Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

Using Negative Control Outcomes and Difference-in-Differences Analysis to Estimate Treatment Effects in an Entirely Treated Cohort: The Effect of Ivacaftor in Cystic Fibrosis.

When an entire cohort of patients receives a treatment, it is difficult to estimate the treatment effect in the treated because there are no directly comparable untreated patients. Attempts can be made to find a suitable control group (e.g., historical controls), but underlying differences between the treated and untreated can result in bias. Here we show how negative control outcomes combined with difference-in-differences analysis can be used to assess bias in treatment effect estimates and obtain unbiased estimates under certain assumptions. Causal diagrams and potential outcomes are used to explain the methods and assumptions. We apply the methods to UK Cystic Fibrosis Registry data to investigate the effect of ivacaftor, introduced in 2012 for a subset of the cystic fibrosis population with a particular genotype, on lung function and annual rate (days/year) of receiving intravenous (IV) antibiotics (i.e., IV days). We consider 2 negative control outcomes: outcomes measured in the pre-ivacaftor period and outcomes among persons ineligible for ivacaftor because of their genotype. Ivacaftor was found to improve lung function in year 1 (an approximately 6.5-percentage-point increase in ppFEV1), was associated with reduced lung function decline (an approximately 0.5-percentage-point decrease in annual ppFEV1 decline, though confidence intervals included 0), and reduced the annual rate of IV days (approximately 60% over 3 years).

De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.

Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.

Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data.

RATIONALE: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results. OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences. METHODS: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics). RESULTS: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK. CONCLUSIONS: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

Projecting the impact of triple CFTR modulator therapy on intravenous antibiotic requirements in cystic fibrosis using patient registry data combined with treatment effects from randomised trials.

BACKGROUND: Cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision. METHODS: We combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV1% and approach 2 based on effect estimates on exacerbation rate. RESULTS: ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections. CONCLUSIONS: This work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.

Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus.

Motile cilia move body fluids and gametes and the beating of cilia lining the airway epithelial surfaces ensures that they are kept clear and protected from inhaled pathogens and consequent respiratory infections. Dynein motor proteins provide mechanical force for cilia beating. Dynein mutations are a common cause of primary ciliary dyskinesia (PCD), an inherited condition characterized by deficient mucociliary clearance and chronic respiratory disease coupled with laterality disturbances and subfertility. Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus and in one case male infertility. DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium and in DNAH9-mutated nasal respiratory epithelial cilia we found a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region. This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion. 3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume. Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability. We find that DNAH9 is widely expressed in the airways, despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract. In summary, DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum.

Survival estimates in European cystic fibrosis patients and the impact of socioeconomic factors: a retrospective registry cohort study.

BACKGROUND: Median survival for cystic fibrosis (CF) patients in Europe is unknown and is likely to be influenced by socioeconomic factors. Using the European CF Society Patient Registry (ECFSPR), median survival estimates were obtained for CF patients across Europe and the impact of socioeconomic status on survival was examined. METHODS: CF subjects known to be alive and in the ECFSPR between 2010 and 2014 were included. Survival curves were estimated using the Kaplan-Meier method. Differences in the survival curves were assessed using the log-rank test. Cox regression was used to estimate the association between socioeconomic factors and the age-specific hazard of death, with adjustment for sex, age at diagnosis, CF transmembrane conductance regulator (CFTR) genotype and transplant status. RESULTS: The final analysis included 13 countries with 31 987 subjects (135 833 person-years of follow-up) and 1435 deaths. Median survival age for these patients in the ECFSPR was 51.7 (95% CI 50.0-53.4) years. After adjusting for potential confounders age at diagnosis, sex, CFTR genotype and transplant status, there remained strong evidence of an association between socioeconomic factors and mortality (p<0.001). Countries in the highest third of healthcare spending had a 46% lower hazard of mortality (HR 0.54, 95% CI 0.45-0.64) than countries in the lowest third of healthcare spending. CONCLUSIONS: Median survival for patients with CF in Europe is comparable to that reported in other jurisdictions and differs by socioeconomic factors.

Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases. METHODS: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. RESULTS: Disease severity at diagnosis, measured by forced expiratory volume in 1 s (FEV1) z-score, was significantly worse in individuals with CCDC39 mutations (compared to other gene mutations) and better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. CONCLUSIONS: This large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutation) and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.

Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales.

BACKGROUND: Poor growth during infancy and childhood is a characteristic feature of cystic fibrosis (CF). However, the impact of CF on intrauterine growth is unclear. We studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth. METHODS: We conducted national registry linkage studies in two countries, using data for 2.2 million singletons born in Denmark (between 1980 and 2010) and Wales (between 1998 and 2015). We used hospital inpatient and outpatient data to identify 852 children with CF. Using causal mediation methods, we estimated the direct and indirect (via gestational age) effect of CF on birth weight after adjustment for sex, parity and socioeconomic background. We tested the robustness of our results by adjusting for additional factors such as maternal smoking during pregnancy in subpopulations where these data were available. RESULTS: Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs 5% and 9.4% vs 5.8% preterm; 11.9% vs 4.2% and 11% vs 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be -178.8 g (95% CI -225.43 to -134.47 g) in the Danish population and -210.08 g (95% CI -281.97 to -141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age. CONCLUSIONS: CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation.

Hypersensitivity reactions to intravenous antibiotics in cystic fibrosis.

Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required.

Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient.

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.

Scoliosis convexity and organ anatomy are related.

PURPOSE: Primary ciliary dyskinesia (PCD) is a respiratory syndrome in which 'random' organ orientation can occur; with approximately 46% of patients developing situs inversus totalis at organogenesis. The aim of this study was to explore the relationship between organ anatomy and curve convexity by studying the prevalence and convexity of idiopathic scoliosis in PCD patients with and without situs inversus. METHODS: Chest radiographs of PCD patients were systematically screened for existence of significant lateral spinal deviation using the Cobb angle. Positive values represented right-sided convexity. Curve convexity and Cobb angles were compared between PCD patients with situs inversus and normal anatomy. RESULTS: A total of 198 PCD patients were screened. The prevalence of scoliosis (Cobb >10°) and significant spinal asymmetry (Cobb 5-10°) was 8 and 23%, respectively. Curve convexity and Cobb angle were significantly different within both groups between situs inversus patients and patients with normal anatomy (P ≤ 0.009). Moreover, curve convexity correlated significantly with organ orientation (P < 0.001; ϕ = 0.882): In 16 PCD patients with scoliosis (8 situs inversus and 8 normal anatomy), except for one case, matching of curve convexity and orientation of organ anatomy was observed: convexity of the curve was opposite to organ orientation. CONCLUSIONS: This study supports our hypothesis on the correlation between organ anatomy and curve convexity in scoliosis: the convexity of the thoracic curve is predominantly to the right in PCD patients that were 'randomized' to normal organ anatomy and to the left in patients with situs inversus totalis.

Pancreatic enzyme prescription following ivacaftor licensing: A retrospective analysis of the US and UK cystic fibrosis registries.

BACKGROUND: Relieving gastrointestinal symptoms is a research priority in cystic fibrosis. Emerging evidence highlights effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on gastrointestinal function, including pancreatic sufficiency. This study explores ivacaftor licensing and treatment on recorded pancreatic enzyme replacement therapy (PERT) prescription in the US and UK CF registries. METHODS: Retrospective longitudinal registry study of recorded pancreatic PERT use between 2008 and 2017. Interrupted time series analysis in propensity-matched cohorts estimated annual change and step change according to ivacaftor eligibility before and after licensing year, 2012. Generalised estimating equations assessed adjusted risk of PERT use in individuals treated with ivacaftor after 2012 compared to untreated individuals. RESULTS: In the US CF registry, the difference in annual change in prevalence of PERT use post-2012 between eligible cases and ineligible controls was -5.0 per 1000 people/year (95 %CI -7.6; -2.3, p = 0.001). The step change and annual change in prevalence of PERT use in eligible cases was not significantly different to controls in the UK CF registry. Relative to the relationship in 2013, ivacaftor treatment in the US CF registry was associated with a lower adjusted risk ratio of PERT use compared to untreated individuals by 2016 (0.97, 95 %CI 0.96; 0.99), which was not observed in the UK CF registry. CONCLUSIONS: Licensing of ivacaftor was followed by a lower prevalence of PERT use in the eligible US population compared to pre-licensing period, as well as lower risk of PERT use in those who received treatment. Inconsistencies in US and UK CF registries were observed.

Evaluating the correspondence between the EQ-5D-5L and disease severity and quality of life in adults and adolescents with cystic fibrosis.

BACKGROUND: The EQ-5D is the recommended measure to capture health-related quality of life (HRQoL), recognised for use in health technology appraisal bodies. In order to assess whether it is appropriate to use the EQ-5D for making decisions about the cost-utility of treatments in cystic fibrosis (CF), this study assesses the performance of the EQ-5D-5L in adults and adolescents with CF. METHOD: This was a cross-sectional observational survey study of patients with CF attending a single large CF centre. Participants were asked to complete a survey that included two HRQoL measures; the EQ-5D-5L and CF Quality of Life (CFQoL) questionnaires. RESULTS: Among 213 participants, the median EQ-5D-5L index score was 0.76 (IQR 0.66 - 0.84) and the visual analogue (EQ-VAS) was 70 (60 - 80). Both the EQ-5D index and EQ-VAS discriminated between disease severity based on lung function (p = 0.01 and p < 0.01, respectively) and pulmonary exacerbation (p = 0.02 and p < 0.01, respectively); however, EQ-VAS differentiated between more lung function severity groups compared to EQ-5D index. The EQ-5D-5L demonstrated convergent validity as its dimensions, index score, and EQ-VAS had significant correlations with most CFQoL domains. Though, EQ-VAS significantly predicted more domains of CFQoL (4 domains) compared to EQ-5D index (only 1 domain). CONCLUSION: The generic EQ-5D-5L performed adequately in discriminating between CF disease severity, and its index score and EQ-VAS had moderate correlations with CFQoL. However, using a complementary condition-specific measure alongside the EQ-5D-5L can provide better insight of HRQoL in CF and benefit the process of cost-utility analysis.

Demographic factors associated with within-individual variability of lung function for adults with cystic fibrosis: A UK registry study.

BACKGROUND: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified. METHODS: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort. RESULTS: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived. CONCLUSIONS: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual's lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.

Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.

Impact of COVID-19 infection on lung function and nutritional status amongst individuals with cystic fibrosis: A global cohort study.

BACKGROUND: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF). METHODS: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV1) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection. RESULTS: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV1 pre- and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre- and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection. CONCLUSIONS: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF.