Longitudinal improvements in clinical and functional outcomes following initiation of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis

Background: The advent of highly effective modulator therapies (HEMTs), including elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), for treatment of cystic fibrosis (CF) has resulted in remarkable clinical improvement for modulator-naive patients and for those who have been treated with prior modulator therapies. Intranasal micro-optical coherence tomography (muOCT) has detected functional abnormalities in the mucociliary apparatus of people with CF. The objectivewas to characterize the effects of ELX/TEZ/ IVA on nasal mucociliary clearance by muOCT and monitor the clinical changes conferred as a way to understand the effects. Method(s): Of 26 individuals aged 12 and older with at least one F508del mutation recruited, 24 were enrolled and followed over three visits: baseline and 1 (visit 2) and 6 months (visit 4) after initiation of ELX/TEZ/IVA therapy;the COVID-19 pandemic affected visit windows. Intranasal muOCT imaging was conducted at baseline and visit 2 as previously described;additional imaging for 18 months (visit 5) is in progress. Clinical outcomes, including percentage predicted forced expiratory volume in 1 second (FEV1pp) and sweat chloride levels were computed as part of the parent Prospective Study to Evaluate Biological and Clinical Effects of Significantly Corrected CFTR Function (PROMISE study). A blinded investigator team analyzed in vivo muOCT parameters including mucociliary transport (MCT) rate, ciliary beat frequency (CBF), and periciliary liquid depth (PCL) after devising an improved stabilization algorithm. Analysis of airway surface liquid (ASL) depthswas excluded because of the limited number of cases in which the necessary condition for measurement,which is preservation of a clear air layer between the mucus layer and the probe, was satisfied. Result(s): Twenty-three subjects completed visits 1 and 2, and 18 completed visits 1, 2, and 4. Average age at baselinewas 27 +/- 8.7, 69% were female, and 43% were on prior two-drug modulator therapy. No significant change in body mass index was found between the visits. FEV1pp increased significantly (10.9%, 95% CI, 76.1-98.4%) by visit 2 and persisted at visit 4 (10.6%, 95% CI, 87.7-107.0;p < 0.001). Sweat chloride levels decreased significantly at visit 2 (-36.6 mmol/L, 95% CI, 40.9-54.9 mmol/L) and visit 4 (-41.3 mmol/L, 95% CI, 34.9-51.8 mmol/L) at visit 4 ( p < 0.001). Analysis of muOCT images revealed significant improvement in MCT rate (2.8 +/- 1.5 mm/ min at baseline vs 4.0 +/- 1.5 mm/min at visit 2, p = 0.048), although no discernable changes were noted in CBF or PCL. When stratified based on use of prior modulator therapy, no significant differences were found for any muOCT metric. No significant correlations between change in MCT rates and change in FEV1pp or sweat chloride from baseline to visit 2were found. Conclusion(s): Treatment with ELX/TEZ/IVA in people with CF, including those that were treatment naive and those on prior modulator therapy, resulted in significant, sustained improvement in lung function and decreases in sweat chloride levels at ~10 months, consistent with recently published reports. Functional improvements in MCTratewere evident after initiation of ELX/TEZ/IVA therapy, which may partially explain the findings of better whole-lung mucus clearance and reduction in chronic infections reported previously. muOCT imaging in people with CF is sensitive to the treatment effect of HEMT and suggests better mucociliary transport as a mechanism of action underlying the clinical benefits for lung health. Acknowledgements: On behalf of the PROMISE investigatorsCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Fetal impact of cystic fibrosis transmembrane conductance regulator modulator use during assisted and natural reproduction and partner pregnancy in men with cystic fibrosis

Background: Increasing availability of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) has improved the quality of life and long-term prognosis for many people with CF. Thus, more people with CF are considering parenthood. Almost all menwith CF (MwCF) are infertile because of congenital bilateral absence of the vas deferens (CBAVD). Based on CF animal models, CBAVD occurs early in gestation and is unlikely to be reversible using HEMT, but assisted reproductive techniques (ARTs) can enable MwCF to father children using the sperm in their testes. Animal reproductive models suggest no HEMT teratogenicity, and the amount of exposure of the fetus to HEMT via absorption of seminal fluid through the vaginal wall is predicted to be negligible, although to ensure no sperm exposure to HEMT, the life span of sperm would require MwCF to discontinue CFTR modulators for approximately 3 months before ART. Because abrupt discontinuation of CFTR modulators may result in health decline, MwCF and their providers must consider all potential risks. There are no published data in MwCF regarding use of HEMT during conception and partner pregnancy. Method(s): Beginning in August 2021, CF center staff in the United States, United Kingdom, and Australia completed a two-page anonymous questionnaire regarding MwCF who used CFTR modulators during ART (sperm retrieval and in vitro fertilization) or natural conception with subsequent partner pregnancy. Result(s): Providers have submitted 34 surveys for MwCF on CFTR modulators whose partner became pregnant after use of ART (n = 32) or natural conception (n = 2). The median age of the samplewas 32 (range 24- 43). Fifteen were homozygous for F508del, median percentage predicted forced expiratory volume in 1 second was 76% (range (22-111%), and median body mass index was 24 kg/m2 (range 18.5-32.1). Twenty-three were taking elexacaftor/tezacaftor/ivacaftor. The median time that MwCF were taking CFTR modulators before partner conception was 18 months (range 0-82). One newly diagnosed man initiated HEMT after sperm retrieval. Four MwCF stopped CFTR modulators before sperm retrieval, one of whom experienced pulmonary decline. None of the 19 MwCF whose condom use during pregnancy was known used condoms. Fetal complications in partners of MwCF included three first-trimester miscarriages, two* COVID, two breech presentation, two* vaginal bleeding, and one vasa previa. None of the complications were deemed definitively related to use of CFTR modulators. One MwCF experienced testicular infection after sperm retrieval#. Postpartum complications included three# infants with hypoxemia requiring neonatal intensive care unit stay, three maternal blood loss, one forceps delivery, and one caesarean section. No congenital anomalies were reported for any infant. (*/# overlap). Conclusion(s): Use of CFTR modulator therapy during partner conception and pregnancy in 34 MwCF has not resulted in higher-than-expected miscarriage rates or congenital anomalies. Providers should consider the risk to the health of MwCF combined with the lack of teratogenicity in animal reproductive models and limited safety data in the human fetus before discontinuing CFTR modulators before ART or natural partner conception. Survey collection is ongoing;results will be updated for presentationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Clinical improvement 2 years after starting elexacaftor/tezacaftor/ivacaftor in patients with advanced lung disease

Background: With the introduction of new cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (elexacaftor/tezacaftor/ ivacaftor), peoplewith CF experiencing severe lung disease can experience significant improvements in clinical symptoms. Method(s): This single-center institutional review board-approved retrospective chart review identified patients with advanced lung disease who met criteria for a compassionate use or expanded access program because of high risk of death or transplant need within 2 years. Clinical data collection for all patients began at baseline, 2 to 4 weeks after therapy initiation, and continued every 3 months for 2 years. Datawere collected on demographic characteristics, clinic progress notes, clinical labs, forced expiratory volume in 1 minute (FEV1),weight, body mass index, respiratory colonization, and hospitalizations after drug initiation. Patients also completed sinus and chest computed tomography (CT) to track clinical changes. Result(s): Eighteen people with CF (aged 15-49, 56% male) from a large midwestern CF center who initiated drug therapy between July and September 2019 in an inpatient hospital or clinic setting were identified. Clinical markers (Table 1) indicated that modulator therapy was well tolerated and not discontinued by any participant;safety lab values did not indicate medical concern or discontinuation. There were 90 admissions for the group in the 2 years before therapy and 17 admissions during the 2 years after, although seven of the posttherapy admissions were for nonrespiratory indications. Monitoring results indicated the safety of modulator therapy because there were no adverse clinical occurrences or laboratory events, and all patients presented with universal stabilization. There have been no deaths and no transplants. Unlike lumacaftor/ivacaftor, therewere no problems with chest tightness or any difficulty with troublesome increases in expectoration burden or choking during initiation of therapy. Most had significant reduction in or loss of spontaneous cough and sputum production. The impact on microbial colonization is unclear, because even in this severe group, inability to produce sputum on command led to considerable missing data in follow-up, leaving colonization status at follow-up unclear. Conclusion(s): This study focused on people with CF who qualified for modulator therapy based on advanced lung disease. Initiation of modulator therapy was deemed safe and resulted in objective positive changes in nutrition;cough;FEV1);and subjective reports of clinical status, level of activity, and reduction in burden of treatment. No evidence was found of difficulty managing the increased expectoration during initial therapy. Limitations were noted in missing data during the COVID-19 pandemic, small sample size, and delayed follow-up for drug monitoring.(Table Presented) Clinical indicators before and after modulator therapy *Completed post-drug initiation (earlier than 12 months), **24 months before and after therapy initiationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Effectiveness and safety of elexacaftor/tezacaftor/ivacaftor therapy: An Italian center experience

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), a triple CFTR modulator combination, has proved to be highly effective in Phe508del homozygous and Phe508del/minimal function compound heterozygous people with cystic fibrosis (PwCF).We report preliminary data on the realworld effectiveness and safety of ELX/TEZ/IVA after 6 months of treatment. Method(s):We collected prospective data on PwCF who started ELX/TEZ/IVA and evaluated changes in pulmonary function (spirometry and lung clearance index [LCI]), nutritional status (body mass index [BMI]), sweat chloride, and rate of hospitalization from baseline to 6 months of treatment. Result(s): Between August 2021 and October 2021, ELX/TEZ/IVAwas started in 24 PwCF (12 female,10 Phe508del-homozygous, median age 20.5 (range 13-37), all with pancreatic insufficiency). After 6 months of treatment, all respiratory function indicators improved (median change: +16% percentage predicted forced expiratory volume in 1 second, +12% percentage predicted forced vital capacity, +23% percentage predicted forced expiratory flow at 25/75%, -2 lung clearance index). Improvement was also observed in BMI (+0.41 z-score) and sweat chloride concentrations (-54 mMol/L, 6 PwCF had Cl concentrations within the limit of normality) (Table 1). Over a 6-month period, only one hospitalization due to pulmonary exacerbations was observed, compared with 22 hospitalizations observed in the 6 months before starting ELX/TEZ/IVA (rate per 100 patient-months 15.3 vs 0.7, rate ratio 0.05, 95% CI, 0.01-0.29). Treatment was well tolerated, with only mild and transient adverse events consisting of headache (n = 4), cutaneous rash (n = 2), and mild hemoptysis (n = 2). One PwCF had intestinal subocclusion and required hospitalization. One patient had liver function test elevation after 6 months of therapy during an Changes in clinical variables and sweat test results from baseline through 6 months in patients treated with elexacaftor, tezacaftor and ivacaftor. Data are medians (interquartile ranges). Baseline vs 6 months compared usingWilcoxon signed-rank test. ppFEV1, percentage predicted forced expiratory volume in 1 second;ppFVC, percentage predicted forced vital capacity;ppFEV25/75, percentage predicted forced expiratory flow at 25/75%;LCI, lung clearance index;BMI, body mass index;Cl, chloride. (Table Presented) episode of SARS-COV2 infection, which required adjustment of the dose administered. Conclusion(s): Our data confirm that ELX/TEZ/IVA treatment is safe, well tolerated, and effective in PwCF. ELX/TEZ/IVA improved pulmonary function and nutritional status and remarkably reduced hospitalization rate. Our data indicate that introduction of ELX/TEZ/IVA in CF care will radically change the natural history of and management approach to the disease.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Increasing interest in post-secondary education in the CF population

Background: Planning for college and post-secondary education has historically been a challenge for people with cystic fibrosis PwCF) because of a shortened life expectancy and the high cost of CF treatments. According to the Cystic Fibrosis Foundation Patient Registry, the median age of death was 32 in 2019 for PwCF in the United States [1]. Those who are healthy enough to plan for post-secondary education typically need financial assistance to offset the cost of tuition. This need has led many PwCF to contact Cystic Fibrosis Foundation Compass, a free, personalized case management service that provides information and resource referrals, for assistance with education-related expenses. Over the course of the pandemic, Compass observed a spike in interest of people seeking financial assistance and other resources to explore further education. We sought to better understand the increase in education requests from 2019 to 2021. Method(s): Compass data from January 1, 2019, through December 31, 2021, were reviewed.We reviewed data for all inquiries categorized as education, which include requests for scholarships, financial aid, and vocational rehabilitation. Compass also collects information on caller demographic characteristics such as age, household size, and household income, and this information was reviewed for all education inquiries during the 3-year period. We do not typically ask why callers are requesting financial assistance. Result(s): There was an increase in requests for financial assistance for education in 2020 and 2021: 98 scholarship requests in 2019, 140 in 2020, and 238 in 2021. The average age of PwCF requesting financial assistance with educationwas 24 all 3 years. One PwCF with an income of $100,000 or more requested financial assistance with education in 2019, five in 2020, and 13 in 2021. Conclusion(s): The number of education requests Compass receives has increased every year since 2019. The average age of PwCF making requests was 24, which is considered a non-traditional student by the National Center for Education Statistics [2]. Therewas also an increase in callers with high household incomes requesting financial assistance with education expenses. The approval of elexacaftor/tezacaftor/ivacaftor in 2019 may have contributed to the increase in requests each year, because PwCF eligible for and taking this medication may be experiencing better health outcomes and able to focus on furthering their educations. The COVID-19 pandemic may also have contributed because fewer people were able to work outside the home and may have elected to further their education as a result. Financial hardships due to the pandemic may also explain the increase in requests for financial assistance, even for those with high household incomes. Our results showa continued increase in requests each year. We are interested in identifying and exploring the cause of this increase through survey or conversations with those seeking education assistance through Compass. We will continue to follow the data to see if the increase continues as the COVID-19 pandemic ends.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

A novel cystic fibrosis-pregnancy service: Two-year review after introduction of elexacaftor/tezacaftor/ivacaftor

Background: As a quality service improvement response since elexacaftor/ tezacaftor/ivacaftor (ELX/TEZ/IVA) became available and the yearly average number of cystic fibrosis (CF) pregnancies (n = 7 pre-2020, n = 33 in 2021) increased significantly at an adult CF center (~600 people with CF), a monthly multidisciplinary CF-maternal health virtual clinic was established with antenatal virtual CF exercise classes dedicated to providing adaptive, specialist support to this cohort, aswell as outreach guidance and education to local obstetric teams. Method(s): This was a single-center retrospective reviewof Royal Brompton Hospital CF-Maternal Health multidisciplinary team clinic records and a patient survey from March 2020 to March 2022. Result(s): Of 47 pregnancies in 41 women (median age 30;) eligible for ELX/ TEZ/IVA at start of pregnancy, 40% (n = 19) were unplanned, and 19% (n = 9) used assisted conception. Three women with a history of infertility conceived naturally, having required assisted conception for previous pregnancies, and five women had multiple pregnancies during the study period. ELX/TEZ/IVA was continued in 60% (n = 28), delayed in 28% (n = 13), and stopped in 13% (n = 6) of pregnancies through maternal choice and careful clinical counselling. Pre-pregnancy pulmonary status was poorer in women who continued than in those who delayed or stopped (Table 1). Of those who stopped, 85% (n = 5) restarted because of pulmonary deterioration by the third trimester. Prenatal CF complications included at least one episode of minor hemoptysis in 21% (n = 9/41) of women, at least one infective exacerbation in 55% of pregnancies (n = 26/47), and noninvasive ventilation in one woman. Other pregnancy-associated complications included one case of ovarian hyperstimulation syndrome, one case of sub-segmental pulmonary embolism, and two cases of pregnancy-induced hypertension. Excluding 10 first trimester terminations, 10 current pregnancies, and one patient relocation, obstetric outcomes available for 26 pregnancies confirmed a live birth rate of 85% (n = 22/26) and a 15% first-trimester miscarriage rate (n = 4). Obstetric complications included preterm delivery rate of 23% (n = 6/26), including two cases of COVID infection resulting in two neonatal intensive care unit admissions, one case of endometritis after cesarean section, and a fourthdegree perineal tear. There were no ectopic pregnancies, maternal or neonatal deaths, or reports of infant cataracts or congenital malformations. Median gestational age was 37/40 weeks (range 29-40). Mode of delivery was via cesarean section in 45% (n = 10/22, of which twowere emergency) and vaginal in 55% (n = 12/22), of which 83% (n = 10/12) were via induction of labor for diabetes (CF or gestational) indication. Deliveries were supported and occurred equally at local obstetric units and in tertiarycare obstetric hospital settings (50%, n = 11/22). Patient-experience survey responses cited high levels of confidence in health optimization and prioritization during pregnancy and praised excellent inter-health care provider communication and peer-to-peer emotional support provided among expectant mothers in the virtual prenatal exercise groups. Table 1. Baseline demographic and clinical characteristics of elexacaftor/tezacaftor/ivacaftoreligible expectant mothers according to therapeutic decision (Table Presented) Conclusion(s): In the absence of clinical trial safety data, the novel approach of a dedicated CF-maternal health multidisciplinary team clinic with local obstetric outreach support has ensured regular specialist clinical and emotional peer-to-peer support for this cohort of women eligible for ELX/ TEZ/IVA to ensure optimal outcomes and experiences of their pregnancies, where appropriate, close to home.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Social worker to therapist: Adaptation of role while addressing inequities in mental health care

Background: 2020 was a year of transformation in cystic fibrosis (CF) care. Many adults with CF started elexacaftor/tezacaftor/ivacaftor while COVID- 19 was unfolding. Occurring almost simultaneously, these two events created a dramatic shift in the disease landscape. Hospital admissions plummeted, and physical health improved. Clinic appointments turned virtual, and people with CF sheltered at home for months. These changes created opportunities for CF team members to adapt roles to meet evolving needs. Social work hours devoted to inpatient care, end of life, and discharge planning could be reallocated to other areas. Although many patients improved from a physical standpoint, mental health problems increased. Between 2020 and 2022, demand for mental health services increased exponentially, creating a national mental health crisis, but inequities in insurance coverage existed between physical and mental health care. Finding a mental health provider became an almost impossible task. This author sought to address insurance inequity and increased demand for mental health services by offering cognitive behavioral therapy (CBT) sessions to adults with CF to optimize their health andwellbeing. CBT is considered an evidence-based approach for most mental health problems. Method(s): Eight adults at the Stanford Adult CF Center were referred for CBT with social work from August 2021 to April 2022. Referrals were based on mental health crisis, mental health screenings, insurance barriers, and availability of mental health providers. Therapy sessions were offered via telehealth as part of the multidisciplinary care at the CF center. Patients were not billed for the sessions. The number of sessions was variable, with a mean of 10.5 sessions per patient. The frequency and content of sessions were tailored to patients' unique needs. Referrals were accepted on a continuous basis, space available. Mental health problems included anxiety, depression, alcohol use disorder, trauma, and gender dysphoria Results: All eight patients receiving CBT demonstrated significant improvement in mental health symptoms, as evidenced by a mean reduction in Patient Health Questionnaire-9 score of 3 and General Anxiety Disorder-7 score of 3.3. (Six of 8 patients were screened before and after therapy.) Other measures of improvement were patient selfreport as documented in therapy notes, sessions being tapered or discontinued as goals were met, and reduction in or stoppage of psychotropic medications. Conclusion(s): Mental health is a vital component of health and should be properly addressed as part of CF care. Although mental health care in CF has come a long way, patients continue to lack proper access to trained providers, especially those with expertise in CBT and CF. Given the current mental health crisis and shortage of therapists to meet newdemands, there are serious implications for long-term health outcomes for people with CF. As more studies are published demonstrating the effectiveness of CBT and other forms of therapy in the CF population, CF providers can adapt roles to implement new interventions in addressing mental health problems as part of CF care rather than referring patients to community providers who often are poorly positioned to meet their needs. The Stanford CF program will continue to use social work role to provide mental health servicesCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Impact of elexacaftor/tezacaftor/ivacaftor on Pseudomonas aeruginosa acquisition and chronic infection at a single pediatric cystic fibrosis center

Background: As cystic fibrosis (CF) lung disease progresses, the airways become colonized with opportunistic pathogens such as Pseudomonas aeruginosa secondary to airway surface liquid depletion. Acquisition of P. aeruginosa is associated with decline in lung function and increase in treatment burden and mortality. In October 2019, the Food and Drug Administration approved elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA), a highly effective modulator therapy (HEMT) for individuals aged 12 and older with one copy of the F508del CFTR mutation. ELX/TEZ/IVA increases the amount of and function of CF transmembrane conductance regulator (CFTR) in the respiratory epithelium, increasing mucociliary clearance (MCC) and reducing static airway mucous, a major trigger for chronic infection and inflammation. Method(s): A retrospective analysis of inhaled tobramycin (iTOB) prescriptions prescribed between January 1, 2016, and December 31, 2021, was performed. This captured data before and after ELX/TEZ/IVA approval at Children's Mercy Kansas City (CMKC). The number of individuals with new P. aeruginosa acquisition was determined by identifying electronic prescriptions for iTOB eradication courses. An eradication course was defined as a first lifetime prescription for iTOB or a new prescription for iTOB submitted at least 1 year after a previous prescription. The number of individuals considered chronically infected with P. aeruginosa was determined by identifying individuals receiving chronic iTOB prescriptions and confirmed by respiratory cultures indicating chronic infection based on the Leeds criteria (P. aeruginosa recovered in >=50% of airway cultures in the previous 12 months). Result(s): Eradication courseswere prescribed to 34 individuals in 2016 (15% of people receiving care at CMKC). The number of eradication prescriptions declined in 2020 and 2021, with only 15 (7%) individuals prescribed eradication therapy in 2020 and 12 (5%) in 2021. A similar pattern was observed for prescriptions for chronic infection. In 2016, 57 individuals (25% of our patient population) were receiving iTOB for chronic P. aeruginosa infection. Reductions were seen in 2020 and 2021, with 28 (13%) and 20 (9%) individuals prescribed chronic therapy, respectively. The number of individuals prescribed iTOB for P. aeruginosa eradication and chronic infection per year is represented in Figure 1.(Figure Presented)Conclusions: CMKC experienced a decrease in the number of courses of iTOB prescribed over the last 6 years. HEMT use is associated with greater MCC and anti-inflammatory effects affecting the airway microbiome. The decrease in respiratory cultures growing P. aeruginosa likely reflects these phenomena. A confounding factor is the SARS-CoV-2 pandemic and widespread use of HEMT. Clinic closures and implementation of telemedicine limited in-person patient visits during 2020 and 2021. Despite limited in-person visits, the average number of respiratory cultures per individual at CMKC in 2020 was 3.5, which is consistent with previous years.Wewere able to obtain frequent surveillance cultures through implementation of a drive-through respiratory specimen collection process. Hence, the decrease in number of iTOB courses cannot be attributed to a decrease in frequency of respiratory cultures, although we cannot assess the impact of school closures and a decrease in social gatherings on new P. aeruginosa acquisition or chronic infection. Looking at all these variables, the widespread use of HEMT likely played a significant role in reducing new P. aeruginosa acquisition and chronic P. aeruginosa infection.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Respiratory microbiological surveillance in people with cystic fibrosis-analysis of respiratory samples before and after elexacaftor/tezacaftor/ivacaftor in a large adult U.K. cystic fibrosis center

Background: Pathogen surveillance is crucial but has become more challenging in the era of highly effective modulator therapy (HEMT), with many people with cystic fibrosis (PwCF) noting a considerable reduction or even absence of sputum on elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). This challenge has been exacerbated by reduced face-toface contact with patients because of variable COVID-19 government restrictions on travel and social interaction (lockdowns) since March 20, relying on PwCF returning high-quality samples by mail. For those with pre-established bronchiectasis, it is likely that chronic infections and risk of new acquisition of infections remain on ELX/TEZ/IVA, although registry data suggest less prevalence of respiratory microorganisms on IVA [1]. We aimed to examine the impact of ELX/TEZ/IVA on frequency of respiratory pathogen surveillance and microorganism growth in our large, adult CF center. Method(s): A retrospective analysis of pathology results from respiratory samples received from March 19 to December 21, 2020, was completed for all patients commenced on ELX/TEZ/IVA at our CF center. Result(s): Respiratory samples from 216 PwCF who had commenced ELX/ TEZ/IVAwere analyzed. Median start date of ELX/TEZ/IVAwas October 10,2020. Before ELX/TEZ/IVA, the average number of respiratory samples per month was 108. This declined by 55% to an average of 48 per month when the first 50 PwCF commenced on ELX/TEZ/IVA and to 20 per month (82% reduction from pre-ELX/TEZ/IVA) when 100 PwCF had commenced ELX/ TEZ/IVA. The number of positive samples per month decreased from January 20, 2020, correlating with the introduction of ELX/TEZ/IVA and the reduction of respiratory samples received (Figure 1). The proportion of cough swabs and sputum samples remained similar from March 19 to December 21, 2020. (Six-month average showed that 19% of samples were cough swabs and 80% sputum for March to June 2019 and July to December 2021). We found no significant changes in proportion of samples positive for non-Pseudomonas spp. gram-negative organisms, Burkholderia spp., or gram-positive organisms (predominantly S. aureus) isolated over the period. There was a reduction by more than 50% of fungi and Candida spp. and a slight trend toward an increase in Pseudomonas spp. (mainly P. aeruginosa). Forty percent of PwCF who had one respiratory sample after ELX/TEZ/IVA initiation and 20% of those who had two or more samples showed a change in organism growth after ELX/TEZ/IVA initiation. In nearly 50% of these cases, the organism changed from gram negative to gram positive (P. aeruginosa to S. aureus in 69% of cases).(Figure Presented) Figure 1. Number of positive respiratory samples per month and number of people with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor March 19 to December 21, 2020 Conclusion(s): The introduction of ELX/TEZ/IVA and its impact on sputum production has reduced surveillance of our patients' respiratory microbiology. This has been exacerbated by reduced face-to-face contact with patients due to the COVID-19 pandemic. The trends showa reduction in the isolation of fungi and yeasts and a slight increase in isolating Pseudomonas spp. In those who we have seen a change in organism growth, many have gone from gram-negative to gram-positive organisms. These data highlight the challenges of monitoring for new positive cultures and changes in microbiology cultures in the era of HEMT.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Impact of elexacaftor/tezacaftor/ivacaftor on depression and anxiety in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is associated with worsening of depression and anxiety symptoms. Elexacaftor/tezacaftor/ivacaftor (Trikafta®), a cystic fibrosis transmembrane regulator (CFTR) modulator approved in 2019, significantly improves lung function, decreases pulmonary exacerbations, and improves quality of life. Studies are needed to evaluate the effects of Trikafta on symptoms of anxiety and depression. RESEARCH QUESTION: Do adults with CF report a change in depression and anxiety symptoms after Trikafta initiation? STUDY DESIGN AND METHODS: A retrospective chart review was conducted of patients with CF (n = 127) receiving care from January 2015 through February 2022. Data collected included demographics, annual PHQ-9 and GAD-7 scores, FEV1 percent predicted at each visit, BMI, consistency and timeline of Trikafta use, mental health diagnoses, counseling/psychotherapy use, psychiatric medication use, prescriber of psychiatric medications, number of psychiatric emergency department visits and psychiatric hospital admissions, and sleep disturbances. RESULTS: Of the 127 patients screened for eligibility, 100 patients were included. Data collected yielded 563 PHQ-9, 563 GAD-7, and 560 ppFEV1 data points. No significant changes in average PHQ-9 or GAD-7 scores were found after Trikafta initiation or due to the COVID-19 pandemic. However, 22% of patients initiated or had a change in psychiatric medications, and patients with changes in psychiatric medications had significantly higher PHQ-9 and GAD-7 scores than patients not prescribed psychiatric medications. Trikafta use improved lung function by an average of 5.23% (p = 8.56e-08). Around a quarter (23%) of all patients reported sleep issues after initiating Trikafta. INTERPRETATION: No significant changes in average PHQ-9 and GAD-7 scores were found after Trikafta initiation. A quarter of patients required a change in psychiatric medications, and significant differences in depression and anxiety scores were found between patients with a change in psychiatric medications and those not prescribed medication. Twenty-three percent of patients reported a prevalence of sleep issues after Trikafta initiation.

A survey assessing the impact of COVID-19 and elexacaftor/tezacaftor/ifavacaftor on both physical and mental health in adults with cystic fibrosis.

In this letter to the editor, we report 82 persons with CF (PwCF) self-reported changes in mental and physical health and potential attribution with either the COVID-19 pandemic and the initiation elexacaftor/tezacaftor/ivacaftor (ETI). Emerging evidence has shown an association with ETI and mental health adverse events. The close proximity of ETI FDA approval and prescribing in PwCF and the COVID-19 pandemic present a challenge in determining the cause of mental health decline. We report 33 (40%) of respondents felt that COVID-19 contributed to a worsening of either their anxiety, depression, or both and 7 (9%) of respondents felt that ETI contributed to a worsening in their anxiety, depression, or both. Eighteen (23%) of respondents felt that ETI had contributed to improvement their mental health. This letter highlights multiple factors that could be impacting mental health beyond ETI. As the COVID-19 pandemic is moving toward an endemic phase, future studies may have more success in deciphering ETI effects on mental health.

Suicide attempts in adolescents with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor therapy.

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.

The Impact of Elexacaftor/Ivacaftor/Tezacaftor on Cystic Fibrosis Patients Who Acquire COVID-19 Infection.

The combination of medication containing elexacaftor, ivacaftor, and tezacaftor (EIT) has dramatically impacted the treatment and prognosis for patients with cystic fibrosis (CF). Lung function, weight, and self-reported quality of life have improved for many of these patients, but little is known about whether this treatment will have a beneficial effect in preventing morbidity and/or mortality from respiratory infections such as COVID-19. EIT received Food and Drug Administration (FDA) approval shortly before the first cases of COVID-19 appeared in the United States. We performed an analysis using the TriNetX (Cambridge, MA, USA) research database to determine if patients being treated with EIT who became infected with COVID-19 experienced significantly different outcomes compared to patients who were not receiving it.

Physical fitness and habitual physical activity in children with cystic fibrosis - do they improve with elexacaftor/tezacaftor/ivacaftor therapy?

Objectives: The aim of this ongoing longitudinal study is to examine the effects of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) on aspects of physical fitness (PF, strength endurance, explosive power, coordination under time pressure, coordination for the precision aspect, trunk flexibility, peak workload, habitual physical activity (HPA, steps/day, intensity), and zscores of FEV1 and BMI in children with cystic fibrosis (CF)). All children have been receiving ELX/TEZ/IVA for 19.2 ± 10.4 (11–33) months. Methods: Six children with CF agreed to participate (3f/3 m) mean age 13 ± 4yrs (9–17 yrs), FEV1 z-score − 1.017 ± 1.817 (-3.2–0.8). PFwas assessed using 5 test items at baseline and 4.51 ± 0.98 years later;strength endurance (PU push-ups, SU sit-ups), explosive power (SLJ standing long jump), coordination under time pressure (JSS jumping side to side), coordination for the precision aspect (BB balancing backward on beams), and trunk flexibility (FB, forward bend). Cycle-ergometry (Godfrey-protocol) was used to determine Wpeak. Lung function was measured by spirometry. Results: Significant improvements were seen in test items representing strength endurance (PU, SU) and coordination under time pressure (JSS) (p < .05). Although HPA expressed as steps/day remained the same, thetime of moderate to vigorous intensity of HPA decreases significantly (p < .05). A slight, not significant, improvement of BMI Z-score was observed (p > .05). No or small changes could be observed for the parameter FEV1 z-score, Wpeak, PF, SLJ, BB and FB (p > 0.05). Conclusion: ELX/TEZ/IVA therapy seems to be a facilitator to increase some aspects of PF. The decrease in intensity of HPA is possibly an effect of the COVID-19 Pandemic that has already been described in healthy and asthmatic children. In this ongoing study, we assume that clearer effects will be shown with a greater number of children included. However, ELX/ TEZ/IVA enhanced muscle strength endurance in children with CF.

Exercise performance before and after introduction of elexacaftor/tezacaftor/ivacaftor (Kaftrio®) in Scottish children with cystic fibrosis: a 2-centre retrospective study

Objectives: Elexacaftor/tezacaftor/ivacaftor (ETI) combination therapy - Kaftrio® was approved for use in the UK in August 2020 for those aged >12 years. Our study aimed to study the effects of ETI therapy on lung function and exercise performance. Methods: Two-centre retrospective analysis of clinical data obtained during patients’ annual review assessments. Patients had undergone spirometry and static lung volume measurements followed by an incremental maximal ramp cardiopulmonary exercise testing (CPET) performed on a cycle ergometer. Data were analysed using a paired sample t-test. Results: Lung function improvement did not reach statistical significance. Of note, four patients had a baseline (pre-ETI) FEV1 belowthe lower limit of normal (LLN <-1.64 Z scores), and one improved their FEV1 from 41% predicted to 87% with Kaftrio®. Five had a VO2peak% predicted below the LLN (< 85% predicted) prior to treatment and 8 post treatment. Therewas a significant fall in VO2peak % predicted, p = 0.03. However, this was not seen in the VO2peak relative to bodyweight, p = 0.07. There was also a significant fall in VO2 at anaerobic threshold (AT) as a % of predicted VO2peak, p = 0.01. Table 1. (Table Presented) (Table Presented) Conclusions: This real-world study suggests Kaftrio® does not improve exercise capacity in the majority of CF patients. It is hypothesised that the lack of improvement may be due to a reduced physical activity over the study period as a result of feeling better on Kaftrio® and also the SARSCoV2 pandemic. The decrease in VO2 at AT would support the hypothesis of physical deconditioning. The reasons for not seeing statistical differences in lung function are likely to represent the relatively high baseline FEV1 alongside small study numbers. In summary, whilst having the potential to be a performance-enhancing drug, performance gains on Kaftrio® can only occur if matched by training, and studies to investigate the training potential of Kaftrio® are required.

Does changing from lumacaftor/ivacaftor (Orkambi) to tezacaftor/ivacaftor + ivacaftor (Symkevi + ivacaftor) offer any clinical benefits in children with cystic fibrosis (CF)?

From September 2020 until January 2022, children with CF in the UK aged 6–12 years homozygous for F508del had a choice of CFTR modulators: Lumacaftor/ivacaftor(LUM/IVA) or tezacaftor/ivacaftor (TEZ/IVA)+ ivacaftor (IVA). Although benefit of the individual agents has been demonstrated in clinical trials, there is no direct comparison between treatments.1 Objectives: Review of Forced Expiratory Volume in 1 second (FEV1) and nutritional clinical benefits of switching from LUM/IVA to TEZ/IVA + IVA. Method: A retrospective review of 18 paediatric patients (pts) swapped from LUM/IVA to TEZ/IVA + IVA. Data collected of length of time on each CFTR modulator, body mass index (BMI) centile, FEV1 (% predicted and zscore). FEV1 data analysed using ANOVA test. Results: 12 female;6 male pts (Mean age 9 yrs 6mths (range 8–12 years)). Two pts swapped from LUM/IVA due to tolerability issues. The other families chose to swap. Mean length of time was 13 mths (±1.3) on LUM/IVA and 9mths ± 1.2 on TEZ/IVA + IVA. Spirometry;table 1 (Table Presented) Conclusion: Swapping CFTR modulators for most pts offered no clear improvement in FEV1 or BMI, the surrogate markers of lung and nutritional health. However, pts did not experience the usual decline in FEV1 seen in CF. There are many potential confounding factors that need to be considered, including that data was collected during the COVID pandemic. As new modulators are developed, further research will be required to better understand their mechanism of action in individual pts to guide optimal personalised prescribing. 1 Walker S., et al., A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 through 11years with cystic fibrosis, J CYST FIBROS;June 2019;18(708–713).

Impact of Trikafta on PHQ-9 and GAD-7 scores

As new therapies emerge for cystic fibrosis (CF), it is important to understand their psychiatric implications. Studies have shown cystic fibrosis transmembrane conductance regulator (CFTR) modulators to be associated with worsening of depression and anxiety symptoms. Trikafta® (elexacaftor/tezacaftor/ivacaftor) is a newly-approved CFTR modulator that significantly improves lung function, decreases pulmonary exacerbations, and improves the quality of life. Further studies are needed to evaluate the effects of Trikafta® on anxiety and depression. Objectives: To evaluate the effects of Trikafta® on PHQ-9 (depression screening questionnaire) and GAD-7 (anxiety screening questionnaire), scores in adult patients with CF seen at an academic health centre in the Southeastern United States. Methods:We conducted a retrospective chart review of 127 adult patients with CF who initiated Trikafta® between (11/2019 to 08/2021). We gathered data, including demographic information (age, sex, race, CF mutation), annual PHQ-9 and GAD-7 scores, corresponding FEV1 percent predicted, BMI, mental health diagnoses, counseling/psychotherapy use, psychiatric medication use, prescriber of those medications, number of psychiatric emergency department visits and psychiatric admissions, and sleep disturbances. We then ran linear mixed models examining the effect of Trikafta® on PHQ- 9 and GAD-7 scores after controlling for timing with respect to the COVID- 19 pandemic. Results: Of the 127 adult patient charts reviewed,100were included. These patients yielded 562 PHQ-9 and 562 GAD-7 scores taken from 01/2015–01/ 2022. No change in PHQ-9 scores was found after initiating Trikafta® or after the beginning of COVID (designated as March 15, 2020). Similarly, GAD-7 scores showed no significant change after Trikafta® or COVID. Table 1. Patient demographics: N = 100 (Table Presented) Conclusion: There is no significant change in PHQ-9 and GAD-7 scores of patients with CF after initiating Trikafta®

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study.

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. METHODS: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. RESULTS: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. CONCLUSIONS: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.