2C5-surface modified nanocarriers targeting neutrophil extracellular traps

Background: Neutrophil extracellular traps (NETs) are composed of processed chromatin bound to granular and selected cytoplasmic proteins and released by neutrophils. NETs consist of smooth filaments composed of stacked nucleosomes. Fully hydrated NETs have a cloud-like appearance and occupy a space 10-15-fold larger than the volume of the cells they originate from. DNases are the enzymes that cleave extracellular DNA including NETs. Together with their protective role in microbial infections, NETs are involved in multiple pathological processes and represent key events in a variety of pathologies including cancer, autoimmunity, and cardiovascular disease. Sites of NETs concentration are dangerous for the host if the process of NETs formation becomes chronic or the mechanism of NETs removal does not work. NETosis has been linked to the development of periodontitis, cystic fibrosis, type 2 diabetes, COVID-19 or rheumatoid arthritis as well as cancer progression. Purpose(s): Thus, the destruction of NETs is of primary significance in many pathologies. In our approach, we are focusing on mimicking one of the natural mechanisms of destroying excessive NETs by delivering deoxyribonuclease I to the specific site of pathological NETs accumulation by modifying the nanoparticles using an anti-nucleosome monoclonal antibody (2C5). The antibody is specific to nucleosomes and can recognize histones in NETs. DNase I is U.S. Food and Drug Administration (FDA)-approved active component and is commonly used in therapeutic methods of modern medicine for cystic fibrosis to clear extracellular DNA fibers in the lungs and systemic lupus erythematosus. Recent findings have also shown the effectiveness of DNase I in the digestion of NETs. However, the low serum stability and fast deactivation by environmental stimuli have been considered as the limiting factors for clinical applications of DNase I, which can be overcome by its targeted specific delivery in pharmaceutical nanocarriers. Method(s): In this study, we generate NETs in vitro using human neutrophils and HL-60 cells differentiated into granulocyte-like cells. We used interleukin-8, lipopolysaccharide from E.Coli (LPS), phorbol myristate acetate (PMA), and calcium ionophore A23187 (CI) to generate the NETs. We confirmed the specificity of 2C5 toward NETs by ELISA, which showed that it binds to NETs with the specificity like that for purified nucleohistone substrate. We further utilized that feature to create two delivery systems (liposomes and micelles) for DNAse I enzyme to destroy NETs, which was confirmed by staining NETs with SYTOX Green dye and followed by flow cytometric measurements and microscopic images. Conclusion(s): Our results suggest that 2C5 could be used to identify and visualize NETs and serve as a ligand for NET-targeted diagnostics and therapies. Also, we proved that our carrier can successfully deliver DNase to NETs to provide their degradation.

COVID-19 pandemic in the Belgian cystic fibrosis patients compared with the international cystic fibrosis patients and the general Belgian population

Objectives The study compared the impact of the COVID pandemic on the Belgian people with Cystic Fibrosis (pwCF) with the international pwCF and the general Belgian population. Methods pwCF followed in a Belgian CF center were eligible. Their demographic and clinical outcome data was compared with the international pwCF (Carr et al, JCF 2022) and with the general Belgian population (epistat.sciensano.be/covid). CF registry annual data collections for 2020 and 2021 included if a test was performed for SARS-CoV-2 (by any specific method), and the respective result. Details on COVID symptoms and treatment were collected separately in a form from Global CF. Results Among the 1392 pwCF seen in 2020 and/or 2021, over half of the pwCF were tested for SARS CoV-2 (51% in 2020, 59% in 2021), similar for pwCF with or without a transplant (57% vs 54%). With similar positivity rate with or without transplant (13%), 179 pwCF had a positive result either in 2020 (50) or 2021 (141). This positivity rate was higher than in the general Belgian population (8.6%). Compared to the international pwCF, Belgian pwCF presented with more risk factors (transplant, age). Details and outcome are showed in tables below. Conclusion Belgian pwCF infected by SARS-CoV-2 tended to be less hospitalized but have more deaths than the international pwCF, in line with a higher transplant rate. While pwCF were on average younger, hospitalization was more frequent than for the general Belgian population, but death only if transplanted. [Formula presented]Copyright © 2023 European Cystic Fibrosis Society

Gain and loss of function CFTR alleles modulate COVID-19 clinical outcome

Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.

Discussed Poster Abstracts – PM1

B PM1-030 b B Adverse drug reaction profile of drug interactions involving a protein kinase inhibitor indicated in chronic myeloid leukemia from pharmacovigilance databases b M. C. Pajiep, M. Lapeyre-Mestre and F. Despas I Centre Hospitalier Universitaire (CHU) de Toulouse, France i B Introduction: b The introduction of protein kinase inhibitors (PKIs) for chronic myeloid leukemia (CML) has considerably improved prognosis of the disease but has also demonstrated a great potential for drug-drug interactions. Service de Médecine Interne et Infectiologie, Groupe Hospitalier Diaconesses-Croix Saint-Simon, Paris, France i B Introduction: b Despite an important drug-drug interaction, it was previously suggested the clindamycin-rifampicin combination could be used in patients with bone and joints infections (BJIs) provided clindamycin is administered by continuous infusion. Most of eligible patients to the antiviral drug can benefit from it despite the risk of drug-drug interaction. Twenty patients received clindamycin without rifampicin, 19 patients received clindamycin concomitantly with rifampicin and the remaining 85 received clindamycin successively without and with rifampicin. B Results: b Among 957 patients treated with anti-PD-1/PD-L1 during the data collection period, 686 patients were included: 430 new users of a SD regimen, 161 patients who started with SD and switched to ED regimen during follow-up, and 95 new users of an ED regimen. [Extracted from the article] Copyright of Fundamental & Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Clinical outcomes of adults and children with cystic fibrosis during the COVID-19 pandemic.

BACKGROUND: The onset of the COVID-19 pandemic was associated with restricted community movement and limited access to healthcare facilities, resulting in changed clinical service delivery to people with cystic fibrosis (CF). This study aimed to determine clinical outcomes of Australian adults and children with CF in the 12-months following the onset of the COVID-19 pandemic. METHODS: This longitudinal cohort study used national registry data. Primary outcomes were 12-month change in percent predicted forced expiratory volume in one second (FEV1 %pred), body mass index (BMI) in adults and BMI z-scores in children. A piecewise linear mixed-effects model was used to determine trends in outcomes before and after pandemic onset. RESULTS: Data were available for 3662 individuals (median age 19.6 years, range 0-82). When trends in outcomes before and after pandemic onset were compared; FEV1 %pred went from a mean annual decline of -0.13% (95%CI -0.36 to 0.11) to a mean improvement of 1.76% (95%CI 1.46-2.05). Annual trend in BMI improved from 0.03 kg/m2 (95%CI -0.02-0.08) to 0.30 kg/m2 (95%CI 0.25-0.45) and BMI z-scores improved from 0.05 (95%CI 0.03-0.07) to 0.12 (95%CI 0.09-0.14). Number of hospitalisations decreased from a total of 2656 to 1957 (p < 0.01). Virtual consultations increased from 8% to 47% and average number of consultations per patient increased from median (IQR) of 4(2-5) to 5(3-6) (p < 0.01). CONCLUSION: In the 12-months following the onset of the COVID-19 pandemic, there was an improvement in the clinical outcomes of people with CF when compared to the pre-pandemic period.

The Role of the Physical Therapist in Cystic Fibrosis Care.

In looking back on 2020 and 2021, this Perspective reflects on the monumental impacts of the rollout of cystic fibrosis (CF) transmembrane conductance regulator highly effective modulator therapies and the COVID-19 pandemic on the management of CF. Advancements in the clinical management of people with CF have been both enormous and rapid, and physical therapists specializing in the care of people with CF have been at the forefront of driving this evolution in care. This year sees the thirtieth anniversary of the UK Association of Chartered Physiotherapists in Cystic Fibrosis and, as is inevitable in reaching such milestones, thoughts have turned to origins, role, impacts, and the future. With the changing demographics of the population of people with CF after the introduction of highly effective modulator therapies, potentially with fewer secondary complications, the future role of the physical therapist who specializes in CF is in question. This Perspective reflects upon and highlights the role of physical therapy within CF and provides insights into how physical therapists and respiratory therapists can evolve their roles to ensure relevance for the future.

Seroprevalence and clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) have chronic lung disease and may be at increased risk of coronavirus disease 2019 (COVID-19)-related morbidity and mortality. This study aimed to determine seroprevalence and clinical characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children with cystic fibrosis (CF), and to assess antibody responses following SARS-CoV-2 infection or vaccination. METHODS: Children and adolescents with CF followed at Seattle Children's Hospital were enrolled between July 20, 2020 and February 28, 2021. SARS-CoV-2 serostatus was determined on enrollment at 6 and 11 months (±2 months) for nucleocapsid and spike IgG. Participants completed intake and weekly surveys inquiring about SARS-CoV-2 exposures, viral/respiratory illnesses, and symptoms. RESULTS: Of 125 PwCF enrolled, 14 (11%) had positive SARS-CoV-2 antibodies consistent with recent or past infection. Seropositive participants were more likely to identify as Hispanic (29% vs. 8%, p = 0.04) and have pulmonary exacerbations requiring oral antibiotics in the year prior (71% vs. 41%, p = 0.04). Five seropositive individuals (35.7%) were asymptomatic, while six (42.9%) reported mild symptoms, primarily cough and nasal congestion. Antispike protein IgG levels were approximately 10-fold higher in participants following vaccination compared with participants who had natural infection alone (p < 0.0001) and resembled levels previously reported in the general population. CONCLUSIONS: A majority of PwCF have mild or no symptoms of SARS-CoV-2 making it difficult to distinguish from baseline respiratory symptoms. Hispanic PwCF may be disproportionately impacted, consistent with racial and ethnic COVID-19 disparities among the general US population. Vaccination in PwCF generated antibody responses similar to those previously reported in the general population.

Crosslink between SARS-CoV-2 replication and cystic fibrosis hallmarks.

SARS-CoV-2, the etiological cause of the COVID-19 pandemic, can cause severe illness in certain at-risk populations, including people with cystic fibrosis (pwCF). Nevertheless, several studies indicated that pwCF do not have higher risks of SARS-CoV-2 infection nor do they demonstrate worse clinical outcomes than those of the general population. Recent in vitro studies indicate cellular and molecular processes to be significant drivers in pwCF lower infection rates and milder symptoms than expected in cases of SARS-CoV-2 infection. These range from cytokine releases to biochemical alterations leading to morphological rearrangements inside the cells associated with CFTR impairment. Based on available data, the reported low incidence of SARS-CoV-2 infection among pwCF is likely a result of several variables linked to CFTR dysfunction, such as thick mucus, IL-6 reduction, altered ACE2 and TMPRSS2 processing and/or functioning, defective anions exchange, and autophagosome formation. An extensive analysis of the relation between SARS-CoV-2 infection and pwCF is essential to elucidate the mechanisms involved in this lower-than-expected infection impact and to possibly suggest potential new antiviral strategies.

Humoral and cell-mediated immune responses to BNT162b2 vaccine against SARS-CoV-2 in people with cystic fibrosis.

People with cystic fibrosis (pwCF) were considered to be clinically vulnerable to COVID-19 and were therefore given priority in the vaccination campaign. Vaccines induced a humoral response in these patients that was comparable to the response observed among the general population. However, the role of the cell-mediated immune response in providing long-term protection against SARS-CoV-2 in pwCF has not yet been defined. In this study, humoral (antibody titre) and cell-mediated immune responses (interferon-γ release) to the BNT162b2 vaccine were measured at different time points, from around 6-8 months after the 2nd dose and up to 8 months after the 3rd dose, in 118 CF patients and 26 non-CF subjects. Subjects were sampled between November 2021 and September 2022 and followed-up for breakthrough infection through October 2022. pwCF mounted a cell-mediated response that was similar to that observed in non-CF subjects. Low antibody titres (<1st quartile) were associated with a higher risk of breakthrough infection (HR: 2.39, 95 % CI: 1.17-4.88), while there was no significant association with low INF-γ levels (<0.3 IU/mL) (HR: 1.38, 95 % CI: 0.64-2.99). Further studies are needed in subgroup of pwCF receiving immunosuppressive therapy, such as organ transplant recipients. This data is important for tailoring vaccination strategies for this clinically vulnerable population.

Telehealth in Cystic Fibrosis. A systematic review incorporating a novel scoring system and expert weighting to identify a 'top 10 manuscripts' to inform future best practices implementation.

The ongoing development and integration of telehealth within CF care has been accelerated in response to the Covid-19 pandemic, with many centres publishing their experiences. Now, as the restrictions of the pandemic ease, the use of telehealth appears to be waning, with many centres returning to routine traditional face-to-face services. For most, telehealth is not integrated into clinical care models, and there is a lack of guidance on how to integrate such a service into clinical care. The aims of this systematic review were to first identify manuscripts which may inform best CF telehealth practices, and second, to analyse these finding to determine how the CF community may use telehealth to improve care for patients, families, and Multidisciplinary Teams into the future. To achieve this, the PRISMA review methodology was utilised, in combination with a modified novel scoring system that consolidates expert weighting from key CF stakeholders, allowing for the manuscripts to be placed in a hierarchy in accordance with their scientific robustness. From the 39 found manuscripts, the top ten are presented and further analysed. The top ten manuscripts are exemplars of where telehealth is used effectively within CF care at this time, and demonstrate specific use cases of its potential best practices. However, there is a lack of guidance for implementation and clinical decision making, which remains an area for improvement. Thus, it is suggested that further work explores and provides guidance for standardised implementation into CF clinical practice.

Pilot of a therapist-guided digital mental health intervention (eHealth CF-CBT) for adults with cystic fibrosis.

BACKGROUND: eHealth CF-CBT is the first digital mental health intervention for depression/anxiety in adults with cystic fibrosis (awCF); an 8-session therapist-guided internet-delivered program that was developed in English and Dutch with stakeholder input and evaluation indicating high acceptability and usability. METHODS: Dutch eHealth CF-CBT was piloted in awCF with mild-moderate symptoms of depression and/or anxiety. Feasibility, usability, acceptability, and preliminary efficacy were assessed, measuring pre-post changes in depression (PHQ-9), anxiety (GAD-7), perceived stress (PSS), and health-related quality of life (CFQ-R). RESULTS: All participants (n = 10, seven female, mean age 29 [range 21-43], mean FEV1 71%pred [range 31-115]) completed all sessions. Patient-rated feasibility, usability, and acceptability of eHealth CF-CBT were positive on validated scales, as were qualitative assessments of content and format. GAD-7 improved in 90% of participants; in 50% by ≥the minimally important difference (MID) of four points. PHQ-9 improved in 90%; 40% by ≥the MID of 5. PSS improved in 80%. CFQ-R improved in the domain health perceptions (70%). CONCLUSIONS: eHealth CF-CBT demonstrated feasibility, usability, acceptability, and promising preliminary efficacy in this pilot trial with Dutch awCF with mild to moderate symptoms of depression and anxiety.

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

Increase in weight-for-age and vegetable intake in young children with cystic fibrosis treated with lumacaftor/ivacaftor for 24 weeks

Background: Modulator therapy has improved nutritional status in individuals with cystic fibrosis (CF), which is associated with favorable outcomes. Because of the high metabolic demands of CF, nutritional recommendations include energy intake of 110% to 200% of daily estimated needs for healthy individuals. With changes in energy balance after initiation of modulator therapy, these recommendations may no longer be appropriate for some people with CFand may lead to excessiveweight gain. Overweight and obesity are being reported, and nutrition concerns now include dietary quality. Dietary quality in relation to growth in young children starting lumacaftor/ivacaftor therapy has not been examined over a 24-week period and may provide new data for future nutrition guidance for individuals with CF. Method(s): The purpose of this observational study was to determine the effect of lumacaftor/ivacaftor treatment on growth and diet in medicationnaive children. Subjects aged 2 to 5 with D508/D508 mutations were recruited from the United States and Canada. Length/height, weight, and body mass index (BMI) were measured in triplicate and averaged. Z-scores were calculated using Centers for Disease Control and Prevention reference data. Dietary data were captured using 3-day weighted food records after study visits. The Healthy Eating Index (HEI) was generated using the U.S. Department of Agriculture scoring system for each recorded day and averaged. Outcomes were assessed before treatment (baseline) and 12 and 24 weeks after beginning medication. Mixed longitudinal models were used for analysis over time. Result(s): Participants (mean age 2.9 +/- 1.4, 50% female) who completed food records for at least their baseline visit plus one other visit (n = 14) had significant increases inweight-for-age z-score (WAZ) 12 (0.6 +/- 1.7, p = 0.02) and 24 (0.21 +/- 1.8, p = 0.001) weeks after therapy. There was no significant change in height-for-age (HAZ), BMI-for-age (BMIZ), or head circumference- for-age (HCZ) z-score at 12 or 24 weeks. Although not statistically significant, percentage estimated energy requirement (%EER) decreased at 12 (-7 +/- 90%, p = 0.54) and 24 (-27 +/- 90%, p = 0.08) weeks. HEI total score did not change over the 24 weeks, although vegetables and greens and beans HEI subgroup scores decreased significantly from baseline to 24 weeks (-0.73 +/- 2.2, p = 0.02;-0.68 +/- 2.1, p = 0.02, respectively). Pooled visit correlation between total vegetables and WAZ indicated a positive association (r = 0.35, p = 0.04). Conclusion(s): WAZ increased significantly over 24 weeks of lumacaftor/ ivacaftor therapy and was positively correlated with total vegetable intake, suggesting that participants with greater WAZ scores consumed more vegetables, although over the course of the study, total vegetable intake and intake of greens and beans decreased, and WAZ increased. %EER decreased over the course of the study, but not statistically significantly so, probably because of variability in energy intake within this small study sample with some COVID-19 interruptions. In summary, WAZ of children aged 2 to 5 with D508/D508 mutations increased, with no significant changes in HAZ, BMIZ, or HCZ, and they consumed fewer total vegetables and greens and beans after 24 weeks of lumacaftor/ivacaftor therapy. Acknowledgements: Supported by Vertex Pharmaceutics Inc. and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001878.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Use of daily home spirometry to predict clinical outcomes in persons with cystic fibrosis

Background: Use of home spirometry to monitor lung function has been increasing in popularity in persons with cystic fibrosis (PwCF) since the start of the COVID-19 pandemic. Although clinic spirometry is interpreted from validated standards, expected test-to-test variation of home spirometry and how variation during baseline health may relate to clinical changes are unknown. The aim of this study was to determine variation in baseline lung function during daily home spirometry and identify associations with clinical outcomes. Method(s): Subjectswere selected based on available spirometry data from a cohort of PwCF enrolled in a long-term airway microbiome study. Subjects were provided with a PiKo-6 hand-held spirometer (nSpire Health, Inc., Longmont, CO) and asked to perform spirometry maneuvers three times per. Validity of home spirometry (percentage predicted forced expiratory volume in 11 second (FEV1pp)) was compared with that clinic spirometry using Bland-Altman plots. Spirometry acceptability across multiple maneuvers in the same day was assessed using the American Thoracic Society (ATS) guidelines, with grade A or B (two or more maneuvers within 150 mL) considered acceptable. Variation in FEV1pp was assessed by calculating a mean FEV1pp and coefficient of variation (CoV). The association between CoV and pulmonary exacerbations (PEx) was tested using Cox proportional hazards regression models. Result(s): Thirteen subjects (62% female) with a mean age of 28.7 +/- 8.3 and mean FEV1pp of 59.9 +/- 8.2%were included. Median study durationwas 377 days (range, 33-730 days). Subjects used the home spirometer on average 51.2% of the study days (range 15-97%). On average, 58.9% of subjects (range 12-100%) used the home spirometer at least twice aweek, and 76.8% (range 65-100%) at least once aweek. To focus on periods of baseline health, days associated with PEx (spirometry performed 2 weeks before and during times of antibiotic therapy) were excluded. A median of 204 days (range 11-728 days) of baseline spirometry readings was available for further analysis. Comparing validity of home spirometry with that of clinic spirometry, Bland-Altman plots demonstrated overall good agreement with a slight bias (+0.042 L) toward higher readings for clinic FEV1pp (95% limits of agreement, -0.11-0.19 L). Spirometry quality was graded as acceptable on most study days (mean 90.6 +/- 4.6%) in which two or more maneuvers were recorded. Intra-individual variation in baseline FEV1pp was high, with a mean variation of 17.6 +/- 5.9% day to day and 15.2 +/- 6.2% week to week. Neither rates of acceptable spirometry grades nor CoV was associated with lung disease severity. Of the 13 subjects, 10 experienced one or more PEx, for a total of 32 PEx during the study. CoV was not associated with time to first PEx (hazard ratio [HR], 0.78;95% confidence interval [CI], 0.51-1.21;p = 0.24) or time to subsequent PEx (HR, 0.91;95% CI, 0.73-1.12;p = 0.28) during the study. Conclusion(s): Although home spirometry has generally good validity and acceptability, variation in lung function during baseline health is present and often exceeds expected variation in clinic spirometry per ATS standards. Variability may represent normal physiological variation or be related to the home spirometer itself or other factors but did not portend upcoming PEx. Recognition of variation during baseline health provides important context for interpretation of home spirometry.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Attitudes amidst the pandemic: Virtual delivery of care in an adult cystic fibrosis population

Background: The COVID-19 pandemic has altered how we deliver care to people with cystic fibrosis (CF) across the spectrum of disease severity. Because of lockdowns and avoiding exposure to COVID-19 by limiting inperson clinic visits, clinical care has pivoted from standard practices to virtual care in combination with in-person traditional visits. This approach has allowed patients to be monitored and treated in a timely manner. Such virtual visits have the advantage of reducing the time commitment for clinic visits because the patient does not have to travel to and from the hospital, but virtual care lacks the ability to conduct a physical examination and to obtain objective and standardized testing of key measurements known to be associated with health outcomes in CF. The objective of this study was to evaluate the attitude of patients to virtual delivery of care and their comfort level with such care. Method(s): This is a prospective, cross-sectional survey of adults with CF who are followed at St. Michael's Adult CF Center in Toronto, Canada. An online survey was created using SurveyMonkey to assess attitudes toward and satisfaction with virtual care. The survey was emailed to participants and included the Canadian CF Registry ID;a reminder email sent a week later. Baseline demographic and clinical data were obtained from the Canadian CF Registry and presented as median (range) or proportions as appropriate. Questions using a 3-point Likert scale will be categorized into agree, neutral, and disagree. Result(s): A total of 210 participants (53.0% female) completed the survey (median age 37.8, range 19.2-78.9). Median age of diagnosis was 2.2, 95.7% were Caucasian, 76.0% had completed post-secondary education, 63.0% were employed and 11.0% were students, 75% were pancreatic insufficient, 39.0% had CF-related diabetes, and 12.4% were post lung-transplant. Median percentage predicted forced expiratory volume in 1 second was 65.8% (range 17.9-126.9%), and median body mass index was 23.6 kg/m2 (range 15.5-45.7 kg/m2). Eighty-one percent of respondents had had a virtual visit before completing the survey. Sixty percent of respondents felt that in-person visits were the preferred way of completing a medical assessment, and 27.0% preferred virtual visits. Seventy-three percent felt it was important for the virtual visit to occur at the booked time, 59.0% had concerns that their lung function was not assessed during virtual visits, 46.0% felt they were losing the benefits of allied health team assessments with virtual visits, and 40.0% worried that their health would decline if primarily seen virtually. Just over half of respondents wanted to continue with virtual visits in some capacity after the pandemic. The optimal proportion of in-person visits was felt to be 50.0%. More than 85% of respondents were comfortable with technology (phone or computer) and had reliable access to the Internet to conduct virtual visits. Seventy percent of people would like to have access to a home spirometer, but cost was a barrier. Conclusion(s): From the patient's perspective, in-person visits were still the preferred way to complete a medical assessment, which seemed to be driven by concerns over lack of methods for assessment, particularly lung function, and access to the multidisciplinary team. Home spirometers, if freely available, might increase comfort with virtual appointments.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Cystic Fibrosis Learning Network Learning Structure for Multicenter Spread of Co-Production and Timely Patient Registry Data Entry Practices

Background: The Cystic Fibrosis Learning Network (CFLN) is a group of 34 programs that work and learn together with shared measures and processes to improve patient outcomes. Interventions are organized into change packages (collected, actionable concepts to share tested, refined ideas across multiple care centers). Since 2016, these change packages have helped advance team level co-production and improve timely data entry (TDE) and quality and use of Cystic Fibrosis Foundation Patient Registry (CFFPR) data. In the context of the COVID-19 pandemic, in-person meetings were curtailed, and team membership changed often. New learning structures to promote peer-to-peer learning were needed to spread and sustain these interventions. The objective was to describe the shared multicenter learning method used to spread practices in two series: co-production (recruitment and onboarding of patient and family partners (PFPs)) and TDE entry into the CFFPR. Method(s): In the design phase of the learning structure, we developed objectives specific to each series. Community content experts refined the curriculum from the established change package concepts. Teams were recruited through an open invitation to all CFLN sites. and met virtually biweekly for 30-minute sessions for 10 to 12 weeks. CFLN content experts used the change packages to coach teams and share their experiences during learning structure huddles. These sessionswere followed by 2-week action periods to review and test change package ideas. Teams shared progress at each meeting in round-robin format. Progress toward smart aims, team experience, and participation were assessed using descriptive surveys before, during, at the end of the series, and 6 months after it closed. Result(s): In initial surveys, teams self-reported awide range of experiences with co-production and TDE into the CFFPR. Participating teamswere from pediatric and adult programs that varied in number of patients and geographic location. Four teams participated in the co-production series to recruit and onboard PFPs within 6 months of completion. In the 6-month follow-up survey, two of the four teams met their goal of recruiting and onboarding a new PFP. The remaining teams reported barriers related to institutional policies that limited training for volunteers. In the TDE series, five teams joined and aimed to improve TDE into the CFFPR within 8 months. All five teams are on target to meet this goal. For both series, action-period surveys revealed completion of tasks assigned (e.g., reviewof change package concepts, testing tools, process maps, barriers, facilitators). Feedback surveys collected during the final sessions of each series indicated that the learning structure helped teams meet expectations, learn something new, and increase confidence in the interventions. Conclusion(s): This learning structure for spreading standard interventions helped teams meet series' aims. The small-group structure allowed teams to learn and adapt coproduction and timely data change package ideas and sustain practices for at least 6 months. In future iterations, this learning structure could be used as a model to spread standard interventions to other programs in the CFLN and the larger care center network.Copyright © 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

Cystic fibrosis legal information hotline: A reliable resource for the cystic fibrosis community during the pandemic and beyond

Background: The Cystic Fibrosis Legal Information Hotline (CFLIH) provides information on legal issues affecting people with cystic fibrosis (CF). Since 1998, it has provided the CF community with confidential information on health insurance, Social Security, employment, and education. Method(s): The CFLIH tracks each call according to the age of the person with CF, the caller's relationship to the person with CF, and the subject matter of the call. Result(s): The CFLIH received 10 870 calls in 2021;63% were related to a person with CF aged 18 and older and 37% to a child younger than 18;55% were from a person with CF, 7% more than in 2020;and 22% of calls came from CF centers. Of the 2444 calls from CF centers, 95% were from nonphysician staff and 5% from physicians. Twenty-two percent were from a parent of a person with CF, and 1% of callers were the spouse or someone with another relationship to the person with CF. Fifty-seven percent of calls were related to Social Security benefits, 9% more than in 2020. These calls were evenly divided between Supplemental Security Income and Social Security Disability Insurance. Sixteen percent of calls were related to benefits and coverage under a private or public health benefit plan: 34% of these related to private health benefit plans and 66% related to public health benefit plans. Of the public benefit plans, 53% related to Medicare and 47% to Medicaid. Nine percent of calls were related to CF in primary, secondary, and higher education, 22% more than in 2020, and 18% were related to employment. Conclusion(s): Total calls in 2021 stabilized after a record high of 13 405 in 2020. The surge in calls that began in 2020 was driven by problems caused by the COVID-19 pandemic and continued into 2021. Calls in 2021 exceeded pre-pandemic levels. In 2021, calls related to Social Security were 9% higher than in 2020. The increase in Social Security calls is attributed to persons with CF becoming unable to work because of the progression of CF symptoms, many of whom are not eligible for CF transmembrane conductance regulator (CFTR) modulator therapy. Calls also increased from those whose health had improved with CFTR modulator therapy who sought information about maintaining Social Security or health insurance while returning to work. The increase in Social Security calls is also attributed to an increase in the number of Social Security beneficiaries undergoing reviews of their disability status by the Social Security Administration. Employment calls continued to be higher than pre-pandemic levels. Remote work during the pandemic tended to help workers with CF maintain employment. Return to in-person work raised concerns about workplace safety, reasonable accommodations, and other workplace issues. Loss of employment with reasonable accommodations for CF was a common experience. The CFLIH increased health equity by helping maintain health coverage for vulnerable members of the CF community, which avoids disruptions in coverage and care. During the global COVID-19 pandemic, the CFLIH continues to be a reliable source of information in obtaining Social Security benefits, health insurance, employment, and safe access to educationCopyright © 2022, European Cystic Fibrosis Society. All rights reserved

Feasibility of telehealth spirometry for people with cystic fibrosis

Background: Telemedicine has flourished during the COVID-19 pandemic. There is increasing interest in performing spirometry at home as part of a telehealth program, especially in cystic fibrosis (CF), to follow the course of the disease, but it is unclear whether the quality and accuracy of home spirometry are comparable with those of in-clinic spirometry [1-3]. This study aimed to evaluate the feasibility and measurement quality of telehealth spirometry assessments for people with CF. Method(s): Patientswith acceptable hardware at homewere provided with a flow sensor portable spirometer (Spirobank Smart) compatible with ATS/ ERS 2019 standards for volume accuracy. They performed spirometry during "home admissions" or ongoing home monitoring for 1 year during the COVID-19 pandemic (January 2021 to January 2022). At the end of each session, the family forwarded the data to the CF center. Result(s): Twenty-nine people were evaluated (median age 17.4, range 6.7- 34;58% female;mean baseline percentage predicted forced expiratory volume in 1 second 79.8 +/- 21.4%). According to American Thoracic Society/ European Respiratory Society criteria, spirometry was performed successfully in 320 of 430 (74.5%) attempted sessions. The median distance between the subject's home and the hospital was 124 km (range 49- 418 km)-a median travel time saving of 1.5 hours per hospital visit. Conclusion(s): Home-based telehealth spirometry is feasible in people with CF and can support the CF team in ongoing outpatient monitoring.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved