CF Lung Research Articles

P181 Polygenic risk score and socioenvironmental factors predict early-onset lung disease in young children with cystic fibrosis

Although respiratory pathology is known to develop in young children with CF, the determinants of early-onset lung disease have not been elucidated. Our goal was to determine the impact of genetic and socioenvironmental factors during the first 3 years and test the hypothesis that both influence early-onset CF lung disease.

WS09.04 Enhancement of channel activity of the CFTR protein delivered via gene therapy vectors

Objectives: The advancements in developing CFTR-targeted drugs offer effective treatments for most cystic fibrosis patients. However, there is still a small portion of patients who do not respond to the new drugs. In addition, it is still unclear whether the drugs can maintain the lung function of the patients in long term. Thus, other novel therapeutic strategies should be investigated. Using gene therapy to express a copy of functional CFTR gene in CF cells is an attractive strategy. Currently, one of the major challenges is how to deliver enough functional CFTR protein to CF lungs to achieve therapeutic effects. Our group has been using a gene expression cassette based on the human cytokeratin 18 (K18) gene promoter to express the CFTR gene. Since K18 gene expression has been reported to be enhanced by sodium butyrate, here we are examining whether CFTR expression can be further enhanced following vector delivery to CF cells.

P269 Proposed plan for oxygen therapy as an adjuvant to antibiotics in cystic fibrosis

Although the use of modulator treatments targeting the basal defect in the Cystic Fibrosis transmembrane conductance regulator improves lung function and is associated with reduced burden of lung infections, we have not seen bacterial eradication, thus antibiotic treatments remain crucial for targeting chronic Pseudomonas aeruginosa infection. Recent investigations have shown large zones of oxygen (O2) depletion in the infected part of CF lungs due to consumption of O2 by the surrounding neutrophils, where bacterial aerobic respiration is prevented. The restriction of O2 causes reduced uptake of antibiotics, down-regulation of antibiotic targets and inhibited induction of bactericidal amounts of reactive O2 species as seen for P. aeruginosa. By enhancing the aerobic physiology of the bacteria through adjuvant O2 treatment with normobaric O2 treatment (NBOT), the bacteria can be sensitized, and even clones, protected by the O2 depletion, can be treated. We hypothesize that adjuvant intermittent normobaric oxygenation (100% O2) has a beneficiary clinical impact on chronic P. aeruginosa lung infection.

P276 Updating the consensus document: laboratory standards for processing microbiological samples from people with cystic fibrosis

The first edition of the consensus document ‘Laboratory Standards for Processing Microbiological Samples from People with Cystic Fibrosis’ was published by Cystic Fibrosis Trust in 2010. Since then, new pathogens have emerged, widening our understanding of the complex balance of the CF lung microbiome. The techniques used for microbiological sample processing have also advanced. Our aim was to update the document to facilitate the best care for people with CF through appropriate, accurate and timely microbiological processing and identification.

WS14.03 Combined therapeutic strategies for the restoration of airway epithelial integrity and function in cystic fibrosis

Background: In CF airways, dysfunctional Cl– secretion and mucociliary clearance favor bacterial infections contributing to progressive lung damage and respiratory failure, the first cause of morbidity and mortality. We thus devote our efforts to identify novel therapeutic strategies to promote CF lung repair. We previously discovered that the capability of CF airway epithelia to repair is less efficient, than in healthy controls, due to the CFTR defect and bacterial infections, in particular with P. aeruginosa (PA) and S. aureus (SA). Our work also unveiled that CFTR modulators enhance airway repair, but both CFTR rescue and repair improvement are dampened by infection.

WS06.05 The volume of trapped air (VTA) from multiple breath washout (MBW) substantially underestimates the extent of trapped air (TA) demonstrated with spirometry-controlled computed tomography

Objectives: A limitation of the lung clearance index (LCI) from MBW is that it may ‘overlook’ areas of TA, a major component of CF lung disease pathophysiology. Previous methodology addressed this by performing 5 inspiratory capacity (5IC) breaths after the standard end of washout to mobilise TA. In calculating the VTA, a fundamental assumption is that the gas mobilized has a [N2] of 78%. We assessed this assumption and the relationship of VTA to TA scores from CT scans.

P194 Computed cardiopulmonography (CCP) and the idealised lung clearance index (iLCI) in early-stage cystic fibrosis

LCI is a sensitive parameter to track CF lung disease but is influenced by extra-pulmonary factors such as equipment deadspace, breathing volume and rate which can reduce accuracy. This study explores a novel approach, CCP, to calculate an idealised LCI (iLCI). CCP utilises two components: (a) a novel, accurate laser gas analyser (LGA; Smith NMJ et al. Sci Rep. 2021) and (b)a lung model with extra-pulmonary factors removed.

WS16.01 Highly-effective CFTR modulator therapy with elexacaftor/tezacaftor/ivacftor (ETI) leads to age-dependent changes of typical cystic fibrosis hallmark pathogens – data from the German cystic fibrosis registry

Objectives: The impressive improvements of CFTR function by elexacaftor/tezacaftor/ivacaftor (ETI) result in remarkable changes of pulmonary function and structural lung disease. Whether these effects translate to changes of microbial patterns, an equally critical aspect of CF lung disease, remains to be shown. To examine the effect of ETI on Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) detections in people with CF (pwCF) ≥12 years.

EPS1.03 Establishing the utility of oxygen-enhanced (OE-)MRI as a structural and functional measure of cystic fibrosis lung disease: relationships with physiological and cystic fibrosis outcomes

Hyperpolarised gas MRI is a popular research tool in the assessment of CF lung disease, but it is likely limited to the research setting in CF because of its expense and need for specialist equipment. OE-MRI has the potential to be a feasible and cheaper alternative. As part of a longitudinal study assessing the clinimetrics of OE-MRI, cross-sectional data from the first visit have been analysed for relationships with conventional (FEV1, FVC, LCI2.5, CT scores) and more novel (MBWShX) [Short et al, 2021, JCF] outcomes of lung disease.

EPS2.09 Cervical cancer in cystic fibrosis: from treatment to prevention

Background: There is an increased incidence of some cancers (e.g. gastrointestinal) in CF. Although cervical cancer does not seem to be more prevalent in CF pre-transplant, immunosuppression after organ transplantation increases the risk of Human Papilloma Virus (HPV) conditions. The risk of complications from CF lung disease can influence treatment options and compromise outcomes.

Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double‐blind, placebo‐controlled phase 1/2 clinical study

BackgroundMRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease. MethodsThis was a randomized, double-blind, placebo-controlled Phase 1/2 study performed in the US. Adults with 2 severe class I and/or II CFTR mutations and baseline ppFEV1 values between 50 and 90% were randomized 3:1 (MRT5005: placebo). Six dose levels of MRT5005 (4, 8, 12, 16, 20, and 24 mg) or placebo (0.9% Sodium Chloride) were administered by nebulization. The single ascending dose cohort was treated over a range from 8 to 24 mg; the multiple ascending dose cohort received five weekly doses (range 8–20 mg); and the daily dosing cohort received five daily doses (4 mg). ResultsA total of 42 subjects were assigned to MRT5005 [31] or placebo [11]. A total of 14 febrile reactions were observed in 10 MRT5005-treated participants, which were mild [3] or moderate [11] in severity; two subjects discontinued related to these events. Additionally, two MRT5005-treated patients experienced hypersensitivity reactions, which were managed conservatively. The most common treatment emergent adverse events were cough and headache. No consistent effects on FEV1 were noted. ConclusionsMRT5005 was generally safe and well tolerated through 28 days of follow-up after the last dose, though febrile and hypersensitivity reactions were noted. The majority of these reactions resolved within 1–2 days with supportive care allowing continued treatment with MRT5005 and careful monitoring. In this small first-in-human study, FEV1 remained stable after treatment, but no beneficial effects on FEV1 were observed.

A Pilot Study of Lung Clearance Index as a Useful Outcome Marker in the Follow-Up of Pediatric Patients with Non-Cystic Fibrosis Bronchiectasis?

The forced expiratory volume in one second (FEV1) is regularly used for the follow-up of patients with non-cystic fibrosis bronchiectasis (nCF-BE). The lung clearance index (LCI), measured by the multiple breath washout test, has been recently proposed as a lung function measure and a potential tool more sensitive than the FEV1 measured by spirometry in assessing airway changes seen on imaging. While several data have been endorsed as a useful endpoint in clinical trials of patients with early or mild CF lung disease and as the main outcome measure in clinical trials with CFTR modulators in children and adolescents with CF, few data are available in the context of non-CF bronchiectasis. The aim of this pilot study was to compare the LCI with the FEV1 as well as the forced vital capacity (FVC), the forced expiratory flow at 25-75% of the FVC (FEF 25-75%), and chest imaging based on the modified Reiff score in patients with primary ciliary dyskinesia (PCD) and non-CF, non-PCD bronchiectasis (PCD-BE and nCFnPCD-BE). Additionally, we compared each test's duration and the preferred technique. Twenty children were included; nine had PCD-BE and eleven had nCFnPCD-BE. The median age was twelve years (ages ranging between five and eighteen years). The median LCI was seven while the median z-scores of the FEV1, FVC, and FEF 25-75% were -0.6, 0, and -0.9, respectively. No significant associations or correlations were observed between LCI, spirometric parameters, or the modified Reiff score. However, nearly half of the population (n = 9) had an abnormal LCI, while only 10% had an abnormal FEV1. A total of 75% of children preferred MBW, despite it lasting five times longer than spirometry. In this paper, the authors suggest that LCI might be useful in a cohort of pediatric patients with PCD-BE and nCFnPCD-BE for detecting early lung function changes during their follow-up. Additionally, MBW seems to be preferred by patients. These data may encourage further studies on this topic.

Genetic Modifiers of Cystic Fibrosis Lung Disease Severity: Whole-Genome Analysis of 7,840 Patients.

Rationale: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance. Objectives: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity. Methods: Whole-genome sequencing data on 4,248 unique pwCF with pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 patients with pancreatic insufficiency from the United States, Canada, and France. This report describes association of approximately 15.9 million SNPs using the quantitative Kulich normal residual mortality-adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using premodulator lung function data. Measurements and Main Results: Testing included common and rare SNPs, transcriptome-wide association, gene-level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize that these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous genome-wide association study findings. These whole-genome sequencing data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or rare variants were found. Multilocus effects at chr5p13 (SLC9A3/CEP72) and chr11p13 (EHF/APIP) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects. Conclusions: This premodulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and postmodulator genetic studies and the development of novel therapeutics for CF lung disease.

Position paper: Models of post-transplant care for individuals with cystic fibrosis

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication.

Regulatory T cell enhancement in adults with cystic fibrosis receiving Elexacaftor/Tezacaftor/Ivacaftor therapy.

Cystic fibrosis (CF), especially CF lung disease, is characterized by chronic infection, immune dysfunction including impairment of regulatory T cells (Tregs) and an exaggerated inflammatory response. CF transmembrane conductance regulator (CFTR) modulators have shown to improve clinical outcomes in people with CF (PwCF) with a wide range of CFTR mutations. However, it remains unclear whether CFTR modulator therapy also affects CF-associated inflammation. We aimed to examine the effect of elexacaftor/tezacaftor/ivacaftor therapy on lymphocyte subsets and systemic cytokines in PwCF. Peripheral blood mononuclear cells and plasma were collected before and at three and six months after the initiation of elexacaftor/tezacaftor/ivacaftor therapy; lymphocyte subsets and systemic cytokines were determined using flow cytometry. Elexacaftor/tezacaftor/ivacaftor treatment was initiated in 77 PwCF and improved percent predicted FEV1 by 12.5 points (p<0.001) at 3 months. During elexacaftor/tezacaftor/ivacaftor therapy, percentages of Tregs were enhanced (+18.7%, p<0.001), with an increased proportion of Tregs expressing CD39 as a marker of stability (+14.4%, p<0.001). Treg enhancement was more pronounced in PwCF clearing Pseudomonas aeruginosa infection. Only minor, non-significant shifts were observed among Th1-, Th2- and Th17-expressing effector T helper cells. These results were stable at 3- and 6-month follow-up. Cytokine measurements showed a significant decrease in interleukin-6 levels during treatment with elexacaftor/tezacaftor/ivacaftor (-50.2%, p<0.001). Treatment with elexacaftor/tezacaftor/ivacaftor was associated with an increased percentage of Tregs, especially in PwCF clearing Pseudomonas aeruginosa infection. Targeting Treg homeostasis is a therapeutic option for PwCF with persistent Treg impairment.

Airway bacterial community composition in persons with advanced cystic fibrosis lung disease

BackgroundThe progression of lung disease in people with cystic fibrosis (pwCF) has been associated with a decrease in the diversity of airway bacterial communities. How often low diversity communities occur in advanced CF lung disease and how they may be associated with clinical outcomes is not clear, however. MethodsWe sequenced a region of the bacterial 16S ribosomal RNA gene to characterize bacterial communities in sputum from 190 pwCF with advanced lung disease (FEV1≤40% predicted), with particular attention to the prevalence and relative abundance of dominant genera. We evaluated relationships between community diversity and clinical outcomes. ResultsAlthough most of the 190 pwCF with advanced lung disease had airway bacterial communities characterized by low diversity with a dominant genus, a considerable minority (40%) did not. The absence of a dominant genus, presence of methicillin-susceptible Staphylococcus aureus, and greater bacterial richness positively correlated with lung function. Higher relative abundance of the dominant genus and greater antimicrobial use negatively correlated with lung function. PwCF with a low diversity community and dominant genus had reduced lung transplant-free survival compared to those without (median survival of 1.6 vs 2.9 years). ConclusionsA considerable proportion of pwCF with advanced lung disease do not have airway bacterial communities characterized by low diversity and a dominant genus and these individuals had better survival. An understanding of the antecedents of low diversity airway communities– and the impact these may have on lung disease trajectory - may provide avenues for improved management strategies.

Clinical outcomes associated with Achromobacter species infection in people with cystic fibrosis

BackgroundAchromobacter species are emerging pathogens isolated from respiratory samples of Patients with cystic fibrosis (pwCF) causing growing concerns in the CF community. The epidemiology and the clinical impact of Achromobacter in CF is unclear since data are restricted to small case control studies or selected populations. AimTo characterize the effect of Achromobacter respiratory infection on CF lung disease. MethodsEuropean CF Society Patient Registry data was analysed for association between Achromobacter infection and demographic/clinical characteristics and outcomes of pwCF. ResultsOf eligible 38,795 patients, Achromobacter infection was reported in 2,093 (prevalence (95% CI) of 5.40% (5.17 - 5.62). The prevalence varied significantly between the countries and increased with age peaking at the age 20–30. Achromobacter infection was more prevalent in pwCF carrying class minimal function mutations, having worse nutrition or lower pulmonary function, and more patients inhaled antibiotics against P. aeruginosa. Patient infected with Achromobacter had similar pulmonary function and BMI to patients infected with P. aeruginosa at all age groups. Being infected with both bacteria was associated with significantly lower pulmonary function and BMI at all age groups. ConclusionsAchromobacter infection was associated with disease severity similar to infection with P. aeruginosa. Being infected with both bacteria is associated with even more severe disease. This suggests to study if eradication will improve the outcome of pwCF.

Elexacaftor-Tezacaftor-Ivacaftor improves exercise capacity in adolescents with cystic fibrosis.

Elexacaftor/Tezacaftor/Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator with the potential to improve exercise capacity. This case series of three adolescents with CF aimed to investigate whether 6 weeks treatment with Elexacaftor/Tezacaftor/Ivacaftor could improve exercise capacity in CFTR modulator naive adolescents with CF. Three adolescents (14.0 ± 1.4 years) with CF (FEV1 % predicted: 62.5 ± 17.1; F508del/F508del genotype) completed an exhaustive maximal cardiopulmonary exercise test on a cycle ergometer to determine peak oxygen uptake ( O2peak ) and measure changes in gas exchange and ventilation during exercise at 6 weeks. We also analyzed wrist-worn device-based physical activity (PA) data in two of the three cases. Validated acceleration thresholds were used to quantify time spent in each PA intensity category. Clinically meaningful improvements in O2peak were observed in all three cases (+17.6%, +52.4%, and +32.9%, respectively), with improvements greatest in those with more severe lung disease and lower fitness at baseline. Although lung function increased in all cases, inconsistent changes in markers of ventilatory and peripheral muscle efficiency likely suggest different mechanisms of improvement in this case group of adolescents with CF. Device-based analysis of PA was variable, with one case increasing and one case decreasing. In this case series, we have observed, for the first time, improvements in exercise capacity following 6 weeks of treatment with Elexacaftor/Tezacaftor/Ivacaftor. Improvements were greatest in the presence of more severe CF lung disease and lower aerobic fitness at baseline. The mechanism(s) responsible for these changes warrant further investigation in larger trials.

The Microbiology of Non-aeruginosa Pseudomonas Isolated From Adults With Cystic Fibrosis: Criteria to Help Determine the Clinical Significance of Non-aeruginosa Pseudomonas in CF Lung Pathology.

Introduction: There is a paucity of reports on non-aeruginosa Pseudomonas (NAPs) in cystic fibrosis, hence this study wished 1). to examine the diversity/frequency of NAPs in an adult CF population, 2) to compare/contrast the microbiology and genomics of NAPs to P. aeruginosa and 3) to propose clinical and laboratory criteria to help determine their clinical significance in CF lung pathology. Materials and Methods: Microbiological data was examined from 100 adult patients with cystic fibrosis from birth to present (31/12/2021), equating to 2455 patient years. 16S rDNA phylogenetic relatedness of NAPs was determined, as well as bioinformatical comparison of whole genomes of P. aeruginosa against P. fluorescens. Results: Ten species were isolated from this patient cohort during this time period, with three species, i.e., P. fluorescens, P. putida and P. stutzeri, accounting for the majority (87.5%) of non-aeruginosa reports. This is the first report of the isolation of P. fragi, P. nitroreducens, P. oryzihabitans and P. veronii in patients with cystic fibrosis. The mean time to first detection of any non-aeruginosa species was 183 months (15.25 years) [median = 229 months (19.1 years)], with a range from 11 months to 338 months (28.2 years). Several of the NAPs were closely related to P. aeruginosa. Discussion: NAPs were isolated infrequently and were transient colonisers of the CF airways, in those patients with CF in which they were isolated. A set of ten clinical and laboratory criteria are proposed to provide key indicators, as to the clinical importance of the non-aeruginosa species isolated.

Use of elexacaftor/tezacaftor/ivacaftor among cystic fibrosis lung transplant recipients

BackgroundCystic fibrosis (CF) lung transplant (LT) recipients may warrant treatment with elexacaftor/tezacaftor/ivacaftor (ETI) to improve extrapulmonary manifestations of CF. Our objectives were to identify reasons for prescribing ETI after LT and evaluate changes in body mass index (BMI), hemoglobin A1c, hemoglobin, and liver enzymes. MethodsThis was an electronic health record-based cohort study, October 2019-September 2020, at 14 CF LT Consortium sites in North America. The study included CF LT recipients prescribed ETI after transplant. Differences in BMI, A1c, and hemoglobin were assessed with paired t-tests. ResultsThere were 94 patients prescribed ETI; indications included sinus disease (68%), GI symptoms (39%), or low BMI (19%). Prescriptions were written by CF physicians (34%), LT physicians (27%), or physicians who practice both CF and LT (39%). Forty patients (42%) stopped ETI at a median of 56 days [IQR 26, 139] after start/prescription date. ETI was not associated with a significant change in BMI (0.2 kg/m2, 95% CI [-0.1, 0.6], p = 0.150), but was associated with decreased A1c (0.4%, 95% CI 0.2, 0.7, p = 0.003), and increased hemoglobin for patients with anemia (0.6 g/dL, 95% CI 0.2, 1.0, p = 0.007). Three people (3%) stopped ETI due to elevated transaminases. ConclusionsETI is rarely prescribed for non-pulmonary indications after LT for CF. Further study is needed to determine the risks and benefits of ETI in the CF lung transplant population given the potential for drug interactions, side effects leading to discontinuation of ETI, and the possible mechanisms for ETI to positively impact long-term post-transplant outcomes.