwCF carrying 3849+10kbC>T/F508del and pwCF carrying R334W/F508del had age-specific FEV1pp and chronic bacterial colonisation similar to pwCF homozygous for F508del.ConclusionThere is a wide spectrum of disease severity between the different RF variants, while some such as 3849+10kbC>T have a a severe disease, which is similar to pwCF homozygous for F508del.

The Association of Depression with Obstructive Sleep Apnea in Patients with Cystic and Non-Cystic Fibrosis Bronchiectasis.

Obstructive sleep apnea (OSA) and cystic fibrosis (CF) are chronic conditions that profoundly impact quality of life. OSA, characterized by repeated episodes of upper airway collapse, can exacerbate CF symptoms due to nocturnal airway obstruction. Recent studies highlight the prevalence of OSA in CF patients, especially in adults, and its detrimental effects on health and quality of life. From April 2019 to December 2021, we conducted a study with 104 bronchiectasis patients at Marmara University Pendik Training and Research Hospital. After exclusions, 70 participants (35 CF and 35 non-CF) were included. Sleep parameters were assessed with polysomnography, and depressive mood was evaluated using the Zung Self-Rating Depression Scale (SDS). Daytime sleepiness was measured using the Epworth Sleepiness Scale (ESS). The statistical analyses included t-tests, chi-square tests, and logistic regression. Among the CF patients, depressive mood was significantly associated with female sex (OR: 4.28, 95% CI: 1.27-12.04) and anemia (OR: 7.87, 95% CI: 1.50-41.27). Higher ESS scores indicated greater daytime sleepiness in the depressive groups (p = 0.051). Depressive CF patients also had a significantly longer disease duration and more frequent annual exacerbations. No significant differences were found in total sleep time, sleep efficiency, or sleep stages between the depressive and non-depressive groups. A lower forced vital capacity (FVC) was observed in the depressive CF patients, although not significantly. Depression is prevalent among adult CF patients with OSA, with significant associations with female sex and anemia. These findings underscore the need for integrated care addressing both physical and mental health aspects, including interventions for respiratory symptoms, anemia management, and sleep quality enhancement to improve overall quality of life.

The diversity of clinical Mycobacterium abscessus isolates in morphology, glycopeptidolipids and infection rates in a macrophage model.

Introduction. Mycobacterium abscessus (MABS) is a pathogenic bacterium that can cause severe lung infections, particularly in individuals with cystic fibrosis. MABS colonies can exhibit either a smooth (S) or rough (R) morphotype, influenced by the presence or absence of glycopeptidolipids (GPLs) on their surface, respectively. Despite the clinical significance of these morphotypes, the relationship between GPL levels, morphotype and the pathogenesis of MABS infections remains poorly understood.Gap statement. The mechanisms and implications of GPL production and morphotypes in clinical MABS infections are unclear. There is a gap in understanding their correlation with infectivity and pathogenicity, particularly in patients with underlying lung disease.Aim. This study aimed to investigate the correlation between MABS morphology, GPL and infectivity by analysing strains from cystic fibrosis patients' sputum samples.Methodology. MABS was isolated from patient sputum samples and categorized by morphotype, GPL profile and replication rate in macrophages. A high-content ex vivo infection model using THP-1 cells assessed the infectivity of both clinical and laboratory strains.Results. Our findings revealed that around 50 % of isolates displayed mixed morphologies. GPL analysis confirmed a consistent relationship between GPL content and morphotype that was only found in smooth isolates. Across morphotype groups, no differences were observed in vitro, yet clinical R strains were observed to replicate at higher levels in the THP-1 infection model. Moreover, the proportion of infected macrophages was notably higher among clinical R strains compared to their S counterparts at 72 h post-infection. Clinical variants also infected THP-1 cells at significantly higher rates compared to laboratory strains, highlighting the limited translatability of lab strain infection data to clinical contexts.Conclusion. Our study confirmed the general correlation between morphotype and GPL levels in smooth strains yet unveiled more variability within morphotype groups than previously recognized, particularly during intracellular infection. As the R morphotype is the highest clinical concern, these findings contribute to the expanding knowledge base surrounding MABS infections, offering insights that can steer diagnostic methodologies and treatment approaches.

Artificial intelligence-driven volumetric CT outcome score in cystic fibrosis: longitudinal and multicenter validation with/without modulators treatment.

Holistic segmentation of CT structural alterations with 3D deep learning has recently been described in cystic fibrosis (CF), allowing the measurement of normalized volumes of airway abnormalities (NOVAA-CT) as an automated quantitative outcome. Clinical validations are needed, including longitudinal and multicenter evaluations. The validation study was retrospective between 2010 and 2023. CF patients undergoing Elexacaftor/Tezacaftor/Ivacaftor (ETI) or corticosteroids for allergic broncho-pulmonary aspergillosis (ABPA) composed the monocenter ETI and ABPA groups, respectively. Patients from six geographically distinct institutions composed a multicenter external group. All patients had completed CT and pulmonary function test (PFT), with a second assessment at 1 year in case of ETI or ABPA treatment. NOVAA-CT quantified bronchiectasis, peribronchial thickening, bronchial mucus, bronchiolar mucus, collapse/consolidation, and their overall total abnormal volume (TAV). Two observers evaluated the visual Bhalla score. A total of 139 CF patients (median age, 15 years [interquartile range: 13-25]) were evaluated. All correlations between NOVAA-CT to both PFT and Bhalla score were significant in the ETI (n = 60), ABPA (n = 20), and External groups (n = 59), such as the normalized TAV (ρ ≥ 0.76; p < 0.001). In both ETI and ABPA groups, there were significant longitudinal improvements in peribronchial thickening, bronchial mucus, bronchiolar mucus and collapse/consolidation (p ≤ 0.001). An additional reversibility in bronchiectasis volume was quantified with ETI (p < 0.001). Intraclass correlation coefficient of reproducibility was > 0.99. NOVAA-CT automated scoring demonstrates validity, reliability and responsiveness for monitoring CF severity over an entire lung and quantifies therapeutic effects on lung structure at CT, such as the volumetric reversibility of airway abnormalities with ETI. Normalized volume of airway abnormalities at CT automated 3D outcome enables objective, reproducible, and holistic monitoring of cystic fibrosis severity over an entire lung for management and endpoints during therapeutic trials. Visual scoring methods lack sensitivity and reproducibility to assess longitudinal bronchial changes in cystic fibrosis (CF). AI-driven volumetric CT scoring correlates longitudinally to disease severity and reliably improves with Elexacaftor/Tezacaftor/Ivacaftor or corticosteroid treatments. AI-driven volumetric CT scoring enables reproducible monitoring of lung disease severity in CF and quantifies longitudinal structural therapeutic effects.

Zafirlukast induces DNA condensation and has bactericidal effect on replicating Mycobacterium abscessus.

Mycobacterium abscessus infections are emerging in cystic fibrosis patients, and treatment success rate in these patients is only 33% due to extreme antibiotic resistance. Thus, new treatment options are essential. An interesting target could be Lsr2, a nucleoid-associated protein involved in mycobacterial virulence. Zafirlukast is a Food and Drug Administration (FDA)-approved drug against asthma that was shown to bind Lsr2. In this study, zafirlukast treatment is shown to reduce M. abscessus growth, with a minimal inhibitory concentration of 16 µM and a bactericidal concentration of 64 µM in replicating bacteria only. As an initial response, DNA condensation, a known stress response of mycobacteria, occurs after 1 h of treatment with zafirlukast. During continued zafirlukast treatment, the morphology of the bacteria alters and the structural integrity of the bacteria is lost. After 4 days of treatment, reduced viability is measured in different culture media, and growth of M. abscessus is reduced in a dose-dependent manner. Using transmission electron microscopy, we demonstrated that the hydrophobic multilayered cell wall and periplasm are disorganized and ribosomes are reduced in size and relocalized. In summary, our data demonstrate that zafirlukast alters the morphology of M. abscessus and is bactericidal at 64 µM. The bactericidal concentration of zafirlukast is relatively high, and it is only effective on replicating bacteria but as zafirlukast is an FDA-approved drug, and currently used as an anti-asthma treatment, it could be an interesting drug to further study in in vivo experiments to determine whether it could be used as an antibiotic for M. abscessus infections.

Burkholderia cenocepacia ST-250 in cystic fibrosis patients in Switzerland: Genomic investigation of transmission routes

This report describes the characterization of Burkholderia cenocepacia isolates belonging to sequence type (ST)-250, detected in eight patients with cystic fibrosis (CF) in Switzerland. We retrospectively analyzed 18 isolates of B. cenocepacia ST-250 isolated between 2003 and 2015 by whole-genome sequencing and evaluated clinical and epidemiological data. Single nucleotide polymorphism analysis of the B.°cenocepacia ST-250 lineage showed that the isolates from all patients cluster tightly, suggesting that this cluster has a recent common ancestor. Epidemiological investigations showed that six out of eight patients acquired B.°cenocepacia ST-250 in the years 2001-2006, where participation in CF summer camps was common. Two patients were siblings. Genomic relatedness of the B. cenocepacia ST-250 isolates supported transmission by close contact, however, a common source or nosocomial routes cannot be excluded. With respect to the fatal outcome in six patients, our study shows the importance of infection control measurements in CF patients with B.°cenocepacia.

Cystic fibrosis-related chronic rhinosinusitis: the key role of a comprehensive evaluation in the era of highly effective modulator therapy.

Chronic rhinosinusitis (CRS) is prevalent in cystic fibrosis (CF), significantly affecting quality of life. The introduction of CFTR modulators, including elexacaftor-tezacaftor-ivacaftor (ETI), offers promise for improving sinonasal outcomes. We conducted a retrospective cohort multicenter study analyzing electronic medical records of 45 adult CF patients with CRS, predominantly heterozygous for the ΔF508 mutation, treated with ETI between January 2018 and December 2023. Assessments included Sinonasal Outcome Test 22 (SNOT-22), Nasal Polyp Score (NPS), modified Lund-Kennedy Score (mLKS), Lund-Mackay Score (LMS), and olfactory function using smell loss visual analog scale (VAS) and Sniffin' Sticks identification test (SSIT). After 12 months of ETI therapy, significant improvements were observed in pulmonary function parameters (FEV1, FVC), CRS severity scores (SNOT-22, NPS, mLKS), radiological findings (LMS), and olfactory function. Subgroup analysis suggested enhanced efficacy in patients with prior endoscopic sinonasal surgery. ETI therapy demonstrates comprehensive improvements in CRS and olfactory function in CF patients, highlighting the potential of CFTR modulators in managing sinonasal manifestations.

Characterization of biofilm-forming ability and antibiotic resistance profiles of clinical Pseudomonas aeruginosa isolates from patients with cystic fibrosis

Background: Pseudomonas aeruginosa is a key pathogen in cystic fibrosis (CF) associated infections, known for its biofilm-forming ability and resistance to multiple antibiotics. Understanding the relationship between biofilm production and antibiotic resistance profiles in clinical isolates can guide treatment strategies. Aims and Objectives: The aims of this study were to investigate the biofilm-forming abilities and antibiotic resistance profiles of clinical P. aeruginosa isolates from patients with CF and to determine the relationship between these two factors and their impact on treatment efficacy. Materials and Methods: A cross-sectional study was conducted on 100 clinical isolates of P. aeruginosa from CF patients. Biofilm-forming capacity was categorized as strong, moderate, or weak based on quantitative assays. Antibiotic resistance was assessed for ciprofloxacin, tobramycin, ceftazidime, meropenem, and piperacillin/tazobactam. Multi-drug resistance was defined as resistance to three or more antibiotic classes. Statistical correlations between biofilm-forming capacity and resistance levels were evaluated using the Chi-square tests. Results: Fifty-six percentages of isolates were strong biofilm producers, while 34% and 10% were moderate and weak producers, respectively. The highest antibiotic resistance was observed against ciprofloxacin (60%), followed by tobramycin (50%) and ceftazidime (45%). Forty percentages of the isolates were classified as multi-drug resistant. Strong biofilm producers demonstrated a significantly high correlation with antibiotic resistance (P&lt;0.05). Two predominant clonal groups were identified among the isolates, suggesting a possible clonal spread of resistance traits. Conclusion: The study confirms a strong association between robust biofilm production and heightened antibiotic resistance in P. aeruginosa isolates from CF patients. These findings highlight the need for targeted therapeutic strategies to disrupt biofilm formation and curb resistance spread.

The Benefits of Physical Activity for Patients with Cystic Fibrosis: A Literature Review

Introduction Cystic fibrosis (CF) is a complex and progressive genetic disorder that significantly impacts multiple organ systems, particularly the lungs and digestive tract. Despite advances in treatment and improved life expectancy, CF remains incurable, necessitating ongoing research and comprehensive management strategies. One of the key components in managing CF is the incorporation of physical activity (PA). Aim of the study The aim of the study is to investigate the role of physical activity in in the management of cystic fibrosis. Materials and methods This study underscores the critical role of physical activity (PA) in the management and overall well-being of individuals with cystic fibrosis (CF). It provides a comprehensive review of the multifaceted benefits of PA for CF patients, highlighting its positive impact on exercise tolerance, pulmonary function, cardiorespiratory fitness, muscle strength, and quality of life. PubMed and Google Scholar database was searched for articles written in English. The search included the keywords. Results The data suggest that while CF patients face unique challenges, including muscle weakness and exercise intolerance, regular PA can mitigate these effects and improve overall health outcomes. Supervised exercise programs have demonstrated significant improvements in exercise tolerance and respiratory muscle endurance without adverse effects, indicating their feasibility and safety for CF patients. Studies have shown that patients with CF who engage in regular PA experience slower declines in lung function, fewer hospitalizations, and better nutritional status. Specific types of exercise, such as anaerobic training, have been particularly effective in increasing muscle strength and body weight.

Impact of Anxiety, Depression, and Coping Strategies on Health-Related Quality of Life in Patients with Cystic Fibrosis.

With the significant increase in the life expectancy of cystic fibrosis (CF) patients, many individuals now reach adulthood and develop specific coping strategies to maintain their physical and mental well-being. This study aims to evaluate coping styles and their relationship with mental health and Health-Related Quality of Life (H-RQoL) in adult CF patients. Thirty adult CF patients completed the Hospital Anxiety and Depression Scale to assess anxiety and depression, the Cystic Fibrosis Questionnaire-Revised to evaluate quality of life, and the Brief Coping Orientation to Problems Experienced questionnaire to assess coping strategies. Twelve individuals (40%) met the diagnostic criteria for being at risk of experiencing anxiety and/or depression. Anxiety risk group exhibited lower life quality scores in the domains of vitality, emotional functioning, and role limitations (P = .027, P = .001, and P = .001, respectively). Patients reporting depressive symptoms had lower scores in emotional functioning and role limitations domains of quality of life (P = .005 and P = .018, respectively). Multivariate analysis indicated that depression and anxiety scores were significant predictors of emotional quality of life. In terms of coping strategies, "acceptance" was the most commonly preferred, while "substance use" was the least preferred strategy among all participants. Patients at risk of anxiety and/or depression often chose "avoidance" as their coping strategy. Anxiety and depressive symptoms are prevalent and associated with poorer H-RQoL in adult CF patients. These patients preferred to employ giving up strategy when dealing with the disease. Therefore, it is essential to screen adult CF patients for mental health risks and to work on improving their coping strategies.

In vitro and intracellular activity of vaborbactam combined with β-lactams against Mycobacterium abscessus.

Mycobacterium abscessus has emerged as an opportunistic pathogen responsible for lung infections, especially in cystic fibrosis patients. In spite of the production of the broad-spectrum β-lactamase BlaMab, the carbapenem imipenem is recommended in the initial phase of the treatment of pulmonary infections. Here, we determine whether the addition of vaborbactam, a second-generation β-lactamase inhibitor belonging to the boronate family, improves the activity of β-lactams against M. abscessus. The activity of β-lactams, alone or in combination with vaborbactam, was evaluated against M. abscessus CIP104536 by determining MICs, time-killing and intramacrophage activity. Kinetic parameters for the inhibition of BlaMab by vaborbactam were determined by spectrophotometry. The combination of vaborbactam (8 mg/L) with β-lactams decreased more than 8 times the MIC of amoxicillin (from >1024 to 128 mg/L) and 2 times the MICs of meropenem (from 16 to 8 mg/L) and imipenem (from 4 to 2 mg/L). The reduction of the MICs was less than that obtained with avibactam at 4 mg/L for amoxicillin (from >1024 to 16 mg/L, more than 64 times less) and for meropenem (from 16 to 4 mg/L, 4 times less). In vitro and intracellularly, M. abscessus was not killed by the meropenem/vaborbactam combination, in spite of significant in vitro inhibition of BlaMab by vaborbactam. Inhibition of BlaMab by vaborbactam decreases the MIC of β-lactams, including that of meropenem. As meropenem/vaborbactam is clinically available, this combination offers an alternative therapeutic option that should be evaluated for the treatment of pulmonary infections due to M. abscessus.

CFTR Modulators Therapy Efficacy in Reducing Cystic Fibrosis (CF) Exacerbation and Improving Selected Spirometry Parameters: A Real-Life Study in a Single-Centre Polish Population.

Background/Objectives: Cystic fibrosis is a genetically determined disease that significantly influences and shortens life. Treatment with CFTR modulators (CFTR-T) is a new hope for patients. It can change the predictive values of a poor prognosis (e.g., exacerbation rate and FEV1 value). The aim of the study was to analyse exacerbation incidence and spirometry data before and after one year (+/- 2 weeks) of CFTR-T in 85 CF patients at the CF Centre in Poznań. To our knowledge, this is the first analysis of CFTR-T efficiency in the Central-Eastern Europe population. Methods: We retrospectively analysed the spirometry and exacerbation data of 85 CF adult patients (both men and women), who in the middle of 2022 began treatment with CFTR modulators. Results: The one-year ratio of hospitalisation caused by severe exacerbations lowered from 1.25 to 0.21 per patient per year. We also saw a 66% decline in ambulatory exacerbations. The median FEV1% increased by 9.60% in absolute values and by 460 mL. Even in the group with very severe obstruction (FEV1 < 35%), there was an increase in median FEV1% of 5.9 in absolute values. We also proved the increase in FVC% (median 17.10% in absolute value and 600 mL) in the study group. Conclusions: After one year of treatment, an impressive improvement was observed in two important predictive values of poor prognosis: exacerbation rate and FEV1 values. Further observation is needed to determine how long the improvement will be present and its influence on quality of life and life expectancy.

Use of Lung Ultrasound in Cystic Fibrosis: Is It a Valuable Tool?

Cystic fibrosis (CF) is a multisystem disorder characterized by progressive respiratory deterioration, significantly impacting both quality of life and survival. Over the years, lung ultrasound (LUS) has emerged as a promising tool in pediatric respiratory due to its safety profile and ease at the bedside. In the era of highly effective CF modulator therapies and improved life expectancy, the use of non-ionizing radiation techniques could become an integral part of CF management, particularly in the pediatric population. The present review explores the potential role of LUS in CF management based on available data, analyzing all publications from January 2015 to January 2024, focusing on two key areas: LUS in CF pulmonary exacerbation and its utility in routine clinical management. Nonetheless, LUS exhibits a robust correlation with computed tomography (CT) scans and serves as an additional, user-friendly imaging modality in CF management, demonstrating high specificity and sensitivity in identification, especially in consolidations and atelectasis in the CF population. Due to its ability, LUS could be an instrument to monitor exacerbations with consolidations and to establish therapy duration and monitor atelectasis over time or their evolution after therapeutic bronchoalveolar lavage. On the basis of our analysis, sufficient data emerged showing a good correlation between LUS score and respiratory function tests. Good sensitivity and specificity of the methodology have been found in rare CF pulmonary complications such as effusion and pneumothorax. Regarding its use in follow-up management, the literature reports a moderate correlation between LUS scores and the type, extent, and CT severity score of bronchiectasis. A future validation of ultrasound scores specifically in CF patients could improve the use of LUS to identify pulmonary exacerbations and monitor disease progression. However, further research is needed to comprehensively establish the role of LUS in the CF population, particularly in elucidating its broader utility and long-term impact on patient care.

Phage Therapy: An Alternative Approach to Combating Multidrug-Resistant Bacterial Infections in Cystic Fibrosis.

Patients with cystic fibrosis (CF) are prone to developing life-threatening lung infections with a variety of pathogens that are difficult to eradicate, such as Burkholderia cepacia complex (Bcc), Hemophilus influenzae, Mycobacterium abscessus (Mab), Pseudomonas aeruginosa, and Staphylococcus aureus. These infections still remain an important issue, despite the therapy for CF having considerably improved in recent years. Moreover, prolonged exposure to antibiotics in combination favors the development and spread of multi-resistant bacteria; thus, the development of alternative strategies is crucial to counter antimicrobial resistance. In this context, phage therapy, i.e., the use of phages, viruses that specifically infect bacteria, has become a promising strategy. In this review, we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.

Liver biochemical indexes and cholesterol metabolism in cystic fibrosis patients with F508del/CFTR variant genotype after elexacaftor/tezacaftor/ivacaftor treatment

Modulators of cystic fibrosis transmembrane conductance regulator (CFTR) improved cystic fibrosis (CF) patients’ outcome. The elexacaftor/tezacaftor/ivacaftor (ETI) combination was safe and effective improving lung function in patients with different CFTR genotypes, including at least one F508del mutation. However, cases with liver damage were reported. We describe 105 CF patients heterozygous for F508del in trans with another CFTR mutation, treated for 1 year with ETI. We analyzed liver biochemical parameters and cholesterol metabolism, including lathosterol and phytosterols, surrogate markers of cholesterol de-novo synthesis and absorption, respectively. The treatment significantly improved sweat chloride, body mass index and forced expiratory volume in 1 s, whereas it caused a significant increase of total and conjugated bilirubin, ALT and GGT, even if no patients developed CF liver disease. Such alterations were less relevant than those previously observed in ETI-treated F508del homozygous patients. Furthermore, ETI treatment significantly increased serum cholesterol by enhancing its absorption (correlation between serum cholesterol and phytosterols). Whereas, we observed a normalization of de-novo biosynthesis (lathosterol reduction) that was not observed in homozygous patients. These data suggest that the second mutation in trans with the F508del contributes to reduce the liver cholesterol accumulation and thus, the triggering of liver inflammation. However, no differences in the alteration of biochemical indexes were observed between CF patients with and without liver steatosis, and between patients with different mutations in trans with the F508del. Such data suggest to further investigate the effects of ETI therapy on liver function indexes and new predictive biomarkers.

Rapid differentiation of cystic fibrosis-related bacteria via reagentless atmospheric pressure photoionisation mass spectrometry

Breath analysis is an area of significant interest in medical research as it allows for non-invasive sampling with exceptional potential for disease monitoring and diagnosis. Volatile organic compounds (VOCs) found in breath can offer critical insight into a person’s lifestyle and/or disease/health state. To this end, the development of a rapid, sensitive, cost-effective and potentially portable method for the detection of key compounds in breath would mark a significant advancement. Herein, we have designed, built and tested a novel reagent-less atmospheric pressure photoionisation (APPI) source, coupled with mass spectrometry (MS), utilising a bespoke bias electrode within a custom 3D printed sampling chamber for direct analysis of VOCs. Optimal APPI-MS conditions were identified, including bias voltage, cone voltage and vaporisation temperature. Calibration curves were produced for ethanol, acetone, 2-butanone, ethyl acetate and eucalyptol, yielding R2 > 0.99 and limits of detection < 10 pg. As a pre-clinical proof of concept, this method was applied to bacterial headspace samples of Escherichia coli (EC), Pseudomonas aeruginosa (PSA) and Staphylococcus aureus (SA) collected in 1 L Tedlar bags. In particular, PSA and SA are commonly associated with lung infection in cystic fibrosis patients. The headspace samples were classified using principal component analysis with 86.9% of the total variance across the first three components and yielding 100% classification in a blind-sample study. All experiments conducted with the novel APPI arrangement were carried out directly in real-time with low-resolution MS, which opens up exciting possibilities in the future for on-site (e.g., in the clinic) analysis with a portable system.