Case Series: Hyperbilirubinemia under elexacaftor/tezacaftor/ivacaftor in the presence of Gilbert's syndrome.

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.

Cystic fibrosis: desensitization in delayed hypersensitivity reactions to elexacaftor/tezacaftor/ivacaftor.

Background: Cystic fibrosis transmembrane conductance regulator modulators are the only available treatment for cystic fibrosis. Although elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is well-tolerated, rash has been reported as very frequent. In severe rashes, ELX/TEZ/IVA withdrawal is necessary, leading to clinical deterioration. The objective of the study is to increment the experience of ELX/TEZ/IVA desensitization. Methods: Adult patients who developed a delayed hypersensitivity rash to ELX/TEZ/IVA between December 2021 and February 2023 and required withdrawal due to ineffective rescue medication were included. Skins test for ELX/TEZ/IVA and IVA were conducted to establish hypersensitivity mechanism. Balijepally ELX/TEZ/IVA desensitization protocol was selected. In cases where desensitization had to be discontinued due to rash, an extended desensitization was proposed. Clinical and health-related quality of life parameters were collected before ELX/TEZ/IVA and after desensitization. Results: 162 patients (81 women, 31.2 [23.8-42.5] years) started ELX/TEZ/IVA, developing rash 12 of them (7.4%, six women). Six patients (five women) required stopping ELX/TEZ/IVA and were selected for desensitization. Skin tests indicated delayed type-IV hypersensitivity in one patient. Two patients presented adequate tolerance to desensitization; while, four patients developed rash. Three of these patients, successfully concluded extended desensitization (one patient declined participation). No significant clinical deterioration or quality of life worsening was observed during desensitization; in fact, there was an improvement in practically all mesured parameters. All five patients who resumed ELX/TEZ/IVA are currently receiving therapy with good tolerance. Conclusion: Desensitization to ELX/TEZ/IVA could be a successful and safe strategy for reintroducing this essential treatment in cases of a delayed hypersensitivity rash.

Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor treatment in children aged 6-11 years with cystic fibrosis in a real-world setting.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor (ETI) is a highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulating therapy for people with CF and at least one F508del variant. However, there is limited data about the safety and efficacy of this therapy in pediatric populations and in real-world settings. This study aimed at evaluating the effectiveness, tolerability, and safety of ETI in children with CF. METHODS: This was a prospective observational study including all children aged 6-11 years who initiated ETI therapy between October 2022 and March 2023 at the Pediatric CF Center of Milan (Italy). Study outcomes included changes in sweat chloride concentration, FEV1, LCI2.5, body mass index (BMI), tolerance, and safety. Mean changes in study outcomes from baseline through 24 weeks were estimated using mixed-effects regression models. RESULTS: The study included 34 children with CF (median age: 8.3 years). At Week 12, we observed an average decrease in LCI2.5 of 2.3 units (95% confidence interval [CI]: -3.1; -1.5). At Week 24, sweat chloride concentration decreased by 63 mEq/L (95% CI: -69; -58), FEV1 increased by 8.8 percentage point (95% CI: 3.7; 13.9) and BMI increased by 0.15 standard deviation scores (95% CI: 0.04; 0.25). Skin rashes appeared in 6 patients which spontaneously resolved within a few days. One month after treatment initiation, one patient experienced an elevation in liver function test results, which subsequently decreased during follow-up visits without necessitating discontinuation of therapy. CONCLUSIONS: Our data indicate that ETI therapy is well tolerated by children with CF and is effective in improving signs of lung function abnormalities from early childhood.

Heterogeneity in response to Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis.

BACKGROUND: Highly effective modulators of the CFTR channel have been demonstrated to dramatically impact disease progression and outcome. However, real-world data indicates that the magnitude of the clinical benefit is not equal among all patients receiving the treatment. We aimed to assess the variability in treatment response (as defined by the 6-month change in sweat chloride concentration, forced expiratory volume in one second [ppFEV1], body mass index [BMI], and CF Questionnaire-Revised [CFQ-R] respiratory domain score) and identify potential predictors in a group of patients receiving Elexacaftor-Tezacaftor-Ivacaftor (ETI) triple combination therapy. METHODS: This was a single-center, prospective cohort study enrolling adults with CF at a major center in Italy. We used linear regression models to identify a set of potential predictors (including CFTR genotype, sex, age, and baseline clinical characteristics) and estimate the variability in treatment response. RESULTS: The study included 211 patients (median age: 29 years, range: 12-58). Median changes (10-90th percentile) from baseline were: - 56 mEq/L (-76; -27) for sweat chloride concentration, +14.5 points (2.5; 32.0) for ppFEV1, +0.33 standard deviation scores (-0.13; 1.05) for BMI and +17 points (0; 39) for the CFQ-R respiratory domain score. The selected predictors explained 23 % of the variability in sweat chloride concentration changes, 18 % of the variability in ppFEV1 changes, 39 % of the variability in BMI changes, and 65 % of the variability in CFQ-R changes. CONCLUSIONS: This study highlights a high level of heterogeneity in treatment response to ETI, which can only be partially explained by the baseline characteristics of the disease.

Clinical and radiological improvement of cavitary Mycobacteroides abscessus disease in cystic fibrosis following initiation of elexacaftor/tezacaftor/ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a CFTR modulator therapy that has dramatically improved the health outcomes for many people with cystic fibrosis (pwCF). There is increasing interest in the role of CFTR modulators in the prevention and treatment of respiratory infections in pwCF. A male patient with F508del homozygous cystic fibrosis developed cavitary Mycobacteroides abscessus subspecies bolletii & massiliense respiratory infection. Antimycobacterial treatment was not given as, in discussion with the patient's family, it was deemed unlikely that the intensive regimen would be tolerated by the patient on account of his autism spectrum disorder. Following initiation of ETI, there was a rapid clinical and radiological improvement in this patient's cavitary lung disease. This case adds to the evidence base that suggests CFTR modulators, particularly ETI, may restore innate immune function leading to improved outcomes for pulmonary infection in pwCF.

The long-term effect of elexacaftor/tezacaftor/ivacaftor on cardiorespiratory fitness in adolescent patients with cystic fibrosis: a pilot observational study.

BACKGROUND: Physical activity is a crucial demand on cystic fibrosis treatment management. The highest value of oxygen uptake (VO2peak) is an appropriate tool to evaluate the physical activity in these patients. However, there are several other valuable CPET parameters describing exercise tolerance (Wpeak, VO2VT1, VO2VT2, VO2/HRpeak, etc.), and helping to better understand the effect of specific treatment (VE, VT, VD/VT etc.). Limited data showed ambiguous results of this improvement after CFTR modulator treatment. Elexacaftor/tezacaftor/ivacaftor medication improves pulmonary function and quality of life, whereas its effect on CPET has yet to be sufficiently demonstrated. METHODS: We performed a single group prospective observational study of 10 adolescent patients with cystic fibrosis who completed two CPET measurements between January 2019 and February 2023. During this period, elexacaftor/tezacaftor/ivacaftor treatment was initiated in all of them. The first CPET at the baseline was followed by controlled CPET at least one year after medication commencement. We focused on interpreting the data on their influence by the novel therapy. We hypothesized improvements in cardiorespiratory fitness following treatment. We applied the Wilcoxon signed-rank test. The data were adjusted for age at the time of CPET to eliminate bias of aging in adolescent patients. RESULTS: We observed significant improvement in peak workload, VO2 peak, VO2VT1, VO2VT2, VE/VCO2 slope, VE, VT, RQ, VO2/HR peak and RR peak. The mean change in VO2 peak was 5.7 mL/kg/min, or 15.9% of the reference value (SD ± 16.6; p= 0.014). VO2VT1 improved by 15% of the reference value (SD ± 0.1; p= 0.014), VO2VT2 improved by 0.5 (SD ± 0.4; p= 0.01). There were no differences in other parameters. CONCLUSION: Exercise tolerance improved after elexacaftor/tezacaftor/ivacaftor treatment initiation. We suggest that the CFTR modulator alone is not enough for recovering physical decondition, but should be supplemented with physical activity and respiratory physiotherapy. Further studies are needed to examine the effect of CFTR modulators and physical therapy on cardiopulmonary exercise tolerance.

Tezacaftor is a direct inhibitor of sphingolipid delta-4 desaturase enzyme (DEGS).

BACKGROUND: We recently demonstrated that 48 h exposure of primary human bronchial epithelial (hBE) cells, obtained from both CF (F508del homozygous) and non-CF subjects, to the triple drug combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) results in a CFTR genotype-independent modulation of the de novo synthethic pathway of sphingolipids, with an accumulation of dihydroceramides (dHCer). Since dHCer are converted into ceramides (Cer) by the action of a delta-4 sphingolipid desaturase (DEGS) enzyme, we aimed to better understand this off-target effect of ETI (i.e., not related to CFTR rescue) METHODS: hBE cells, both F508del and wild-type, were cultured to create fully differentiated bronchial epithelia. We analyzed Cer and dHCer using an LC-MS based method previously developed by our lab. DEGS expression levels in differentiated hBE cells lysates were quantified by western blot analysis. RESULTS: We demonstrated that 1) dHCer accumulate in hBE with time following prolonged ETI exposure, that 2) similar inhibition occurs in wild-type primary human hepatocytes and that 3) this does not result in an alteration of DEGS expression. We then proved that 4) ETI is a direct inhibitor of DEGS, that 5) Tezacaftor is the molecule responsible for this effect, that 6) the inhibition is concentration dependent. Finally, after repeated oral administration of ETI to naïve, non-CF, mice, we observed a slight accumulation of dHCer in the brain. CONCLUSIONS: We believe that further investigations on Tezacaftor should be envisaged, particularly for the use of ETI during pregnancy, breastfeeding and in the early stages of development. DEGS dysfunction and dHCer accumulation causes impairment in the development of the nervous system, due to a derangement in myelin formation and maintenance.

Pharmacokinetic variability of CFTR modulators from standard and alternative regimens.

Elexacaftor, tezacaftor, ivacaftor (ETI) is a CFTR modulator combination approved for use in ∼90 % of people with cystic fibrosis (pwCF) over 2 years old. While most pwCF tolerate this therapy well, some are intolerant to standard dosing, and others show little response. Clinical providers may adjust ETI dosing to combat these issues, but these adjustments are not well guided by pharmacokinetic evidence. Our post-approval study aimed to describe pharmacokinetic variability of ETI plasma concentrations in 15 participants who were administered a standard or reduced dose. ETI were quantified by LC-MS/MS in plasma samples taken prior to the morning dose. Results showed non-significant differences for each compound regardless of dosing regimen and after dose equivalence normalization. The majority of participants in both dosing groups had concentrations expected to elicit clinical response to ETI therapy. These findings indicate that dose reduction may be a viable strategy to maintain clinical benefit while managing intolerance.

Extent of foetal exposure to maternal elexacaftor/tezacaftor/ivacaftor during pregnancy.

BACKGROUND AND PURPOSE: Cystic fibrosis (CF) patients are living longer and healthier due to improved treatments, e.g. cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI), with treatment possibly occurring in pregnancy. The risk of ETI to foetuses remain unknown. Thus the effect of maternally administered ETI on foetal genetic and structural development was investigated. EXPERIMENTAL APPROACH: Pregnant Sprague Dawley rats were orally treated with ETI (6.7 mg·kg-1·day-1 elexacaftor + 3.5 mg·kg-1·day-1 tezacaftor + 25 mg·kg-1·day-1 ivacaftor) for 7 days from E12 to E19. Tissue samples collected at E19 were analysed using histology and RNA sequencing. Histological changes and differentially expressed genes (DEG) were assessed. KEY RESULTS: No overt structural abnormalities were found in foetal pancreas, liver, lung and small intestine after 7-day ETI exposure. Very few non-functionally associated DEG in foetal liver, lung and small intestine were identified using RNA-seq. 29 DEG were identified in thymus (27 up-regulated and two down-regulated) and most were functionally linked to each other. Gene ontology enrichment analysis revealed that multiple muscle-related terms were significantly enriched. Many more DEG were identified in cortex (44 up-regulated and four down-regulated) and a group of these were involved in central nervous system and brain development. CONCLUSION AND IMPLICATION: Sub-chronic ETI treatment in late pregnancy does not appear to pose a significant risk to the genetic and structural development of many foetal tissues. However, significant gene changes in foetal thymic myoid cells and cortical neuronal development requires future follow-up studies to assess the risk to these organs.

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, 2024.

PREFUL MRI for Monitoring Perfusion and Ventilation Changes after Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis: A Feasibility Study.

Purpose To assess the feasibility of monitoring the effects of elexacaftor-tezacaftor-ivacaftor (ETI) therapy on lung ventilation and perfusion in people with cystic fibrosis (CF), using phase-resolved functional lung (PREFUL) MRI. Materials and Methods This secondary analysis of a multicenter prospective study was carried out between August 2020 and March 2021 and included participants 12 years or older with CF who underwent PREFUL MRI, spirometry, sweat chloride test, and lung clearance index assessment before and 8-16 weeks after ETI therapy. For PREFUL-derived ventilation and perfusion parameter extraction, two-dimensional coronal dynamic gradient-echo MR images were evaluated with an automated quantitative pipeline. T1- and T2-weighted MR images and PREFUL perfusion maps were visually assessed for semiquantitative Eichinger scores. Wilcoxon signed rank test compared clinical parameters and PREFUL values before and after ETI therapy. Correlation of parameters was calculated as Spearman ρ correlation coefficient. Results Twenty-three participants (median age, 18 years [IQR: 14-24.5 years]; 13 female) were included. Quantitative PREFUL parameters, Eichinger score, and clinical parameters (lung clearance index = 21) showed significant improvement after ETI therapy. Ventilation defect percentage of regional ventilation decreased from 18% (IQR: 14%-25%) to 9% (IQR: 6%-17%) (P = .003) and perfusion defect percentage from 26% (IQR: 18%-36%) to 19% (IQR: 13%-24%) (P = .002). Areas of matching normal (healthy) ventilation and perfusion increased from 52% (IQR: 47%-68%) to 73% (IQR: 61%-83%). Visually assessed perfusion scores did not correlate with PREFUL perfusion (P = .11) nor with ventilation-perfusion match values (P = .38). Conclusion The study demonstrates the feasibility of PREFUL MRI for semiautomated quantitative assessment of perfusion and ventilation changes in response to ETI therapy in people with CF. Keywords: Pediatrics, MR-Functional Imaging, Pulmonary, Lung, Comparative Studies, Cystic Fibrosis, Elexacaftor-Tezacaftor-Ivacaftor Therapy, Fourier Decomposition, PREFUL, Free-Breathing Proton MRI, Pulmonary MRI, Perfusion, Functional MRI, CFTR, Modulator Therapy, Kaftrio Clinical trial registration no. NCT04732910 Supplemental material is available for this article. © RSNA, 2024.

International disparities in diagnosis and treatment access for cystic fibrosis.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has revolutionized cystic fibrosis (CF) treatment. However, previous research has demonstrated profound global disparities in diagnosis and treatment access. If unaddressed, these threaten to widen existing health inequities. Therefore, in this analysis we aimed to reappraise gaps and evaluate progress in diagnosis and treatment equity in high-income (HIC) versus low- and middle-income countries (LMICs). METHODS: Estimates of the global CF population were made in 158 countries using patient registries, systematic literature searches, and an international survey of 14 CF experts. Estimates of the global burden of undiagnosed CF were made using epidemiological studies identified in literature searches and registry coverage data. The proportion of people receiving ETI was estimated using publicly available revenue data and a survey of 23 national drug pricing databases. RESULTS: 188,336 (163,421-209,204) people are estimated to have CF in 96 countries. Of these, 111,767 (59%) were diagnosed and 51,322 (27%) received ETI. The undiagnosed patient burden is estimated to be 76,569 people, with 82% in LMICs. ETI is reimbursed in 35 HICs, but only one LMIC. Four years after approval, there are 13,723 people diagnosed with CF who live in a country where ETI is inaccessible. This increases to 76,199 when including the estimated undiagnosed population. CONCLUSIONS: Equitable access to CFTR modulators must become a top priority for the international CF community. ETI costs up to $322,000 per year but could be manufactured for $5000 to allow access under a voluntary license. Given the extent of disparities, other mechanisms to improve access that circumvent the manufacturer should also be considered.

Real-world effectiveness of elexacaftor/tezacaftor/ivacaftor on the burden of illness in adolescents and adults with cystic fibrosis.

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has been shown to be safe and efficacious in people with cystic fibrosis (CF) aged ≥2 years. Here, we describe results from an observational study assessing change in burden of illness following initiating ELX/TEZ/IVA in real-world settings. Methods: This US-based, multicenter, observational study used data from electronic medical records to evaluate real-world burden of illness before and after ELX/TEZ/IVA initiation in people with CF aged ≥12 years heterozygous for F508del and a minimal function mutation (F/MF) or an uncharacterized CFTR mutation. Endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI) and BMI-for-age z-score, glycated hemoglobin (HbA1c), and numbers of pulmonary exacerbations (PEx). Results: Overall, 206 people with CF were enrolled (mean [SD] age 22.5 [11.1] years; 192 [93.2%] with F/MF genotype). Mean follow-up was 15.6 (SD, 1.6) months. Improvements in ppFEV1 (7.3 [95% CI: 5.7, 8.8] percentage points) were observed from baseline through follow-up. Increases in BMI (1.40 [95% CI: 1.07, 1.77] kg/m2) and BMI-for-age z-score (0.14 [95% CI: 0.00, 0.28]) were also observed from baseline at 12 months. The estimated annualized rate of any PEx was 1.31 at baseline and 0.61 over follow-up (rate ratio 0.47 [95% CI: 0.39, 0.55]), with annualized rates of PEx requiring antibiotics and hospitalizations of 0.55 and 0.88 in the baseline period and 0.12 and 0.36 over follow-up (rate ratios 0.22 [95% CI: 0.15, 0.31] and 0.41 [95% CI: 0.32, 0.51]), respectively. Absolute change in HbA1c was -0.22 (95% CI: -0.38, -0.06) from baseline through follow-up. Conclusions: ELX/TEZ/IVA treatment was associated with improved lung function, increased BMI, reduced frequency of PEx, and improved (i.e., reduced) HbA1c. These results confirm the broad clinical benefits of ELX/TEZ/IVA seen in clinical trials and show the potential for ELX/TEZ/IVA to improve markers of glucose metabolism.

Improved Nutritional Outcomes and Gastrointestinal Symptoms in Adult Cystic Fibrosis Patients Treated with Elexacaftor/Tezacaftor/Ivacaftor.

INTRODUCTION: Cystic fibrosis transmembrane conductance regulator modulator therapy improves nutritional status and quality of life. Clinical trials have shown pancreatic insufficiency conversion, mostly in pediatric patients treated with ivacaftor. Studies with elexacaftor/tezacaftor/ivacaftor (ETI) in older patients have not suggested restoration of exocrine pancreas function, but quality data in adults are lacking. Our aim was to show the effect of ETI in adults with cystic fibrosis (CF) on nutritional status and digestive function. We hypothesized improvement of nutritional parameters and gastrointestinal symptoms, reduction of pancreatic enzyme replacement therapy, but uncertain improvement in exocrine pancreatic function. METHODS: We prospectively enrolled adults with CF treated with ETI from August 2021 to June 2022. We measured anthropometric parameters, laboratory nutritional markers, change of fecal elastase, pancreatic enzymes replacement therapy needs, and gastrointestinal symptoms. RESULTS: In the cohort of 29 patients (mean age 29.1 years), 82.8% suffered exocrine pancreatic insufficiency. After ETI, mean BMI increased by 1.20 kg/m2 (p < 0.001), mean body weight by 3.51 kg (p < 0.001), albumin by 2.81 g/L, and prealbumin by 0.06 (both p < 0.001). Only 1 patient, initially pancreatic insufficient (4.5%, p < 0.001), developed pancreatic sufficiency, indicated by increased fecal elastase from 45 µg/g to 442.1 µg/g. Mean change in lipase substitution decreased by 1,969 units/kg/day (p < 0.001) and stools frequency by 1.18 per day (p < 0.001). CONCLUSION: Our data suggest increased nutritional parameters, lower pancreatic substitution requirements, and improved defecation in adult CF patients on ETI. Improvement in exocrine pancreatic function might be mutation-specific and needs further study.

Elexacaftor/Tezacaftor/Ivacaftor use in Pediatric Cystic Fibrosis Patients with Advanced Liver Disease.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy extends the life expectancy of people with cystic fibrosis (PwCF). However, CFTR modulators have not been well studied in patients with cystic fibrosis liver disease (CFLD), specifically those with advanced liver disease with portal hypertension. The purpose of this report is to describe the use of elexacaftor/tezacaftor/ivacaftor (ETI) in pediatric CF patients with advanced CFLD. METHODS: This retrospective case series included PwCF < 18 years old with baseline advanced CFLD initiated on ETI. RESULTS: Eleven PwCF and advanced CFLD were treated with ETI; six started a reduced dose regimen. No patient required treatment interruption and four patients received dose changes related to increase in transaminase and/or bilirubin elevations. Mean (SD) change in ppFEV1 from prior to ETI to highest value during therapy was 14.27 % (4.25) (p = 0.007). When evaluating the group as whole, AST decreased from baseline to last reported -15.18 (23.23) units/L (p = 0.054) and ALT slightly increased 0.73 (39.13) units/L (p = 0.96). Bilirubin increased minimally overall for patients with mean change from baseline of 0.83 (1.33) mg/dL [range -0.5-3] (p = 0.17). A model for time on ETI showed a significant decrease in AST over time of 0.955 per month of ETI but no other liver biochemistries were significant. No patient experienced decompensation of CFLD. CONCLUSION: ETI therapy in pediatric CF patients with advanced CFLD can be beneficial in improving pulmonary and nutritional outcomes without negative impact on liver biochemistries or hepatic outcomes. Close monitoring is recommended to ensure safety and tolerability.

Pulmonary Ionocytes Regulate Airway Surface Liquid pH in Primary Human Bronchial Epithelial Cells.

Rationale: Pulmonary ionocytes are a newly discovered airway epithelial cell type proposed to be a major contributor to cystic fibrosis (CF) lung disease based on observations they express the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel at a higher level than any other cell type in the airway epithelia. Moreover, genetically manipulated experimental models that lack ionocytes develop NaCl transport abnormalities and airway surface liquid (ASL) dehydration consistent with CF. However, no direct evidence indicates ionocytes engage in NaCl transport or contribute to ASL formation, questioning the relevance of ionocytes to CF lung disease. Objectives: To determine the ion transport properties of pulmonary ionocytes and club cells in genetically intact healthy and CF airway epithelia. Methods: We measured ion transport at the single-cell level using a self-referencing ion-selective microelectrode technique in primary human bronchial epithelial cell culture. Measurements and Main Results: cAMP-stimulated non-CF ionocytes do not secrete Na+ or Cl- into the ASL, but rather modulate its pH by secreting bicarbonate via CFTR-linked Cl-/bicarbonate exchange. Non-CF club cells secrete Na+ and Cl- to the lumen side after cAMP stimulation. CF ionocytes and club cells do not transport ions in response to cAMP stimulation, but incubation with CFTR modulators elexacaftor/tezacaftor/ivacaftor restores transport properties. Conclusions: We conclude that ionocytes do not contribute to ASL formation but regulate ASL pH. Club cells secrete the bulk of airway fluid. In CF, abnormal ionocyte and club cell function results in acidic and dehydrated ASL, causing reduced antimicrobial properties and mucociliary clearance. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Safety and efficacy of elexacaftor/tezacaftor/ivacaftor in people with Cystic Fibrosis following liver transplantation: A systematic review.

BACKGROUND & AIMS: Cystic Fibrosis (CF) liver disease progresses to liver failure requiring transplantation in about 3 % of patients, 0.7 % of CF patients are post liver transplant. The prognosis of CF has improved with the introduction of elexacaftor/tezacaftor/ivacaftor (ETI). Due to the paucity of data and concerns regarding interactions with immunosuppressive drug regimens, there is no general consensus on use of ETI post liver transplantation. The aim of this review is to report the safety and efficacy of ETI in CF patients who underwent liver transplantation. METHODS: A systematic review was conducted through MEDLINE/Pubmed and EMBASE databases. English-written articles reporting clinical data on liver transplanted CF patients treated with ETI were included. Article quality was evaluated using the Critical Appraisal Checklist for Case Reports. RESULTS: Twenty cases were retrieved from 6 reports. Temporary discontinuation and/or dose reduction due to elevated transaminases was required in 5 cases. ETI restarted on a reduced dose was tolerated in 3 out of 5 patients, 1 patient tolerated full dose. Tacrolimus dose change was required in 14 cases, in 1 case ETI was discontinued due to tacrolimus toxicity. Improvement in percentage predicted FEV1 was noted in 15/19 patients (median +17 %, range 8 %-38 %). CONCLUSIONS: In the majority of liver transplanted patients ETI is well tolerated, although adverse events and liver function abnormalities may occur. Close monitoring of liver function and tacrolimus level is warranted. Significant improvement in lung function after ETI initiation is confirmed, highlighting the importance of accessing this medication for this group of patients.