Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction Research Articles

The ageing of people living with cystic fibrosis: what to expect now?

The prognosis of people with cystic fibrosis (pwCF) has improved dramatically with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRm). The ageing of the cystic fibrosis (CF) population is changing the disease landscape with the emergence of different needs and increasing comorbidities related to both age and long-term exposure to multiple treatments including CFTRm. Although the number of pwCF eligible for this treatment is expected to increase, major disparities in care and outcomes still exist in this population. Moreover, the long-term impact of the use of CFTRm is still partly unknown due to the current short follow-up and experience with their use, thus generating some uncertainties. The future spread and initiation of these drugs at an earlier stage of the disease is expected to reduce the systemic burden of systemic inflammation and its consequences on health. However, the prolonged life expectancy is accompanied by an increasing burden of age-related comorbidities, especially in the context of chronic disease. The clinical manifestations of the comorbidities directly or indirectly associated with CFTR dysfunction are changing, along with the disease dynamics and outcomes. Current protocols used to monitor slow disease progression will need continuous updates, including the composition of the multidisciplinary team for CF care, with a greater focus on the needs of the adult population.

Arsenic exposure is associated with elevated sweat chloride concentration and airflow obstruction among adults in Bangladesh: a cross sectional study.

Arsenic is associated with lung disease and experimental models suggest that arsenic-induced degradation of the chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) is a mechanism of arsenic toxicity. We examined associations between arsenic exposure, sweat chloride concentration (measure of CFTR function), and pulmonary function among 285 adults in Bangladesh. Participants with sweat chloride ≥ 60 mmol/L had higher arsenic exposures than those with sweat chloride < 60 mmol/L (water: median 77.5 μg/L versus 34.0 μg/L, p = 0.025; toenails: median 4.8 μg/g versus 3.7 μg/g, p = 0.024). In linear regression models, a one-unit μg/g increment in toenail arsenic was associated with a 0.59 mmol/L higher sweat chloride concentration, p < 0.001. We found that toenail arsenic concentration was associated with increased odds of airway obstruction (OR: 1.97, 95%: 1.06, 3.67, p = 0.03); however, sweat chloride concentration did not mediate this association. Our findings suggest that sweat chloride concentration may be a novel biomarker for arsenic exposure and also that arsenic likely acts on the lung through mechanisms other than CFTR dysfunction.

Cystic fibrosis.

Cystic fibrosis is a rare genetic disease caused by mutations in CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR). The discovery of CFTR in 1989 has enabled the unravelling of disease mechanisms and, more recently, the development of CFTR-directed therapeutics that target the underlying molecular defect. The CFTR protein functions as an ion channel that is crucial for correct ion and fluid transport across epithelial cells lining the airways and other organs. Consequently, CFTR dysfunction causes a complex multi-organ disease but, to date, most of the morbidity and mortality in people with cystic fibrosis is due to muco-obstructive lung disease. Cystic fibrosis care has long been limited to treating symptoms using nutritional support, airway clearance techniques and antibiotics to suppress airway infection. The widespread implementation of newborn screening for cystic fibrosis and the introduction of a highly effective triple combination CFTR modulator therapy that has unprecedented clinical benefits in up to 90% of genetically eligible people with cystic fibrosis has fundamentally changed the therapeutic landscape and improved prognosis. However, people with cystic fibrosis who are not eligible based on their CFTR genotype or who live in countries where they do not have access to this breakthrough therapy remain with a high unmet medical need.

New drugs, new challenges in cystic fibrosis care.

Cystic fibrosis (CF) is a genetic disease caused by variants in the gene encoding for the CF transmembrane conductance regulator (CFTR) protein, a chloride and bicarbonate channel. CFTR dysfunction results in a multiorgan disease with the main clinical features being exocrine pancreatic insufficiency and diffuse bronchiectasis with chronic airway infection leading to respiratory failure and premature death. Over the past decades, major progress has been made by implementing multidisciplinary care, including nutritional support, airway clearance techniques and antibiotics in specialised CF centres. The past decade has further seen the progressive development of oral medications, called CFTR modulators, for which around 80% of people with CF are genetically eligible in Europe. CFTR modulators partially restore ion transport and lead to a rapid and major improvement in clinical manifestations and lung function, presumably resulting in longer survival. CFTR modulators have been game-changing in the care of people with CF. However, many questions remain unanswered, such as the long-term effects of CFTR modulators, especially when treatment is started very early in life, or the new CF-related disease emerging due to CFTR modulators. Moreover, severe complications of CF, such as diabetes or cirrhosis, are not reversed on CFTR modulators and around 20% of people with CF bear CFTR variants leading to a CFTR protein that is unresponsive to CFTR modulators. Challenges also arise in adapting CF care to a changing disease. In this review article, we highlight the new questions and challenges emerging from this revolution in CF care.

Predicting weight gain in patients with cystic fibrosis on triple combination modulator.

Cystic fibrosis (CF) is caused by CF transmembrane conductance regulator (CFTR) gene mutations producing dysfunctional CFTR proteins leading to progressive clinical disease. Elexacaftor-tezacaftor-ivacaftor (ETI) remarkably improves lung disease but is associated with substantial weight gain. We performed a single-center longitudinal study predicting 6-month weight gain after ETI initiation. We used linear mixed effects modeling (LME) to determine association of ETI treatment with changing body mass index (BMI). Using linear regression, we examined BMI prediction models with distinct combinations of main effects to identify a model useful for patient counseling. We used up to eight commonly observed clinical characteristics as input variables (age, sex, percent predicted FEV1 [FEV1%], F508del homozygous state, pancreatic sufficiency, HgbA1c, prior modulator use and prior year number of pulmonary exacerbations). We evaluated 154 patients (19-73 years old, 54% female, FEV1% = 19-121, 0-6 prior year pulmonary exacerbations). LME demonstrated an association between ETI use and weight increases. Exhaustive testing suggested a parsimonious linear regression model well-fitted to data that is potentially useful for counseling. The two variable model shows that on average, BMI decreases by 0.045 (95% Confidence Interval [CI] = -0.069 to -0.021, p < 0.001) for every year of age and increases by 0.322 (CI = 0.142 to 0.502, p = 0.001) for each additional prior year exacerbation at the time of ETI initiation. Young patients with many prior year pulmonary exacerbations likely have the largest 6 month weight gain after starting ETI.

Structural identification of a selectivity filter in CFTR

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that regulates transepithelial salt and fluid homeostasis. CFTR dysfunction leads to reduced chloride secretion into the mucosal lining of epithelial tissues, thereby causing the inherited disease cystic fibrosis. Although several structures of CFTR are available, our understanding of the ion-conduction pathway is incomplete. In particular, the route that connects the cytosolic vestibule with the extracellular space has not been clearly defined, and the structure of the open pore remains elusive. Furthermore, although many residues have been implicated in altering the selectivity of CFTR, the structure of the "selectivity filter" has yet to be determined. In this study, we identify a chloride-binding site at the extracellular ends of transmembrane helices 1, 6, and 8, where a dehydrated chloride is coordinated by residues G103, R334, F337, T338, and Y914. Alterations to this site, consistent with its function as a selectivity filter, affect ion selectivity, conductance, and open channel block. This selectivity filter is accessible from the cytosol through a large inner vestibule and opens to the extracellular solvent through a narrow portal. The identification of a chloride-binding site at the intra- and extracellular bridging point leads us to propose a complete conductance path that permits dehydrated chloride ions to traverse the lipid bilayer.

CF Lung Disease - a German S3 Guideline: Pseudomonas aeruginosa

Cystic Fibrosis (CF) is the most common autosomal recessive genetic multisystemic disease. In Germany, it affects at least 8000 people. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the airway epithelial lining fluid which leads to reduction of the mucociliary clearance.Even if highly effective, CFTR modulator therapy has been available for some years and people with CF are getting much older than before, recurrent and chronic infections of the airways as well as pulmonary exacerbations still occur. In adult CF life, Pseudomonas aeruginosa (PA) is the most relevant pathogen in colonisation and chronic infection of the lung, leading to further loss of lung function. There are many possibilities to treat PA-infection.This is a S3-clinical guideline which implements a definition for chronic PA-infection and demonstrates evidence-based diagnostic methods and medical treatment in order to give guidance for individual treatment options.

Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases

AbstractCystic Fibrosis (CF) is a genetic disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leading to a faulty CFTR protein. Dysfunctional CFTR causes chloride ion imbalance, resulting in dense mucus accumulation in various organs, particularly the lungs. CF treatments focus on symptom management and addressing CFTR′s functional defects. Notably, development of CFTR modulator therapies has significantly advanced CF treatment. These drugs target CFTR protein structural defects induced by mutations, restoring its function and improving CF symptoms. VX‐770, a CFTR potentiator, and CFTR correctors like VX‐809, VX‐661, and VX‐445, have gained FDA approval and widespread clinical use, greatly enhancing the health and survival of many CF patients. However, some CFTR mutations lack effective targeted therapies, leaving approximately 6 % of CF patients without suitable options. CFTR modulator therapies have proven essential for combating the underlying causes of protein misfolding diseases, serving as a blueprint for similar treatments in other membrane protein misfolding diseases. This review explores current and future CFTR modulator therapies, and applications of established paradigms to membrane protein misfolding diseases. Ongoing research and innovation hold the potential for further improvements in CF management and the treatment of protein misfolding diseases.

Two rare variants that affect the same amino acid in CFTR have distinct responses to ivacaftor.

Some residues in the cystic fibrosis transmembrane conductance regulator (CFTR) channel are the site of more than one CFTR variant that cause cystic fibrosis. Here, we investigated the function of S1159F and S1159P, two variants associated with different clinical phenotypes, which affect the same pore-lining residue in transmembrane segment 12 that are both strongly potentiated by ivacaftor when expressed in CFBE41o- bronchial epithelial cells. To study the single-channel behaviour of CFTR, we applied the patch-clamp technique to Chinese hamster ovary cells heterologously expressing CFTR variants incubated at 27°C to enhance channel residence at the plasma membrane. S1159F- and S1159P-CFTR formed Cl- channels activated by cAMP-dependent phosphorylation and gated by ATP that exhibited thermostability at 37°C. Both variants modestly reduced the single-channel conductance of CFTR. By severely attenuating channel gating, S1159F- and S1159P-CFTR reduced the open probability (Po ) of wild-type CFTR by ≥75% at ATP (1mM); S1159F-CFTR caused the greater decrease in Po consistent with its more severe clinical phenotype. Ivacaftor (10-100nM) doubled the Po of both CFTR variants without restoring Po values to wild-type levels, but concomitantly, ivacaftor decreased current flow through open channels. For S1159F-CFTR, the reduction of current flow was marked at high (supersaturated) ivacaftor concentrations (0.5-1μM) and voltage-independent, identifying an additional detrimental action of elevated ivacaftor concentrations. In conclusion, S1159F and S1159P are gating variants, which also affect CFTR processing and conduction, but not stability, necessitating the use of combinations of CFTR modulators to optimally restore their channel activity. KEY POINTS: Dysfunction of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes the genetic disease cystic fibrosis (CF). This study investigated two rare pathogenic CFTR variants, S1159F and S1159P, which affect the same amino acid in CFTR, to understand the molecular basis of disease and response to the CFTR-targeted therapy ivacaftor. Both rare variants diminished CFTR function by modestly reducing current flow through the channel and severely inhibiting ATP-dependent channel gating with S1159F exerting the stronger adverse effect, which correlates with its association with more severe disease. Ivacaftor potentiated channel gating by both rare variants without restoring their activity to wild-type levels, but concurrently reduced current flow through open channels, particularly those of S1159F-CFTR. Our data demonstrate that S1159F and S1159P cause CFTR dysfunction by multiple mechanisms that require combinations of CFTR-targeted therapies to fully restore channel function.

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways.

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel by genetic mutations causes the inherited disease cystic fibrosis (CF). CF lung disease that involves multiple disorders of epithelial function likely results from loss of CFTR function as an anion channel conducting chloride and bicarbonate ions and its function as a cellular regulator modulating the activity of membrane and cytosol proteins. In the absence of CFTR activity, abundant mucus accumulation, bacterial infection and inflammation characterize CF airways, in which inflammation-associated tissue remodeling and damage gradually destroys the lung. Deciphering the link between CFTR dysfunction and bacterial infection in CF airways may reveal the pathogenesis of CF lung disease and guide the development of new treatments. Research efforts towards this goal, including high salt, low volume, airway surface liquid acidosis and abnormal mucus hypotheses are critically reviewed.

Immunodeficiencies and CFTR dysfunction: results from a systematic screening in a cohort of adults with cystic fibrosis and CFTR-related disorders

Background: Immunodeficiencies (IDs) are conditions caused by immune system dysfunctions which predispose to chronic infections. Cystic fibrosis (CF) patients are characterized by the presence of bronchiectasis filled with hyper-viscous secretions that constitute the ideal environment for infections. Although CF and IDs might share similarities in the pathophysiological mechanism of bronchiectasis development, they each offer different treatment options. We hypothesize that the introduction of a bundle of tests would increase the number of ID diagnoses among adults with Cystic Fibrosis Transmembrane conductance Regulator (CFTR) dysfunction. Objectives: The primary objectives of this study were (1) assessing the prevalence of IDs in CF and (2) defining clinical characteristics of adults with both CF and IDs. The secondary objectives were: (1) assessing the prevalence of IDs in CFTR-Related Disorder (CFTR-RD) patients; (2) comparing the prevalence of IDs in CF and CFTR-RD; (3) comparing the prevalence of treatable IDs in CF and CFTR-RD. Design: We conducted an observational, prospective, consecutive study on a cohort of 190 adult patients affected by CF or CFTR-RD. Methods: Blood samples underwent a standardized immunological screening, including complete white blood count, IgG, IgA, IgM, IgG subclasses, total IgE, lymphocyte subsets, and HIV test. Comprehensive clinical history was assessed to identify risk factors for secondary IDs. Results: We identify a high prevalence of immunodeficiencies among the entire cohort: 34 (20.1%) CF patients and 10 (47.6%) CFTR-RD patients are diagnosed with IDs via a blood screening. No statistically significant difference in terms of clinical characteristics was found between immunocompromised and immunocompetent CF patients. Conclusion: We identify a high prevalence of immunodeficiencies in both CF and CFTR-RD.

Hypoxia-induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis.

Hypoxia due to sinus obstruction is a major pathogenic mechanism leading to sinusitis. The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo. Cystic fibrosis bronchoepithelial cells expressing wild-type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O2 for 24h. Time-dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole-cell and cell-attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro-optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF-1α, pH, sinus potential difference (SPD), and MCT were determined. Ussing chamber (p<0.05), whole-cell (p<0.001), and single channel patch-clamp (p<0.0001) showed significant inhibition of Cl- currents in hypoxic cells. Cytoplasmic free radicals showed time-dependent elevation peaking at 4h (p<0.0001). Airway surface liquid (p<0.0001), periciliary liquid (p<0.001), and MCT (p<0.01) were diminished. Co-incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (p<0.0001), increased HIF1α mRNA (p<0.05), reduced pH (p<0.01), and decreased MCT (p<0.001). SPD measurements demonstrated markedly diminished transepithelial Cl- transport (p<0.0001). Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.

Effects of modulator therapies on endocrine complications in adults with cystic fibrosis: a narrative review.

Cystic fibrosis is a monogenic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which transports chloride ions in secretory organs. Modulator therapies are small molecules that correct CFTR dysfunction and can lead to a wide range of benefits for both pulmonary and extrapulmonary complications of cystic fibrosis. With advancements in airway, antimicrobial and nutritional therapies and now introduction of modulator therapies, most people living with cystic fibrosis in Australia are now adults. For adults with cystic fibrosis, endocrine manifestations such as cystic fibrosis-related diabetes, metabolic bone disease, and reproductive health are becoming increasingly important, and emerging evidence on the endocrine effects of CFTR modulator therapies is promising and is shifting paradigms in our understanding and management of these conditions. The management of cystic fibrosis-related diabetes will likely need to pivot for high responders to modulator therapy with dietary adaptions and potential use of medications traditionally reserved for adults with type 2 diabetes, but evidence to support changing clinical care needs is currently lacking. Increased attention to diabetes-related complications screening will also be required. Increased exercise capacity due to improved lung function, nutrition and potentially direct modulator effect may have a positive impact on cystic fibrosis-related bone disease, but supporting evidence to date is limited. Fertility can improve in women with cystic fibrosis taking modulator therapy. This has important implications for pregnancy and lactation, but evidence is lacking to guide pre-conception and antenatal management. Provision of multidisciplinary clinical care remains ever-important to ensure the emergence of endocrine and metabolic complications are optimised in adults with cystic fibrosis.

Cystic fibrosis

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR dysfunction results in abnormal chloride and bicarbonate transport in epithelial cells, leading to a multiorgan disease dominated by respiratory and digestive manifestations. The respiratory disease, which is characterized by airway mucus plugging, chronic bacterial infection and progressive development of bronchiectasis, may lead to chronic respiratory failure, which is the main cause of premature death in people with CF. Over the past 50 years, major progress has been obtained by implementing multidisciplinary care, including nutritional support, airway clearance techniques and antibiotics in specialized CF centers. The past 10 years have further seen the progressive development of oral medications, called CFTR modulators, that partially restore ion transport and lead to a major improvement in clinical manifestations and lung function, presumably resulting in longer survival. Although an increasing proportion of people with CF are being treated with CFTR modulators, challenges remain regarding access to CFTR modulators due to their high cost, and their lack of marketing approval and/or effectiveness in people with rare CFTR variants. The anticipated increase in the number of adults with CF and their aging also challenge the current organization of CF care. The purpose of this review article is to describe current status and future perspective of CF disease and care.

Influenza A-induced cystic fibrosis transmembrane conductance regulator dysfunction increases susceptibility to Streptococcus pneumoniae.

Influenza A virus (IAV) infection is commonly complicated by secondary bacterial infections that lead to increased morbidity and mortality. Our recent work demonstrates that IAV disrupts airway homeostasis, leading to airway pathophysiology resembling cystic fibrosis disease through diminished cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we use human airway organotypic cultures to investigate how IAV alters the airway microenvironment to increase susceptibility to secondary infection with Streptococcus pneumoniae (Spn). We observed that IAV-induced CFTR dysfunction and airway surface liquid acidification is central to increasing susceptibility to Spn. Additionally, we observed that IAV induced profound transcriptional changes in the airway epithelium and proteomic changes in the airway surface liquid in both CFTR-dependent and -independent manners. These changes correspond to multiple diminished host defense pathways and altered airway epithelial function. Collectively, these findings highlight both the importance of CFTR function during infectious challenge and demonstrate a central role for the lung epithelium in secondary bacterial infections following IAV.

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy.

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

Real-world outcomes and direct care cost before and after elexacaftor/tezacaftor/ivacaftor initiation in commercially insured members with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a chronic, progressive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene resulting in a dysfunctional CFTR protein. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a triple combination oral drug therapy with an annual cost greater than $300,000 and available to nearly 90% of the CF population based on age and genotype. Limited real-world direct medical cost offset data are available for ELX/TEZ/IVA among commercially insured individuals. OBJECTIVE: To describe and compare total cost of care and health care resource utilization (HRU) 180 days before and 180 days after first ELX/TEZ/IVA drug claim among CFTR modulator treatment-naive, commercially insured members. METHODS: This study was a retrospective analysis of integrated pharmacy and medical claims data from 17.9 million commercially insured members. A 180-day prestudy and 180-day poststudy design was used to compare outcomes prior to and following ELX/TEZ/IVA initiation. Study inclusion was limited to members with first ELX/TEZ/IVA claim (index date) between October 21, 2019, and December 31, 2021, continuously enrolled 180 days before and 180 days after index date, and no CFTR-modulator drug claim 180 days prior to index date. Total paid amounts from medical and pharmacy claims after network discounts (defined as total cost of care), HRU, and pulmonary exacerbation events were summarized using descriptive statistics and compared using Wilcoxon signed rank test. RESULTS: 494 members newly initiating ELX/TEZ/IVA met inclusion criteria. Prestudy to poststudy mean member total cost of care increased from $58,180 to $198,815 (difference: $140,635; P < 0.001). Mean member medical benefit costs decreased from $28,764 to $12,484 (difference: -$16,280; P < 0.001), whereas mean member pharmacy benefit costs increased from $29,416 to $186,331 (difference: $156,915; P < 0.001). Mean member inpatient hospitalizations (62% absolute reduction; P < 0.001), emergency department visits (43% absolute reduction; P < 0.01), and pulmonary exacerbation events (44% absolute reduction; P < 0.001) were significantly lower in the postperiod compared with the preperiod. CONCLUSIONS: Among members with CF newly initiating CFTR modulator with ELX/TEZ/IVA, mean member total cost of care increased 3-fold despite significant and meaningful reductions in pulmonary exacerbation events, HRU, and medical benefit spend. Pharmacy benefit spend outpaced medical benefit spend at a rate of $9.64 to $1 in the 180 days following ELX/TEZ/IVA initiation. Real-world data should be used to objectively measure the clinical and economic benefits of costly medications, such as CFTR modulators, to align price with value. DISCLOSURES: Drs Marshall, Espinosa, Starner, and Gleason are employees of Prime Therapeutics. The study was funded by Prime Therapeutics.

Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor

Characterization of sleep in emerging adults with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor

Cystic fibrosis transmembrane conductance regulator potentiators attenuate platelet activation and aggregation in blood of healthy donors and COVID-19 patients

Cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl - channel and ABC transporter; its mutations cause the clinical picture of cystic fibrosis (CF). Of late, CFTR has emerged as an important regulator of platelet function, as CFTR dysfunction causes agonist-induced platelet hyperactivation. These findings are reminiscent of platelets from SARS-CoV-2 infected patients since thromboembolic complications represent hallmarks of severe COVID-19 that may critically contribute to morbidity and mortality. CFTR modulators have recently been introduced as a treatment for patients with various CFTR mutations, but have also been reported by us and others to enhance channel function of wild type CFTR. We therefore postulated that CFTR modulators may exert anti-coagulant effects on platelets of healthy donors (HD) and COVID-19 patients.We recruited 36 COVID-19 patients with moderate, and 34 COVID-19 patients with severe disease course (all w/o anti-platelet drugs), and 38 HDs. In line with our hypothesis, we observed significant reductions in platelet agonists adenosine diphosphate (ADP)- or thrombin receptor activating protein-6 (TRAP6)-induced CD62p/CD63 expression, Ca 2+ -mobilization, aggregation, and adhesion of platelets from HDs by pre-treatment with ivacaftor. In blood from COVID-19 patients, platelet activation correlates with disease severity, as demonstrated by a 5-fold and 8-fold increase in the proportion of CD62p + platelets from patients with moderate and severe disease, respectively, relative to HDs. Similarly, the proportion of CD63 + platelets in patients with severe COVID-19 was 2-fold higher than in HDs. Retrospective analysis of clinical data from a total of 4,050 CF patients with COVID-19 receiving single or combination therapy of ivacaftor, lumacaftor, tezacaftor, or elexacaftor in comparison to an untreated cohort revealed that CF therapy reduced the relative risk to suffer thromboembolism-associated cardiovascular events such as heart attack or deep vein thrombosis by 50.0% or 61.1%, respectively, suggesting an anti-thrombotic effect of CFTR modulators in CF COVID-19 patients. In line with this observation, ex vivo pre-treatment of platelets from acute COVID-19 patients with ivacaftor reduced Ca 2+ mobilization, adhesion, and aggregation of platelets .Our results demonstrate an anticoagulant effect of CFTR potentiators on platelets from HDs and severe COVID-19 patients and thus, suggest CFTR potentiators as a promising strategy to reduce the risk of thrombotic events in the clinical management of COVID-19 and similar pro-thrombotic disease states. F. Behrens received funding from the Berlin Institute of Health (BIH). L. Michalick reports grants from the BIH and the German Centre for Cardiovascular Research (DZHK). A. Haghikia is participant in the BIH-Charité Advanced Clinician Scientist Pilotprogram funded by the Charité - Universitätsmedizin Berlin and the BIH and reports a research grant within the BIH &amp; MDC Focus Area Translational Vascular Biomedicine. R. Preissner reports partial funding of this work by the German Research Foundation (KFO339, TRR295). M. Witzenrath reports grants from the German Research Foundation (SFB-TR84 C06 and C09, SFB 1449 B02), and from the German Ministry of Education and Research (BMBF) in the framework of CAPSyS (01ZX1604B, 01ZX1304B), SYMPATH (01ZX1906A), PROVID (01KI20160A), Phage4Cure (16GW0141), MAPVAP (16GW0247) and NUM-NAPKON. W. M. Kuebler reports grants from the German Research Foundation (SFB-TR84 A2 and C9, SFB 1449 B1, SFB 1470 A4, KU1218/9-1, KU1218/11-1, and KU1218/12-1), the BMBF in the framework of SYMPATH (01ZX1906A) and PROVID (01KI20160A), and the DZHK. S. Simmons reports grants from the DZHK and the German Foundation for Heart Research (F-09-19). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prevalence of CFTR variants in primary immunodeficiency patients with bronchiectasis is an important modifying cofactor

Cystic fibrosis (CF) is one of the most common life-limiting autosomal-recessive disorders and is caused by genetic defects in the CF transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID). We hypothesized that a carrier CFTR status might be associated with worse outcome regarding structural lung disease in patients with PID. A within-cohort and population-level statistical genomic analysis of a large European cohort of PID patients was performed using genome sequence data. Genomic analysis of variant pathogenicity was performed. Compared to the general population, p.Phe508del carriage was enriched in lung-related PID. Additionally, carriage of several pathogenic CFTR gene variants were increased in PID associated with structural lung damage compared to PID patients without the structural lung damage. We identified 3 additional biallelic cases, including several variants not traditionally considered to cause CF. Genome sequencing identified cases of CFTR dysfunction in PID, driving an increased susceptibility to infection. Large national genomic services provide an opportunity for precision medicine by interpreting subtle features of genomic diversity when treating traditional Mendelian disorders.