Host and pathogen response to bacteriophage engineered against Mycobacterium abscessus lung infection.

Two mycobacteriophages were administered intravenously to a male with treatment-refractory Mycobacterium abscessus pulmonary infection and severe cystic fibrosis lung disease. The phages were engineered to enhance their capacity to lyse M. abscessus and were selected specifically as the most effective against the subject's bacterial isolate. In the setting of compassionate use, the evidence of phage-induced lysis was observed using molecular and metabolic assays combined with clinical assessments. M. abscessus isolates pre and post-phage treatment demonstrated genetic stability, with a general decline in diversity and no increased resistance to phage or antibiotics. The anti-phage neutralizing antibody titers to one phage increased with time but did not prevent clinical improvement throughout the course of treatment. The subject received lung transplantation on day 379, and systematic culturing of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of a successful phage treatment of M. abscessus in advanced lung disease.

Distribution of pathogenic variants in the CFTR gene in a representative cohort of people with cystic fibrosis in the Kingdom of Bahrain.

BACKGROUND: Cystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the  CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm). METHODS: CFTR genotyping  and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype-phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity. RESULTS: Altogether 18 CF-causing mutations  were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births. CONCLUSION: The most commonCF-causing  mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two F508del Alleles.

Rationale: We recently demonstrated that triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in airway and intestinal epithelia to 40-50% of normal in patients with cystic fibrosis (CF) with one or two F508del alleles. In previous studies, this improvement of CFTR function was shown to improve clinical outcomes; however, effects on the lung clearance index (LCI) determined by multiple-breath washout and abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) have not been studied. Objectives: To examine the effect of ELX/TEZ/IVA on LCI and lung MRI scores in patients with CF and one or two F508del alleles aged ⩾12 years. Methods: This prospective, observational, multicenter, postapproval study assessed LCI and lung MRI scores before and 8-16 weeks after initiation of ELX/TEZ/IVA. Measurements and Main Results: A total of 91 patients with CF, including 45 heterozygous for F508del and a minimal function mutation (MF) and 46 homozygous for F508del, were enrolled in this study. Treatment with ELX/TEZ/IVA improved LCI in F508del/MF (-2.4; interquartile range [IQR], -3.7 to -1.1; P < 0.001) and F508del homozygous (-1.4; IQR, -2.4 to -0.4; P < 0.001) patients. Furthermore, ELX/TEZ/IVA improved the MRI global score in F508del/MF (-6.0; IQR, -11.0 to -1.3; P < 0.001) and F508del homozygous (-6.5; IQR, -11.0 to -1.3; P < 0.001) patients. Conclusions: Our data demonstrate that improvement of CFTR function by ELX/TEZ/IVA improves lung ventilation and abnormalities in lung morphology, including airway mucus plugging and wall thickening, in adolescent and adult patients with CF and one or two F508del alleles in a real-world, postapproval setting. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).

Effects of CFTR-modulator triple therapy on sinunasal symptoms in children and adults with cystic fibrosis.

PURPOSE: Sinunasal symptoms and chronic rhinusinutitis are common in patients with cystic fibrosis. Cystic fibrosis transmembrane regulator (CFTR) modulators have led to dramatic improvements of respiratory symptoms and quality of life in patients with cystic fibrosis. This study aims to evaluate subjective and objective sinunasal symptoms after start of CFTR-modulator triple therapy. METHODS: 43 patients (n = 6 < 18 years), treated with highly effective CFTR-modulator therapy with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) were included, as were 20 controls with cystic fibrosis but without CFTR-modulator therapy (n = 6 < 18 years). All assessed their sinunasal symptoms retrospectively and the intervention group at a mean of 9.3 (2-16) months after start of ELX/TEZ/IVA. RESULTS: Improvements in SNOT-22 overall score from m = 32.7 to m = 15.7 points (p < 0.0001) as well in the nasal, emotional, otologic, and sleep subdomains could be demonstrated in the intervention group. No changes were found in the control group. Children showed lower SNOT-22 scores than adults and a reduction of SNOT-22 total score from m = 9.4 to m = 2.2 (p = 0.25) was found. 8 patients were evaluated by an otorhinolaryngologist before and after start of ELX/TEZ/IVA and showed pronounced objective clinical improvement. CONCLUSIONS: Highly effective CFTR-modulator therapy has a significant positive impact on both subjective and objective sinunasal symptoms in patients with CF and some improvement could be demonstrated in children < 18 years as well.

CFTR Function Restoration upon Elexacaftor/Tezacaftor/Ivacaftor Treatment in Patient-Derived Intestinal Organoids with Rare CFTR Genotypes.

Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The combination of the CFTR modulators elexacaftor, tezacaftor, and ivacaftor (ETI) enables the effective rescue of CFTR function in people with the most prevalent F508del mutation. However, the functional restoration of rare CFTR variants remains unclear. Here, we use patient-derived intestinal organoids (PDIOs) to identify rare CFTR variants and potentially individuals with CF that might benefit from ETI. First, steady-state lumen area (SLA) measurements were taken to assess CFTR function and compare it to the level observed in healthy controls. Secondly, the forskolin-induced swelling (FIS) assay was performed to measure CFTR rescue within a lower function range, and to further compare it to ETI-mediated CFTR rescue in CFTR genotypes that have received market approval. ETI responses in 30 PDIOs harboring the F508del mutation served as reference for ETI responses of 22 PDIOs with genotypes that are not currently eligible for CFTR modulator treatment, following European Medicine Agency (EMA) and/or U.S. Food and Drug Administration (FDA) regulations. Our data expand previous datasets showing a correlation between in vitro CFTR rescue in organoids and corresponding in vivo ppFEV1 improvement upon a CFTR modulator treatment in published clinical trials, and suggests that the majority of individuals with rare CFTR variants could benefit from ETI. CFTR restoration was further confirmed on protein levels using Western blot. Our data support that CFTR function measurements in PDIOs with rare CFTR genotypes can help to select potential responders to ETI, and suggest that regulatory authorities need to consider providing access to treatment based on the principle of equality for people with CF who do not have access to treatment.

What is the Perceived Role of the Dietitian Amongst People with Cystic Fibrosis? Results of an International survey.

Cystic fibrosis (CF) is a chronic condition requiring continued input from the CF dietitian as an integral part of the CF multidisciplinary team. In recent years, the longer life expectancy experienced by people with CF (PwCF) means that nutrition advice and therapy are evolving from a focus on nutrition support to prevention and management of comorbidities. Little has been reported regarding the perceived role of the CF dietitian amongst PwCF. We report the responses to 11 questions that were part of a larger international survey distributed to members of national CF charities in 2018-2019. These questions evaluated PwCFs' perspectives on (i) the importance of the CF diet, (ii) how often PwCF obtain dietary/nutritional advice from their dietitian, (iii) the perceived reliability of information given by the dietitian, (iv) other sources of CF information and their perceived reliability, and (v) how CF nutrition/diet, as well as CF-related diabetes, ranked as research priorities. There were 295 respondents from 13 countries. Almost half of the respondents (46.8%) contacted their CF dietitian on a frequent/more regular basis, compared to medical/scientific journals/medical/scientific search engines. The CF dietitian was considered a reliable source of information, as 84% of the respondents indicated that the information provided was very/generally reliable. At a time when CF care and expectations are changing rapidly, PwCF are in need of trusted and reliable information to make positive changes in lifestyle and habits. Dietitians working with PwCF should appreciate the pivotal and valued role they perform as purveyors of robust evidence-based information to this chronic disease population.

A new era for people with cystic fibrosis.

Cystic fibrosis is the most prevalent inherited disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impaired electrolyte homeostasis caused by the mutated or absent protein leads to symptoms in multiple organ systems. However, the pulmonary manifestation with chronic infections and eventually respiratory failure remains the most important threat. Until one decade ago, only symptomatic treatment was available. However, since 2012, different combinations of CFTR modulators are available for people with cystic fibrosis (pwCF) that carry different mutations. The advent of these drugs has impressively changed life expectancy and quality of life in people with cystic fibrosis and raised new challenges regarding long-term complications and tapering of conventional therapies.Conclusion: In this review, we provide an update on the latest developments around diagnostics, treatment, and prognosis of pwCF. What is Known: • Cystic fibrosis is an incurable and life-shortening disease asking for life-long symptomatic treatment. • Three combination CFTR modulating drugs has gained marked approval over the last 10 years. What is New: • The emerge of new (modulating) therapies contribute to the increasing life expectancy. • A high unmet need to develop new therapies for people with CF who cannot access or benefit from these drugs remains. This review gives an update on the current status.

Impact of extended Elexacaftor/Tezacaftor/Ivacaftor therapy on the gut microbiome in cystic fibrosis.

BACKGROUND: There is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF). STUDY DESIGN: Faecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships. RESULTS: Extended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI. CONCLUSIONS: Whilst differences persisted, a positive trajectory towards the microbiota observed in healthy controls was found. We posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF.

Wellness in the modulator era: An observational study of the impact of CFTR modulator therapy on the well-being of people with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) have experienced substantial improvements in health following use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. However, less is known about how modulator therapies impact well-being. METHODS: We used a cross-sectional observational study to identify relationships between CFTR modulator therapies, health-related quality of life (HRQoL), and well-being. Adult PwCF and caregivers of children with CF completed the Wellness in the Modulator Era (Well-ME) survey between June 22 and July 31, 2022. HRQoL was measured with PROMIS Global 10/Global 7 + 2 Parent Proxy. We used a mixed methods analysis to compare experiences and concerns of PwCF who currently (n = 665), no longer (n = 51), or never (n = 184) took modulator therapy. RESULTS: Adult PwCF taking a modulator (n = 416) reported better PROMIS global physical health than those who no longer (n = 37) or never took a modulator (n = 94) and better PROMIS global mental health than those who never took a modulator. Caregiver-reported HRQoL was similar across children with CF who currently, no longer, or never took a modulator. PwCF taking a modulator reported larger improvements in physical health, quality of life, social well-being, and treatment burden than those who no longer or never took a modulator. Nearly one-quarter (23 %) of PwCF taking modulator therapy reported worsening of mental well-being. CONCLUSIONS: This study expands our knowledge of well-being among PwCF in the CFTR modulator era as reported by patients and parents. Findings lay the groundwork for establishing future research priorities, policy efforts, and communications in areas that improve well-being for PwCF.

Prospective evaluation of nontuberculous mycobacteria disease in cystic fibrosis: The design of the PREDICT study.

BACKGROUND: Nontuberculous mycobacteria (NTM) are an important cause of airway infections in people with cystic fibrosis (pwCF). Isolation of NTM from respiratory specimens of pwCF do not mandate treatment in the absence of clinical and radiologic features of NTM pulmonary disease (NTM-PD), as some pwCF clear the infection without treatment and others do not appear to progress to NTM-PD despite persistent infection. An evidence-based protocol to standardize diagnosis of NTM-PD is needed to systematically identify pwCF who may benefit from treatment. METHODS: In this multicenter observational study, eligible pwCF who are 6 years of age and older and who have had a recent positive NTM culture are systematically evaluated for NTM-PD. Participants are identified based on positive NTM culture results obtained during routine clinical care and following enrollment are evaluated for NTM-PD and CF-related comorbidities. Participants are followed in PREDICT until they meet NTM-PD diagnostic criteria and are ready to initiate NTM treatment, or until study termination. Active participants who have not met these criteria are re-consented every 5 years to enable long-term participation. RESULTS: The primary endpoint will summarize the proportion of participants who meet the NTM-PD diagnosis definition. The time from enrollment to NTM-PD diagnosis will be derived from Kaplan-Meier estimates. CONCLUSION: A prospective protocol to identify NTM-PD in pwCF will test if this standardized approach defines a cohort with signs and symptoms associated with NTM-PD, to assist with clinical decision making and to build a framework for future therapeutic trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02073409.

Predictors of Sinonasal Improvement After Highly Effective Modulator Therapy in Adults with Cystic Fibrosis.

OBJECTIVES: The 22-question SinoNasal Outcome Test (SNOT-22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT-22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT-22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF). METHODS: Prospective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT-22 scores were obtained at baseline and after 3-6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution-based methods were used to assess internal consistency and calculate the MCID of the SNOT-22. RESULTS: A total of 184 PwCF participated with mean baseline SNOT-22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre- and post-HEMT data reported improvement in SNOT-22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT-22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02-1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14-18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39-20.11) were associated with greater SNOT-22 improvement. The mean MCID calculated via distribution-based methods was 8.5. CONCLUSION: Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT-22 in PwCF is 8.5 points, similar to non-CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT-22 has strong internal consistency in PwCF. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3965-3973, 2024.

Changes in vitamins and trace elements after initiation of highly effective CFTR modulator therapy in children and adults with cystic fibrosis - a real-life insight.

BACKGROUND: Highly-effective CFTR-modulator therapy with elexa-/teza-/ivacaftor (ETI) has led to improvements in pulmonary outcomes, sweat chloride, body mass index (BMI) and quality of life in people with cystic fibrosis (CF). Improved uptake of fat-soluble vitamins and micronutrients has been reported for CFTR-modulators but data regarding ETI therapy is lacking. METHODS: This single-center retrospective study evaluated forced expiratory volume in one second (FEV-1), sweat chloride, BMI, transaminases (AST, ALT), bilirubin, vitamins A, D, E, zinc and selenium in children and adults eligible for ETI. Parameters were assessed before and up to one year after initiation of ETI. RESULTS: 58 patients (median age m = 28 years, SD ± 11.6 years, 51.7% female14 < 18 years old) were included. FEV-1 and sweat chloride improved significantly after ETI. There were no changes in BMI or AST. ALT was increased significantly after 4 weeks of ETI but returned to normal levels in further course. Bilirubin levels remained elevated after ETI. Vitamin A was significantly higher 12 months after ETI. No changes were found for vitamins D, E, zinc and selenium. CONCLUSIONS: This study adds to the evidence that improvements of some fat-soluble vitamin levels can be found after ETI. No changes regarding micronutrients were noted. Individualized follow-up and supplementation are recommended.

Regulatory adverse drug reaction analyses support a temporal increase in psychiatric reactions after initiation of cystic fibrosis combination modulator therapies.

INTRODUCTION: Despite improved outcomes for many people with cystic fibrosis, there have been reports of adverse neuropsychiatric effects of modulator therapy. The aim of this research is to define temporal associations in adverse drug reaction (ADR) reports for available CFTR modulators. METHODS: Methods include an analysis of the UK Yellow Card Scheme data for ADRs through accessing interactive Drug Analysis Profiles (iDAPs) to define temporal trends in absolute and proportional counts. RESULTS: Since the introduction of ETI, there has been an increase in the absolute number of psychiatric ADRs reported as well as a statistically significant increase in the proportion of psychiatric ADRs in the pre-ETI and post-ETI periods. CONCLUSION: In the post-ETI period, psychiatric ADRs are the most prevalent ADR reported via the Yellow Card scheme. Despite an unclear mechanism, there is significant clinical relevance in counselling and monitoring regarding psychiatric effects of CFTR modulator therapy.

Update on advances in cystic fibrosis towards a cure and implications for primary care clinicians.

During the past quarter century, the diagnosis and treatment of cystic fibrosis (CF) have been transformed by molecular sciences that initiated a new era with discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The knowledge gained from that breakthrough has had dramatic clinical impact. Although once a diagnostic dilemma with long delays, preventable deaths, and irreversible pathology, CF can now be routinely diagnosed shortly after birth through newborn screening programs. This strategy of pre-symptomatic identification has eliminated the common diagnostic "odyssey" that was a failure of the healthcare delivery system causing psychologically traumatic experiences for parents. Therapeutic advances of many kinds have culminated in CFTR modulator treatment that can reduce the effects of or even correct the molecular defect in the chloride channel -the basic cause of CF. This astonishing advance has transformed CF care as described fully herein. Despite this impressive progress, there are challenges and controversies in the delivery of care. Issues include how best to achieve high sensitivity newborn screening with acceptable specificity; what course of action is appropriate for children who are identified through the unavoidable incidental findings of screening tests (CFSPID/CRMS cases and heterozygote carriers); how best to ensure genetic counseling; when to initiate the very expensive but life-saving CFTR modulator drugs; how to identify new CFTR modulator drugs for patients with non-responsive CFTR variants; how to adjust other therapeutic modalities; and how to best partner with primary care clinicians. Progress always brings new challenges, and this has been evident worldwide for CF. Consequently, this article summarizes the major advances of recent years along with controversies and describes their implications with an international perspective.

The Expression of Affective Temperaments in Cystic Fibrosis Patients: Psychopathological Associations and Possible Neurobiological Mechanisms.

The aim of this study was to investigate the association between Cystic Fibrosis (CF) and affective temperaments, considering the relevance of ionic balances in neural excitability, as a possible neurobiological basis for temperamental expression. A cross-sectional study involving 55 adult CF patients was conducted. Sociodemographic, clinical and therapeutic characteristics, temperamental and personality dispositions and depressive and anxiety symptoms were evaluated through standardized semi-structured and structured interviews. The majority of the enrolled CF patients were receiving Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) therapy (72.7%), and most of them had hyperthymic temperament predominance (29.1%). Different TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire) dimensions were not associated with the type of CF phenotype-related mutation or with the use of CFTR-modulator therapy. However, a tendency towards irritability was noted in patients not undergoing CFTR modulator therapy (6.7 ± 4.72 vs. 4.7 ± 4.33; p = 0.13). In light of the limitations imposed by the cross-sectional nature of the study, a hyperthymic temperament was found to be protective against current or lifetime psychopathologic events, whereas the other temperaments were associated with positive psychopathological anamnesis. Based on the measurement of temperament profiles and the study of their associations with clinically relevant variables, we argue that subjecting CF patients to such a temperament assessment could prove beneficial in the transition towards integrated and personalized care.

Tezacaftor/Ivacaftor therapy has negligible effects on the cystic fibrosis gut microbiome.

People with cystic fibrosis (pwCF) experience a range of persistent gastrointestinal symptoms throughout life. There is evidence indicating interaction between the microbiota and gut pathophysiology in CF. However, there is a paucity of knowledge on the potential effects of CF transmembrane conductance regulator (CFTR) modulator therapies on the gut microbiome. In a pilot study, we investigated the impact of Tezacaftor/Ivacaftor dual combination CFTR modulator therapy on the gut microbiota and metabolomic functioning in pwCF. Fecal samples from 12 pwCF taken at baseline and following placebo or Tezacaftor/Ivacaftor administration were subjected to microbiota sequencing and to targeted metabolomics to assess the short-chain fatty acid (SCFA) composition. Ten healthy matched controls were included as a comparison. Inflammatory calprotectin levels and patient symptoms were also investigated. No significant differences were observed in overall gut microbiota characteristics between any of the study stages, extended also across intestinal inflammation, gut symptoms, and SCFA-targeted metabolomics. However, microbiota and SCFA metabolomic compositions, in pwCF, were significantly different from controls in all study treatment stages. CFTR modulator therapy with Tezacaftor/Ivacaftor had negligible effects on both the gut microbiota and SCFA composition across the course of the study and did not alter toward compositions observed in healthy controls. Future longitudinal CFTR modulator studies will investigate more effective CFTR modulators and should use prolonged sampling periods, to determine whether longer-term changes occur in the CF gut microbiome. IMPORTANCE People with cystic fibrosis (pwCF) experience persistent gastrointestinal (GI) symptoms throughout life. The research question "how can we relieve gastrointestinal symptoms, such as stomach pain, bloating, and nausea?" remains a top priority for clinical research in CF. While CF transmembrane conductance regulator (CFTR) modulator therapies are understood to correct underlying issues of CF disease and increasing the numbers of pwCF are now receiving some form of CFTR modulator treatment. It is not known how these therapies affect the gut microbiome or GI system. In this pilot study, we investigated, for the first time, effects of the dual combination CFTR modulator medicine, Tezacaftor/Ivacaftor. We found it had negligible effects on patient GI symptoms, intestinal inflammation, or gut microbiome composition and functioning. Our findings are important as they fill important knowledge gaps on the relative effectiveness of these widely used treatments. We are now investigating triple combination CFTR modulators with prolonged sampling periods.

Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis.

BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

Lung Transplantation in a New Era in the Field of Cystic Fibrosis.

Lung transplantation for people with cystic fibrosis (PwCF) is a critical therapeutic option, in a disease without a cure to this day, and its overall success in this population is evident. The medical advancements in knowledge, treatment, and clinical care in the field of cystic fibrosis (CF) rapidly expanded and improved over the last several decades, starting from early pathology reports of CF organ involvement in 1938, to the identification of the CF gene in 1989. Lung transplantation for CF has been performed since 1983, and CF now accounts for about 17% of pre-transplantation diagnoses in lung transplantation recipients. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been the latest new therapeutic modality addressing the underlying CF protein defect with the first modulator, ivacaftor, approved in 2012. Fast forward to today, and we now have a growing CF population. More than half of PwCF are now adults, and younger patients face a better life expectancy than they ever did before. Unfortunately, CFTR modulator therapy is not effective in all patients, and efficacy varies among patients; it is not a cure, and CF remains a progressive disease that leads predominantly to respiratory failure. Lung transplantation remains a lifesaving treatment for this disease. Here, we reviewed the current knowledge of lung transplantation in PwCF, the challenges associated with its implementation, and the ongoing changes to the field as we enter a new era in the care of PwCF. Improved life expectancy in PwCF will surely influence the role of transplantation in patient care and may even lead to a change in the demographics of which people benefit most from transplantation.

Advances in cystic fibrosis-related diabetes: Current status and future directions.

AIMS: The aim of this review is to give an update of the recent advances in the pathophysiology, prognosis, diagnosis and treatments of cystic fibrosis-related diabetes (CFRD). METHODS: The literature survey focuses on original and review articles dealing with CFRD between 2006 and 2023, and in particular with: pathophysiology, risk and predictive factors, screening, chronic complications of CFRD, management and the effects of CFTR channel modulator therapies on glucose homeostasis, using PubMed®. RESULTS: The rising prevalence of CFRD is due to prolonged life survival among patients with cystic fibrosis (CF). Advances in the understanding of the pathophysiology highlight the singularity of CFRD. Adherence to diagnostic guidelines remains challenging. Besides the classical OGTT, alternative diagnostic tests are being considered: HbA1c measurement, continuous glucose monitoring (CGM), intermediate measurements of alternative glucose tolerance stages through OGTT and homeostatic model assessment (HOMA). Early treatment of (pre)diabetes in CF patients is mandatory. The advent of CFTR channel modulator therapies have created a paradigm shift in the management of CF: they seem to improve glucose homeostasis, but the mechanism remains unclear. CONCLUSION: CFRD management is an ongoing concern. Optimal care has reduced the negative impact of CFRD on lung function, nutrition, and survival. Increasing prevalence of CFRD and prolonged lifespan lead to more microvascular complications. New screening tools (Hba1c, CGM, HOMA) show potential for better classification of patients. The effect of CFTR modulators on glucose metabolism warrants further research.

Airway clearance after highly effective CFTR modulators: Normalizing life and reducing treatment burden.

OBJECTIVES: Airway clearance therapy (ACT) is an important component of therapy for cystic fibrosis (CF) but is associated with significant treatment burden. Highly effective CFTR modulator therapy (HEMT) has improved pulmonary function for many people with CF (pwCF). We sought to understand changes in attitudes and practices about ACT in the post-HEMT era. STUDY DESIGN: Surveys of CF community members and CF care team members. METHODOLOGY: Separate surveys were created for the CF community and CF care providers to evaluate attitudes towards ACT and exercise in the post-HEMT era. We solicited answers from pwCF via the CF Foundation's Community Voice and from CF care providers via CF Foundation listservs. Surveys were available between July 20 and August 3, 2021. RESULTS: Surveys were completed by 153 community members (parents of children and pwCF) and 192 CF care providers. Belief that exercise can substitute partially for ACT was endorsed similarly by community members (59%) and providers (68%). After starting HEMT, 36% of parents of children and 51% of adults did fewer ACT treatments including 13% who stopped ACT. Adults reported altering their ACT regimen more than parents of children, though the sample size was limited. Half of providers had changed their ACT recommendations for those on HEMT. Fifty-three percent of respondents had discussed changing ACT with their care team (36% of parents, 58% of pwCF). CONCLUSIONS: Providers should be aware that ACT management changes may have been undertaken by pwCF who have pulmonary benefits of HEMT. Treatment burden should be considered in co-management decisions regarding ACT and exercise.