Stable Cystic Fibrosis Research Articles

Comparison of 3D UTE free-breathing lung MRI with hyperpolarized 129Xe MRI in pediatric cystic fibrosis.

To compare phase-resolved functional lung (PREFUL) regional ventilation derived from a free breathing 3D UTE radial MRI acquisition to hyperpolarized 129Xe-MRI (Xe-MRI), conventional 2D multi-slice PREFUL MRI, and pulmonary function tests in pediatric cystic fibrosis (CF) lung disease. Free-breathing 3D UTE and 2D multi-slice 1H MRI as well as Xe-MRI were acquired in 12 stable pediatric CF patients. Using PREFUL, regional ventilation (RVent) maps were calculated from the free-breathing data. Ventilation defect percentage (VDP) was determined from 3D and 2D RVent maps (2D VDPRVent and 3D VDPRVent, respectively) and Xe-MRI ventilation (VDPXe). VDP was calculated for the whole lung and for eight regions based on left/right, anterior/posterior, and superior/inferior divisions of the lung. Global and regional VDP was compared between the three methods using Bland-Altman analysis, linear mixed model-based correlation, and one-way analysis of variance and multiple comparisons tests. Global 3D VDPRVent, VDPXe, and 2D VDPRVent were all strongly correlated (all R2 > 0.62, p < 0.0001) and showed minimal, non-significant bias (all <2%, p > 0.05). Three dimensional and 2D VDPRVent significantly correlated to VDPXe in most of the separate lung regions (R2 = 0.18-0.74, p < 0.04), but showed lower inter-agreement. The superior/anterior lung regions showed the least agreement between all three methods (all p > 0.12). Absolute VDP assessed by 3D UTE PREFUL MRI showed good global agreement with Xe-MRI and 2D multi-slice PREFUL MRI in pediatric CF lung disease. Therefore, 3D UTE PREFUL MRI offers a sensitive and potentially more accessible alternative to Xe-MRI for regional volumetric evaluation of ventilation.

A phase I clinical trial assessing the safety, tolerability, and pharmacokinetics of inhaled ethanol in humans as a potential treatment for respiratory tract infections.

Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial. The study was conducted as a single-centre, open-label clinical trial in 18 healthy adult volunteers, six with no significant medical comorbidities, four with stable asthma, four with stable cystic fibrosis, and four active smokers. A dose-escalating design was used, with participants receiving three dosing cycles of 40, 60%, and then 80% ethanol v/v in water, 2 h apart, in a single visit. Ethanol was nebulised using a standard jet nebuliser, delivered through a novel closed-circuit reservoir system, and inhaled nasally for 10 min, then orally for 30 min. Safety assessments included adverse events and vital sign monitoring, blood alcohol concentrations, clinical examination, spirometry, electrocardiogram, and blood tests. No serious adverse events were recorded. The maximum blood alcohol concentration observed was 0.011% immediately following 80% ethanol dosing. Breath alcohol concentrations were high (median 0.26%) following dosing suggesting high tissue levels were achieved. Small transient increases in heart rate, blood pressure, and blood neutrophil levels were observed, with these normalising after dosing, with no other significant safety concerns. Of 18 participants, 15 completed all dosing cycles with three not completing all cycles due to tolerability. The closed-circuit reservoir system significantly reduced fugitive aerosol loss during dosing. These data support the safety of inhaled ethanol at concentrations up to 80%, supporting its further investigation as a treatment for respiratory infections.Clinical trial registration: identifier ACTRN12621000067875.

Galectin-3 levels in children with cystic fibrosis.

Cystic fibrosis (CF) is a multisystemic disease in which airway obstruction, infection, and inflammation play a critical role in the pathogenesis and progression of CF lung disease. The carbohydrate-binding protein Galectin-3 is increased in several inflammatory and fibrotic diseases and has recently been forwarded as a biomarker in these diseases. We aimed to define the role of serum Galectin-3 in children with CF by comparison with healthy subjects. This is a cross-sectional, case-control study. 143 CF and 30 healthy subjects were enrolled in the study. Peripheral blood and sputum concentrations of Galectins-3, interleukin (IL)-17A, IL-8, and neutrophil elastase (NE) were determined with commercial ELISA kits. There was no significant difference between the groups in age and gender (p = 0.592, p = 0.613, respectively). Serum Galectin-3 and NE concentrations were higher in the patient group than in healthy controls (p = 0.002, p < 0.001, respectively). There were no significant differences between groups according to IL-17A and IL-8 concentrations. Serum Galectin-3 was correlated with age (r = 0.289, p < 0.001) and body mass index (BMI) (r = 0.493, p < 0.001) in children with CF. Sputum Galectin-3 levels are negatively correlated with percent predictive forced expiratory volume in 1s (FEV1) (r = - 0.297, p = 0.029), FEV1 z-score, (r = - 0.316, p = 0.020), percent predictive forced vital capacity (FVC) (r = - 0.347, p = 0.010), and FVC z-score (r = - 0.373, p = 0.006). Conclusion: The study shows that serum Galectin-3 levels increased in clinically stable CF patients, and serum Galectin-3 response may depend on age, gender, and BMI. The sputum Galectin-3 was found to be negatively correlated with patients' lung functions. What is known: • Galectin-3 is a key regulator of chronic inflammation in the lung, liver, kidney, and tumor microenvironment. What is new: • Children with cystic fibrosis (CF) have higher serum Galectin-3 concentrations than healthy children. • Serum Galectin-3 expression influenced by age, BMI, and gender in children with CF.

Impact of Reanalysis of Nitrogen Multiple-Breath Washout on its Relationship with Chest Magnetic Resonance Imaging Findings in Clinically Stable and Pulmonary Exacerbated Children with Cystic Fibrosis.

Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects lung disease in children with cystic fibrosis (CF). Correction of a cross-talk error in the software of the MBW device Exhalyzer D in a new software version has generated significant interest regarding its impact on previous MBW findings. Since LCI and chest magnetic resonance imaging (MRI) correlated before in CF children, this study aims to reassess previous MBW data after correction. Reanalysis of the main findings from a previously published study comparing MBW and MRI in a pediatric CF cohort by reassessment of nitrogen (N2) MBW of 61 stable children with CF, 75 age-matched healthy controls (HC), and 15 CF children with pulmonary exacerbation (PEx) in the corrected software version. The corrected LCI (N2LCIcor) decreased in the entire cohort (-17.0 (11.2)%), HC (-8.5 (8.2)%), stable CF children (-22.2 (11.1)%), and within the PEx group at baseline, at PEx and after antibiotic therapy (-21.5 (7.3)%; -22.5 (6.1)%; -21.4 (6.6)%; all P<0.01). N2LCIcor and N2LCIpre correlated with chest MRI scores in stable CF (r=0.70 to 0.84; all P<0.01) without a significant difference between N2LCIcor and N2LCIpre. Change in LCI from baseline to PEx and from PEx to after therapy decreased from N2LCIpre to N2LCIcor, but these changes remained significant (all P=0.001). Our results indicate that N2LCIcor is significantly lower than N2LCIpre, but key results published in the original study demonstrating N2MBW and MRI as complementary methods for clinical surveillance in children with CF remain unaffected.

Commensal colonization reduces Pseudomonas aeruginosa burden and subsequent airway damage.

Pseudomonas aeruginosa dominates the complex polymicrobial cystic fibrosis (CF) airway and is a leading cause of death in persons with CF. Interestingly, oral streptococcal colonization has been associated with stable CF lung function. The most abundant streptococcal species found in stable patients, Streptococcus salivarius, has been shown to downregulate pro-inflammatory cytokines in multiple colonization models. However, no studies have demonstrated how S. salivarius potentially improves lung function. Our lab previously demonstrated that the P. aeruginosa exopolysaccharide Psl promotes S. salivarius biofilm formation in vitro, suggesting a possible mechanism by which S. salivarius is incorporated into the CF airway microbial community. In this study, we demonstrate that co-infection of rats leads to enhanced S. salivarius colonization and reduced P. aeruginosa colonization. Histological scores for tissue inflammation and damage are lower in dual-infected rats compared to P. aeruginosa infected rats. Additionally, pro-inflammatory cytokines IL-1β, IL-6, CXCL2, and TNF-α are downregulated during co-infection compared to P. aeruginosa single-infection. Lastly, RNA sequencing of cultures grown in synthetic CF sputum revealed that P. aeruginosa glucose metabolism genes are downregulated in the presence of S. salivarius, suggesting a potential alteration in P. aeruginosa fitness during co-culture. Overall, our data support a model in which S. salivarius colonization is promoted during co-infection with P. aeruginosa, whereas P. aeruginosa airway bacterial burden is reduced, leading to an attenuated host inflammatory response.

Lung Ultrasound in the Evaluation of Lung Disease Severity in Children with Clinically Stable Cystic Fibrosis: A Prospective Cross-Sectional Study.

With the increasing longevity of cystic fibrosis (CF), there is a growing need to minimise exposure to ionising radiation in patients who undergo regular imaging tests while monitoring the course of the lung disease. This study aimed to define the role of lung ultrasounds (LUS) in the evaluation of lung disease severity in children with clinically stable CF. LUS was performed on 131 patients aged 5 weeks to 18 years (study group) and in 32 healthy children of an equivalent age range (control group). Additionally, an interobserver study was performed on 38 patients from the study group. In CF patients, the following ultrasound signs were identified: I-lines; Z-lines; single, numerous and confluent B-lines; Am-lines; small and major consolidations; pleural line abnormalities and small amounts of pleural fluid. The obtained results were evaluated against an original ultrasound score. LUS results were correlated with the results of chest X-ray (CXR) [very high], pulmonary function tests (PFTs) [high] and microbiological status [significant]. The interobserver study showed very good agreement between investigators. We conclude that LUS is a useful test in the evaluation of CF lung disease severity compared to routinely used methods. With appropriate standardisation, LUS is highly reproducible.

Exhaled breath profiles to detect lung infection with Staphylococcus aureus in children with cystic fibrosis

BackgroundAn electronic nose (eNose) can be used to detect volatile organic compounds (VOCs). Exhaled breath contains numerous VOCs and individuals’ VOCs mixtures create distinct breath profiles. Previous reports have shown that eNose can detect lung infections. Whether eNose can detect Staphylococcus aureus airway infections in breath of children with cystic fibrosis (CF) is currently unclear. MethodsIn this cross-sectional observational study, a cloud-connected eNose was used for breath profile analysis of clinically stable paediatric CF patients with airway microbiology cultures positive or negative for CF pathogens. Data-analysis involved advanced signal processing, ambient correction and statistics based on linear discriminant and receiver operating characteristics (ROC) analyses. ResultsBreath profiles from 100 children with CF (median predicted FEV1 91%) were obtained and analysed. CF patients with positive airway cultures for any CF pathogen were distinguishable from no CF pathogens (no growth or usual respiratory flora) with accuracy of 79.0% (AUC-ROC 0.791; 95% CI: 0.669–0.913) and between patients positive for Staphylococcus aureus (SA) only and no CF pathogen with accuracy of 74.0% (AUC-ROC 0.797; 95% CI: 0.698–0.896). Similar differences were seen for Pseudomonas aeruginosa (PA) infection vs no CF pathogens (78.0% accuracy, AUC-ROC 0.876, 95% CI: 0.794–0.958). SA- and PA-specific signatures were driven by different sensors in the SpiroNose suggesting pathogen-specific breath signatures. ConclusionsBreath profiles of CF patients with SA in airway cultures are distinct from those with no infection or PA infection, suggesting the utility of eNose technology in the detection of this early CF pathogen in children with CF.

Intra- and Inter-visit Repeatability of 129 Xenon Multiple-Breath Washout MRI in Children With Stable Cystic Fibrosis Lung Disease.

Multiple-breath washout (MBW) 129 Xe MRI (MBW Xe-MRI) is a promising technique for following pediatric cystic fibrosis (CF) lung disease progression. However, its repeatability in stable CF needs to be established to use it as an outcome measure for novel therapies. To assess intravisit and intervisit repeatability of MBW Xe-MRI in healthy and CF children. Prospective, longitudinal cohort study. A total of 18 pediatric subjects (7 healthy, 11 CF). A 3 T/2D coronal hyperpolarized (HP) 129 Xe images using GRE sequence. All subjects completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, nitrogen [N2 ] MBW for lung clearance index [LCI]) and ventilation defect percent (VDP) at baseline (visit 1) and 1-month after. Fractional ventilation (FV), coefficient of variation (CoVFV ) maps were calculated from MBW Xe-MRI data acquired between intervening air washout breaths performed after an initial xenon breath-hold. Skewness of FV and CoVFV map distributions was also assessed. Repeatability: intraclass correlation coefficients (ICC), within-subject coefficient of variation (CV%), repeatability coefficient (CR). Agreement: Bland-Altman. For correlations between MBW Xe-MRI, VDP and PFTs: Spearman's correlation. Significance threshold: P < 0.05. For FV, intravisit median [IQR] ICC was high in both healthy (0.94 [0.48, 0.99]) and CF (0.83 [0.04, 0.97]) subjects. CoVFV also had good intravisit ICC in healthy (0.92 [0.42, 0.99]) and CF (0.79 [0.02, 0.96]) subjects. Similarly, for FV, intervisit ICC was high in health (0.94 [0.68, 0.99]) and CF (0.89 [0.61, 0.97]). CoVFV also had good intervisit ICC in health (0.92 [0.42, 0.99]) and CF (0.78 [0.26, 0.94]). FV had better intervisit repeatability than VDP. CoVFV correlated significantly with LCI (R=0.56). Skewness of FV distributions significantly distinguished between cohorts at baseline. MBW Xe-MRI had high intravisit and intervisit repeatability in healthy and stable CF subjects. CoVFV correlated with LCI, suggesting the importance of ventilation heterogeneity to early CF. 1. Stage 2.

Efficacy of the Simeox® Airway Clearance Technology in the Homecare Treatment of Children with Clinically Stable Cystic Fibrosis: A Randomized Controlled Trial.

Cystic fibrosis (CF) patients require regular airway clearance therapy (ACT). The aim of this study was to evaluate homecare therapeutic effects of a new ACT (Simeox®) added to the optimal standard of care, including home chest physiotherapy, in the treatment of clinically stable children. Forty pediatric CF patients (8-17 years old) with stable disease were randomized 1:1 in a single-center, prospective, open-label, cross-over trial into two groups: with or without Simeox®. Lung function (impulse oscillometry, spirometry, body plethysmography, multi-breath nitrogen washout) results, health-related quality of life, and safety were assessed during the study after 1 month of therapy at home. A significant decrease in proximal airway obstruction (as supported by improvement in airway resistance at 20 Hz (R20Hz) and maximum expiratory flow at 75% of FVC (MEF75)) compared to the control group was observed after 1 month of therapy with the device. Lung-clearance index was stable in the study group, while it worsened in the control group. In addition, the device group demonstrated a significant increase in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) physical score. No side effects were identified during the study. Simeox® may improve drainage of the airways in children with clinically stable CF and could be an option in chronic treatment of the disease.

Inter- and intravisit repeatability of free-breathing MRI in pediatric cystic fibrosis lung disease.

The purpose of this study is to assess the intra- and interscan repeatability of free-breathing phase-resolved functional lung (PREFUL) MRI in stable pediatric cystic fibrosis (CF) lung disease in comparison to static breath-hold hyperpolarized 129-xenon MRI (Xe-MRI) and pulmonary function tests. Free-breathing 1-hydrogen MRI and Xe-MRI were acquired from 15 stable pediatric CF patients and seven healthy age-matched participants on two visits, 1 month apart. Same-visit MRI scans were also performed on a subgroup of the CF patients. Following the PREFUL algorithm, regional ventilation (RVent) and regional flow volume loop cross-correlation maps were determined from the free-breathing data. Ventilation defect percentage (VDP) was determined from RVent maps (VDPRVent ), regional flow volume loop cross-correlation maps (VDPCC ), VDPRVent ∪ VDPCC , and multi-slice Xe-MRI. Repeatability was evaluated using Bland-Altman analysis, coefficient of repeatability (CR), and intraclass correlation. Minimal bias and no significant differences were reported for all PREFUL MRI and Xe-MRI VDP parameters between intra- and intervisits (all P > 0.05). Repeatability of VDPRVent , VDPCC , VDPRVent ∪ VDPCC , and multi-slice Xe-MRI were lower between the two-visit scans (CR=14.81%, 15.36%, 16.19%, and 9.32%, respectively) in comparison to the same-day scans (CR=3.38%, 2.90%, 1.90%, and 3.92%, respectively). pulmonary function tests showed high interscan repeatability relative to PREFUL MRI and Xe-MRI. PREFUL MRI, similar to Xe-MRI, showed high intravisit repeatability but moderate intervisit repeatability in CF, which may be due to inherent disease instability, even in stable patients. Thus, PREFUL MRI may be considered a suitable outcome measure for future treatment response studies.

Safety and microbiological activity of phage therapy in persons with cystic fibrosis colonized with Pseudomonas aeruginosa: study protocol for a phase 1b/2, multicenter, randomized, double-blind, placebo-controlled trial

BackgroundBacteriophages (phages) are a promising anti-infective option for human disease. Major gaps remain in understanding their potential utility.MethodsThis is a randomized, placebo-controlled, double-blind study of a single dose of intravenous phage in approximately 72 clinically stable adult cystic fibrosis volunteers recruited from up to 20 US sites with Pseudomonas aeruginosa airway colonization. The single dose of phage consists of a mixture of four anti-pseudomonal phages. Six sentinel participants will be sequentially enrolled with dose escalation of the phage mixture by one log10 beginning with 4 × 107 plaque-forming units in an unblinded stage 1. If no serious adverse events related to the study product are identified, the trial will proceed to a double-blinded stage 2. In stage 2a, 32 participants will be randomly assigned to one of three phage dosages or placebo in a 1:1:1:1 allocation. An interim analysis will be performed to determine the phage dosage with the most favorable safety and microbiological activity profile to inform phage dosing in stage 2b. During stage 2b, up to 32 additional volunteers will be randomized 1:1 to the phage or placebo arm. Primary outcomes include (1) the number of grade 2 or higher treatment-emergent adverse events, (2) change in log10P. aeruginosa total colony counts in sputum, and (3) the probability of a randomly selected subject having a more favorable outcome ranking if assigned to receive phage therapy versus placebo. Exploratory outcomes include (1) sputum and serum phage pharmacokinetics, (2) the impact of phage on lung function, (3) the proportion of P. aeruginosa isolates susceptible to the phage mixture before and after study product administration, and (4) changes in quality of life.DiscussionThis trial will investigate the activity of phages in reducing P. aeruginosa colony counts and provide insights into the safety profile of phage therapy.Trial registrationClinicalTrials.gov NCT05453578. Registered on 12 July 2022.

Role of Bronchial Artery Embolization as Early Treatment Option in Stable Cystic Fibrosis Patients with Sub-Massive Hemoptysis: Personal Experience and Literature Review.

(1) Background: We describe our experience with cystic fibrosis (CF) patients treated with bronchial artery embolization (BAE) for sub-massive hemoptysis to understand if early treatment of sub-massive hemoptysis can reduce the volume of any subsequent bleedings. (2) Materials: We performed a retrospective study including CF patients who underwent angiographic procedures for BAE following sub-massive hemoptysis, from March 2016 to December 2021. All patients underwent an initial chest angio-CT study. BAE was realized with microspheres or coils. (3) Results: Thirteen patients were included, subjected to at least one BAE after sub-massive hemoptysis, for a total of 19 procedures. Technical success was 94.7%; in a single case, the catheterization of the bronchial arterial feeder was not achievable and the procedure was repeated. Primary clinical success was 92.3%; secondary clinical success was 69.2%. Relative clinical success was 85%. A higher incidence of recurrent hemoptysis following treatment with coils was observed (100% of cases) compared to treatment with microspheres (54.5% of cases) χ2 = 5.43 (p < 0.05). (4) Conclusions: BAE is a safe and effective method for the treatment of hemoptysis in CF patients; it should be practiced not only after massive or recurrent hemoptysis but also in patients with sub-massive bleeding to improve their life expectancy and quality of life.

Specific circulating neutrophils subsets are present in clinically stable adults with cystic fibrosis and are further modulated by pulmonary exacerbations

The progressive lung destruction in cystic fibrosis (CF) is tightly associated with chronic bacterial infection and neutrophil-dominated airway inflammation. CF pulmonary disease is complicated by episodes of acute exacerbations, contributing to irreversible lung damage. We hypothesized that circulating subsets of neutrophils from clinically stable adults with CF present some phenotypic specificities that could amplify their activation during an infectious episode. The aim of the present study was to examine the different neutrophil subsets in whole blood and in the low density neutrophils (LDN) that co-purify with peripheral blood mononuclear cells (PBMC) in clinically stable adults with CF and in CF adults during pulmonary exacerbations compared to healthy donors. Blood samples were obtained from 22 adults with CF (16 in stable state and 6 during pulmonary exacerbations) and from 20 healthy donors. Flow cytometry analysis of 13 different markers related to lineage (CD45, CD15), maturity (CD16, CD10, and CD33), activation (CD62L, CD11b, CD66b, and CD114), metabolism (GLUT-1, LOX1) and immunosuppression (PD1, PD-L1) was carried out within whole blood and within the LDN fraction. Unsupervised analysis of flow cytometry data was performed using visual t-distributed stochastic neighbor embedding (vi-tSNE). A significant increase in the CD11b expression in neutrophils from CF patients during exacerbations was observed compared to neutrophils from stable CF patients or to healthy donors, indicative of a circulating activation state due to an infectious status. The percentage of LDN was not increased in stable CF patients but increased during exacerbations. Analysis of neutrophil subsets using the double CD16/CD62L labeling revealed a significant increase in the CD16high/CD62Llow subset in all CF patients compared to healthy donors. In contrast, an increase in the CD16low/CD62Lhigh subset was observed only in CF patients during exacerbations. Unsupervised analysis identified a PD-L1high/CD114high population that was present in stable CF patients and as well as in CF patients during exacerbations.

Short-term effects of a novel bronchial drainage device: A pilot cohort study in subjects with cystic fibrosis.

Background and AimsIn cystic fibrosis (CF) airways, impaired airway mucociliary clearance and mucus accumulation due to cystic fibrosis transmembrane conductance regulator defects contribute to inflammation, progressive structural lung damage, and decline of lung function. Physiotherapy is essential to promote mucus mobilization and removal in CF and is a key element of rehabilitation measures, but conventional techniques may be suboptimal to mobilize viscous mucus. This study aimed to test the specific effects of a novel bronchial drainage device (BDD) (Simeox®; PhysioAssist) in subjects with CF and evaluate lung function, diaphragm mobility, and sputum properties.MethodsThis prospective monocentric clinical cohort study in the setting of outpatient physiotherapy of CF patients (n = 21) with stable CF lung disease collected pulmonary lung function tests (PFT), diaphragm mobility, and sputum properties before and after two physiotherapy sessions using the novel BDD. PFT was assessed using spirometry and diaphragm mobility using m‐mode ultrasound analysis. Spontaneous sputum samples were collected before and after using the BDD and analyzed for microstructure and DNA concentrations.ResultsPFT parameters (FEV1, FVC, MEF25/50/75) were not affected by the use of the BDD. Ultrasound analysis of diaphragm mobility revealed an increase in maximum diaphragm excursion upon the intervention. Mucus analysis demonstrated altered microstructure and higher DNA concentrations collected after using the BDD compared to samples collected before. Pearson correlation analysis showed significant correlations between changes in mucus properties and DNA levels in respective mucus samples.ConclusionOur results demonstrate that the novel BDD improves diaphragm mobility and alters sputum properties in subjects with CF. The novel BDD with unique properties may be further studied as a device in CF‐specific physiotherapy to facilitate sputum mobilization of CF patients.

Feasibility of the A-STEP for the assessment of exercise capacity in people with cystic fibrosis.

To evaluate feasibility of the Alfred Step Test Exercise Protocol (A-STEP) for the assessment of exercise capacity in adults and children with cystic fibrosis (CF); in adults to test whether demographics and/or lung function correlated with exercise capacity. Adults and children with stable CF from two centres completed the A-STEP (a recently developed incremental maximal-effort step test). Feasibility was evaluated by: usefulness for exercise capacity assessment (measures of exercise capacity were: level reached, exercise-induced desaturation, and achievement of at least one maximal effort criteria); safety; operational factors; time to complete; floor and/or ceiling effects. We used multiple linear regression to test whether demographics and/or lung function correlated with exercise capacity. A total of 49 participants: 38 adults (18 male), percent predicted (pp) forced expiration in one second (FEV1 ) 29-109, aged 22-48 years and 11 children (6 male), ppFEV1 68-107, aged 10-15 years were included. Levels reached (mean (SD) [range]) were 10.2 (2.4) [6-15] (adults), 10.1 (2.5) [7-14] (children); desaturation (change between baseline and peak-exercise SpO2 ): was 8.4 (3.8 [0-15]% (adults), 2.0 (2.0) [0-7]% (children). A total of 8 (21%) adults and no children desaturated <90% SpO2 . At least one criterion for maximal effort was reached by 33 (84%) adults and 10 (91%) children. There were no adverse events. The A-STEP was straightforward to use and carried out by one operator. A total of 26 (68.4%) adults and 7 (63.6%) children completed the test within the recommended 8-12 min. All participants completed a minimum of 6 levels, and completed the test before the final 16th level. In adults, ppFEV1 and ppFVC correlated with the level reached (r = 0.55; p = <0.001 and r = 0.66, p = <0.0001) and desaturation (r = 0.55, p = <0.001 and r = 0.45, p = <0.005). In adults and children with stable CF, the A-STEP was feasible, safe, and operationally easy to use for the assessment of exercise capacity, without floor or ceiling effects. In adults, lung function correlated with exercise capacity.

Effects of a Long-Term Wearable Activity Tracker-Based Exercise Intervention on Cardiac Morphology and Function of Patients with Cystic Fibrosis.

Several studies have shown that patients with cystic fibrosis (CF), even at a young age, have pulmonary and cardiac abnormalities. The main complications are cardiac right ventricular (RV) systolic and/or diastolic dysfunction and pulmonary hypertension, which affects their prognosis. Exercise training (ET) is recommended in patients with CF as a therapeutic modality to improve physical fitness and health-related quality of life. However, questions remain regarding its optimal effective and safe dose and its effects on the patients’ cardiac function. The study aimed to provide a wearable activity tracker (WAT)-based ET to promote physical activity in CF patients and assess its effects on cardiac morphology and function. Forty-two stable CF individuals (aged 16.8 ± 3.6 years) were randomly assigned to either the intervention (Group A) or the control group (Group B). Group A participated in a 1-year WAT-based ET program three times per week. All patients underwent a 6-min walking test (6-MWT) and an echocardiographic assessment focused mainly on RV anatomy and function at the baseline and the end of the study. RV systolic function was evaluated by measuring the tricuspid annular plane systolic excursion (TAPSE), the systolic tricuspid annular velocity (TVS’), the RV free-wall longitudinal strain (RVFWSL), and the right ventricular four-chamber longitudinal strain (RV4CSL). RV diastolic function was assessed using early (TVE) and late (TVA) diastolic transtricuspid flow velocity and their ratio TVE/A. Pulmonary artery systolic pressure (PASP) was also estimated. In Group A after ET, the 6MWT distance improved by 20.6% (p < 0.05), TVA decreased by 17% (p < 0.05), and TVE/A increased by 13.2% (p < 0.05). Moreover, TAPSE, TVS’, RVFWSL, and RV4CSL increased by 8.3% (p < 0.05), 9.0% (p < 0.05), 13.7% (p < 0.05), and 26.7% (p < 0.05), respectively, while PASP decreased by 7.6% (p < 0.05). At the end of the study, there was a significant linear correlation between the number of steps and the PASP (r = −0.727, p < 0.01) as well as the indices of RV systolic function in Group A. In conclusion, WAT is a valuable tool for implementing an effective ET program in CF. Furthermore, ET has a positive effect on RV systolic and diastolic function.

Pseudomonas aeruginosa polysaccharide Psl supports airway microbial community development

Pseudomonas aeruginosa dominates the complex polymicrobial cystic fibrosis (CF) airway and is a leading cause of death in persons with CF. Oral streptococcal colonization has been associated with stable CF lung function. However, no studies have demonstrated how Streptococcus salivarius, the most abundant streptococcal species found in individuals with stable CF lung disease, potentially improves lung function or becomes incorporated into the CF airway biofilm. By utilizing a two-species biofilm model to probe interactions between S. salivarius and P. aeruginosa, we discovered that the P. aeruginosa exopolysaccharide Psl promoted S. salivarius biofilm formation. Further, we identified a S. salivarius maltose-binding protein (MalE) that is required for promotion of biofilm formation both in vitro and in a Drosophila melanogaster co-infection model. Finally, we demonstrate that promotion of dual biofilm formation with S. salivarius is common among environmental and clinical P. aeruginosa isolates. Overall, our data supports a model in which S. salivarius uses a sugar-binding protein to interact with P. aeruginosa exopolysaccharide, which may be a strategy by which S. salivarius establishes itself within the CF airway microbial community.

Cystic Fibrosis-Related Diabetes Mellitus and Pregnancy: A Retrospective Study.

IntroductionCystic fibrosis-related diabetes mellitus (CFRDM) is becoming a more common issue in pregnancy care as the life expectancy of females living with cystic fibrosis has improved, with an increasing number of pregnancies in this population. Despite the Republic of Ireland having the highest incidence of cystic fibrosis globally, there is limited Irish data on pregnancy outcomes for those with CFRDM. This study aimed to retrospectively review maternal and foetal outcomes of pregnancies affected by maternal CFRDM.MethodsThe patient records of all women with CFRDM who attended the National Maternity Hospital Dublin for obstetric care between 2015 and 2019 were retrospectively reviewed.ResultsA search of patient records identified 15 pregnancies in 12 women with CFRDM during the study period. CFRDM was diagnosed pre-conception in ten of the 15 pregnancies. Median neonatal weight at birth was lower in women with CFRDM diagnosed pre-conception compared to women diagnosed during pregnancy (2.8 vs. 3.02 kg). The median weight gain in women with CFRDM diagnosed pre-conception was 10.9 kg compared to 11.9 kg for those diagnosed during pregnancy. The majority of women (62.5%) with CFRDM diagnosed pre-conception delivered via caesarean section. Admission for CF exacerbations during pregnancy in women with CFRDM diagnosed pre-conception was very common (87.5%) compared with 75% of those diagnosed during their pregnancy.ConclusionWomen diagnosed with CFRDM were likely to require caesarean section, to be treated with insulin, and to be frequently admitted to hospital for CF exacerbations. Our review highlights the importance of good glucose control, stable cystic fibrosis before pregnancy and a multidisciplinary team approach.

Cardiac involvement in cystic fibrosis evaluated using cardiopulmonary magnetic resonance

Cystic fibrosis (CF) transmembrane conductance regulator is expressed in myocardium, but cardiac involvement in CF remains poorly understood. The recent development of a combined cardiopulmonary magnetic resonance imaging technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. The aim of this study was to investigate myocardial manifestations in adults with CF, both in a stable state and during an acute respiratory exacerbation, and to investigate the relationship between cardiac and pulmonary disease. Healthy adult volunteers (n = 12) and adults with CF (n = 10) were studied using a multiparametric cardiopulmonary magnetic resonance protocol. CF patients were scanned during an acute respiratory exacerbation and re-scanned when stable. Stable CF was associated with left ventricular dilatation and hypertrophy (LVH; left ventricular mass: CF 59 ± 9 g/m2 vs. control 50 ± 8 g/m2; p = 0.028). LVH was predominantly driven by extracellular myocardial matrix expansion (extracellular matrix mass: CF 27.5 ± 3.4 g vs. control 23.6 ± 5.2 g; p = 0.006; extracellular volume [ECV]: CF 27.6 [24.7–29.8]% vs. control 24.8 [22.9–26.0]%; p = 0.030). Acute CF was associated with an acute reduction in left ventricular function (ejection fraction: acute 57 ± 3% vs. stable 61 ± 5%; p = 0.025) and there was a suggestion of myocardial oedema. Myocardial oedema severity was strongly associated with the severity of airflow limitation (r = − 0.726, p = 0.017). Multiparametric cardiopulmonary magnetic resonance technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. Stable CF is associated with adverse myocardial remodelling, including left ventricular systolic dilatation and hypertrophy, driven by myocardial fibrosis. CF exacerbation is associated with acute myocardial contractile dysfunction. There is also a suggestion of myocardial oedema in the acute period which is related to pulmonary disease severity.

Effect of Salbutamol on Lung Ventilation in Children with Cystic Fibrosis: Comprehensive Assessment Using Spirometry, Multiple-Breath Washout, and Functional Lung Magnetic Resonance Imaging

Background: Inhalation therapy is one of the cornerstones of the daily treatment regimen in patients with cystic fibrosis (CF). Recommendations regarding the addition of bronchodilators, especially salbutamol are conflicting due to the lack of evidence. New diagnostic measures such as multiple-breath washout (<underline>MBW)</underline> and functional magnetic resonance imaging (MRI) have the potential to reveal new insights into bronchodilator effects in patients with CF. Objective: The objective of the study was to comprehensively assess the functional response to nebulized inhalation with salbutamol in children with CF. Methods: Thirty children aged 6–18 years with stable CF performed pulmonary function tests, MBW, and matrix pencil-MRI before and after standardized nebulized inhalation of salbutamol. Results: Lung clearance index decreased (improved) by −0.24 turnover (95% confidence interval [CI]: −0.53 to 0.06; p = 0.111). Percentage of the lung volume with impaired fractional ventilation and relative perfusion decreased (improved) by −0.79% (CI: −1.99 to 0.42; p = 0.194) and −1.31% (CI: −2.28 to −0.35; p = 0.009), respectively. Forced expiratory volume (FEV₁) increased (improved) by 0.41 z-score (CI: 0.24–0.58; p < 0.0001). We could not identify specific clinical factors associated with a more pronounced effect of salbutamol. Conclusions: There is a positive short-term effect of bronchodilator inhalation on FEV₁ in patients with CF, which is independent of ventilation inhomogeneity. Heterogeneous response between patients suggests that for prediction of a therapeutic effect this should be tested by spirometry in every patient individually.