Cystic Fibrosis Cases Missed by Newborn Bloodspot Screening-Towards a Consistent Definition and Data Acquisition.

Repeated European surveys of newborn bloodspot screening (NBS) have shown varied strategies for collecting missed cases, and information on data collection differs among countries/regions, hampering data comparison. The ECFS Neonatal Screening Working Group defined missed cases by NBS as either false negatives, protocol-related, concerning analytical issues, or non-protocol-related, concerning pre- and post-analytical issues. A questionnaire has been designed and sent to all key workers identified in each NBS programme to assess the feasibility of collecting data on missed cases, the stage of the NBS programme when the system failed, and individual patient data on each missed case.

Reduction in abdominal symptoms (CFAbd-Score), faecal M2-pyruvate-kinase and Calprotectin over one year of treatment with Elexacaftor-Tezacaftor-Ivacaftor in people with CF aged ≥12 years - The RECOVER study.

BACKGROUND: RECOVER is a multicentre post-approval study of Elexacaftor/Tezacaftor/Ivacaftor (ETI) in pwCF in Ireland and the UK. The CFAbd-Score is the first validated CF-specific patient reported outcome measure (PROM) focusing on gastrointestinal symptoms; it comprises 28 items in 5 domains. In a preliminary study, we previously reported reductions in abdominal symptoms (AS) in pwCF after 26 weeks of ETI-therapy using the CFAbd-Score. AIM: to assess changes in AS in a second, large cohort and explore novel GI-biomarkers of gut inflammation and cell-proliferation in pwCF over one year of ETI-therapy. METHODS: Participants were recruited as part of the RECOVER study at 8 sites (Ireland&UK). The CFAbd-Score was administered prior to ETI-initiation, and subsequently at 1,2,6 and 12 months on treatment. Faecal M2-pyruvate kinase (M2-PK) and calprotectin (FC) were quantified in samples collected at baseline, 1 and 6 months. RESULTS: 108 CFAbd-Scores and 73 stool samples were collected at baseline. After 12 months of ETI-therapy, total CFAbd-Scores had significantly declined (15.0±1.4→9.8±1.2pts/p<0.001), and so had all its five domains of "pain" (16.9±2.0pts→9.9±1.8pts/p<0.01), "GERD" (14.4±1.8→9.9±1.6/p<0.05), "disorders of bowel movements" (19.2±1.4→14.1±1.5/p<0.01), "appetite" (7.0±1.1→4.6±1.2/p<0.01) and "impaired-QoL" (13.3±1.9→7.5±1.5/p<0.001). Levels of M2-PK and FC significantly decreased during ETI-therapy. DISCUSSION: In-depth analysis of AS with the CFAbd-Score reveals a statistically significant, clinically relevant and sustained improvement with ETI. We attribute this to high sensitivity of the implemented CF-specific PROM, developed and validated following FDA-guidelines. Furthermore, for the first time during ETI-therapy a significant decline in faecal M2-PK, a marker of inflammation and cell-proliferation, was found, in parallel to FC.

Improvement in Lung Clearance Index and Chest Computed Tomography Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older - The RECOVER Trial.

Rationale: Clinical trials have shown that use of elexacaftor/tezacaftor/ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition, and quality of life in people with cystic fibrosis (CF). Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. Objectives: RECOVER is a real-world study designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (lung clearance index; LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest computed tomography (CT) scores. Methods: The study was conducted in seven sites in Ireland and the United Kingdom. Participants ages 12 years and older who were homozygous for the F508del mutation (F508del/F508del) or heterozygous for F508del and a minimum-function mutation (F508del/MF) were recruited before starting ETI and were followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline and at 6 and 12 months. Spirometry was performed as per the criteria of the American Thoracic Society and the European Respiratory Society. Spirometry-controlled chest CT scans were performed at baseline and at 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R), and sweat chloride. Measurements and Main Results: One hundred seventeen people with CF ages 12 and older were recruited to the study. Significant improvements were seen in LCI scores (-2.5; 95% confidence interval [CI], -3.0, -2.0) and in the percents predicted for FEV1 (8.9; 95% CI, 7.0, 10.9), FVC (6.6; 95% CI, 4.9, 8.3), and forced expiratory flow between 25% and 75% of expired volume (12.4; 95% CI, 7.8, 17.0). Overall PRAGMA-CF scores reflecting airway disease improved significantly (-3.46; 95% CI, -5.23, -1.69). Scores for trapped air, mucus plugging, and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1; 95% CI, -47.4, -38.9) and F508del/MF (-42.8; 95% CI, -48.5, -37.2) groups. Scores on the Respiratory Domain of the CFQ-R improved by 14.2 points (95% CI, 11.3, 17.2). At 1 year, sweat chloride levels were significantly lower for the F508del/F508del group compared with scores for the F508del/MF group (33.93 vs. 53.36, P < 0.001). Conclusions: ETI is associated with substantial improvements in LCI2.5, spirometry, and PRAGMA-CF CT scores in people with CF ages 12 years and older. ETI led to improved nutrition and quality of life. People in the F508del/F508del group had significantly lower sweat chloride on ETI treatment compared with the F508del/MF group. Clinical trial registered with www.clinicaltrials.gov (NCT04602468).

The clinical impact of Lumacaftor-Ivacaftor on structural lung disease and lung function in children aged 6-11 with cystic fibrosis in a real-world setting.

BACKGROUND: Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV1 in children with Cystic Fibrosis (CF) aged 6-11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6-11 years. METHODS: This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV1, nutritional indices and exacerbations requiring hospitalisation. RESULTS: Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (AlumenA ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p < 0.0001), height (0.05 (0.02 to 0.09), p = 0.002) and BMI (0.09 (0.03 to 0.15) p = 0.005) z-scores were seen with LUM/IVA treatment. The mean annual change from baseline ppFEV1 (-2.45 (-4.44 to 2.54), p = 0.66) measurements over two years were not significant. CONCLUSION: In a real-world setting, the use of LUM/IVA over two years in children with CF aged 6-11 resulted in improvements in air trapping on CT but worsening in bronchiectasis scores. Our results suggest that LUM/IVA use in this age group improves air trapping but does not prevent progression of bronchiectasis over two years of treatment.

Design and initial testing of a novel disposable oscillating positive expiratory pressure device.

BACKGROUND: Oscillating positive expiratory pressure (OPEP) devices play a key role in airway clearance, particularly in patients with cystic fibrosis. These devices, however, have the potential to become reservoirs for pathogenic organisms and require daily, or even more frequent, cleaning. This places a large burden on patients and their carers. AIMS: The objective of this work was to develop a disposable OPEP device, with comparable mechanical performance to commercial devices, that negates the need for cleaning after use thus reducing microbiological risks. METHODS: 3D printing was used to iterate and develop a prototype disposable device (The University of Limerick OPEP, abbreviated to the UL-OPEP) that was compared with a selection of commercially available devices for mean pressure and oscillation amplitude (cmH2O), as well as oscillation frequency (Hz). All devices were tested using a healthy volunteer at a target expiratory flow of ~ 20 L/min. The target therapeutic range was 10-20 cmH2O at a flow rate of 10-20 L/min as is reported widely in the literature. RESULTS: The prototype disposable device achieved a mean pressure of 14.82 cmH2O at a mean flow rate of 18.82 L/min, and generated an oscillation frequency of 26 Hz with an amplitude of 1.28 cmH2O. These characteristics compare favourably with existing, more complex, reusable OPEP devices. CONCLUSIONS: The UL-OPEP device is a small, disposable OPEP device, that generates pressure and oscillation amplitudes for clinically effective airway clearance. The device negates the need for cleaning and disinfecting, removing the risk of devices acting as a potential reservoir for pathogenic organisms while maintaining mucus-clearing benefits.

European survey of newborn bloodspot screening for CF: opportunity to address challenges and improve performance.

BACKGROUND: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance. METHODS: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise. RESULTS: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis. CONCLUSIONS: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably.

Indwelling central venous catheter infection with Chryseobacterium shandongense - successful eradication in a 5-year-old with cystic fibrosis.

Introduction: Chryseobacterium shandongense is a Gram-negative Flavobacterium bacillus with intrinsic multidrug-resistant properties. Case Presentation: Herein, we present the first case report of human C. shandongense infection, relating to an implantable portal and catheter (port-a-cath) central line in a 5-year-old female with cystic fibrosis. The infection was identified using a Bruker MALDI-TOF Biotyper with BDAL (v12) of blood, which was cultured due to pyrexia and rigour following port-a-cath access. This report details the effective eradication of C. shandongense infection from the port-a-cath device using initial empirical gentamicin followed by targeted ciprofloxacin locks and systemic antibiotics. Conclusion: We demonstrated successful eradication of C. shandongense from a port-a-cath device, including the minimum inhibitory concentrations (MICs) required in this case. The result was eradication of central access infection, preventing progression to bacteraemia/septicaemia and preserving central access in a child with cystic fibrosis and established respiratory disease.

Troponin-T type 1 (TNNT1)-related nemaline myopathy: unique respiratory phenotype and muscle pathology findings.

Biallelic pathogenic variants in the troponin T type 1 (TNNT1) gene cause a severe form of congenital nemaline myopathy. Typical features include severe motor delay, proximal contractures and weakness, pectus carinatum, chest wall rigidity and tremor. If left untreated, respiratory failure leads to early death at a median age of 18 months. Here we report on three non-Amish, unrelated patients harbouring novel TNNT1 variants. The peculiar combination of respiratory muscle weakness and chest wall stiffness caused early severe hypoventilation warranting the use of high pressures on BiPAP ventilator, with subsequent rapid escalation of pressures delivered with limited efficacy secondary to the extreme rib cage stiffness. Severe respiratory impairment occurred despite a relatively milder motor involvement in one patient. Muscle biopsies from two individuals showed predominant involvement of type 1 fibres, abundant nemaline bodies, marked fibrosis and loss of TNNT1 protein. We aim to increase the awareness of the challenges of managing respiratory support in patients with this unique respiratory phenotype.

Sweat testing in the modern era: A national survey of sweat testing practice in the Republic of Ireland.

BACKGROUND: The sweat test has been the "gold standard" diagnostic test for cystic fibrosis for more than 40 years. We hypothesized that there would be a change in the pattern of sweat testing in Ireland since the introduction of cystic fibrosis newborn screening in 2011, when practices were last reviewed. This is a follow up survey looking at sweat testing numbers and practices. METHODS: A national survey compiled data on sweat collection, conductivity and sweat chloride testing in all hospitals previously identified as performing sweat tests. RESULTS: All 13 centres in Ireland performing sweat testing in 2018 responded to the survey (100% return rate). Our results indicate that 1007 sweat tests were performed in 2018 compared to 2555 in 2011, equating to a 61% reduction. Seven out of 13 centres are performing less than 50 sweat tests per year. Nine out of 13 centres (69%) had a sweat test failure rate greater than the recommended allowable rate of ≤ 10%. We detected a trend of sweat testing in patients with an existing diagnosis of CF who had commenced cystic fibrosis transmembrane conductance regulator (CFTR) modulators. CONCLUSIONS: There has been a significant reduction in the number of sweat tests performed in Ireland since the introduction of newborn screening for CF. There remains a lack of standardisation in many aspects of the service ranging from sample collection to reporting of results. We have identified a new trend of sweat testing in the cystic fibrosis transmembrane conductance regulator modulator era.

An initial evaluation of the safety of a disposable oscillating positive expiratory pressure device in patients with chronic obstructive pulmonary disease: a sort-term pilot study.

BACKGROUND: Handheld oscillating positive expiratory pressure (OPEP) devices have been a mainstay of treatment for patients with hypersecretory conditions such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) since the 1970s. Current devices are reusable and require regular cleaning and disinfection to prevent harbouring potentially pathogenic organisms. Adherence to cleaning regimens for respiratory devices is often poor and in response to this, a prototype disposable OPEP device-the 'UL-OPEP' (University of Limerick-Oscillating Positive Expiratory Pressure device)-was developed to mitigate the risk of contamination by pathogens. The device was previously evaluated successfully in a group of paediatric CF patients. The aim of the current study was to initially evaluate the safety of the prototype in patients with COPD over a period of 1 month to ensure no adverse events, negative impacts on lung function, exercise tolerance, or quality of life. Data on user experience of the device were also collected during post-study follow-up. METHODS: A sample of 50 volunteer participants were recruited from pulmonary rehabilitation clinics within the local hospital network. The patients were clinically stable, productive, and not current or previous users of OPEP devices. Participants were invited to use a prototype disposable OPEP device daily for a period of 1 month. Pre- and post-study lung function was assessed with standard spirometry, and exercise tolerance with the 6-min-walk-test (6MWT). Quality of life was assessed using the St. George's Respiratory Questionnaire (SGRQ), and user experience of the prototype device evaluated using a post-study questionnaire. RESULTS: 24 Participants completed the study: 9 were female. Overall median age was 67.5 years, range 53-85 years. Lung function, 6-min walk test, and SGRQ scores showed no significant change post-study. User feedback was positive overall. CONCLUSIONS: The results indicate that the UL-OPEP is safe to use in patients with COPD. No adverse events were recorded during the study or in the follow-up period of 2 weeks. The device did not negatively impact patients' lung function, exercise tolerance, or quality of life during short term use (1 month), and usability feedback received was generally positive. Larger, longer duration studies will be required to evaluate efficacy. Registration The study was approved as a Clinical Investigation by the Irish Health Products Regulatory Authority (CRN-2209025-CI0085).

A short-term evaluation of a prototype disposable Oscillating Positive Expiratory Pressure (OPEP) device in a cohort of children with cystic fibrosis.

BACKGROUND: Oscillating Positive Expiratory Pressure (OPEP) devices are important adjuncts to airway clearance therapy in patients with cystic fibrosis (CF). Current devices are typically reusable and require daily, or often more frequent, cleaning to prevent risk of infection by acting as reservoirs of potentially pathogenic organisms. In response, a daily disposable OPEP device, the UL-OPEP, was developed to mitigate the risk of contamination and eliminate the burdensome need for cleaning devices. METHODS: A convenience sample of 36 participants, all current OPEP device users, was recruited from a paediatric CF service. For one month, participants replaced their current OPEP device with a novel daily disposable device. Assessment included pre- and post-intervention lung function by spirometry, as well as Lung Clearance Index. Quality of life was assessed using the Cystic Fibrosis Questionnaire - Revised, while user experience was evaluated with a post-study survey. RESULTS: 31 participants completed the study: 18 males; median age 10 years, range 4-16 years. Lung function (mean difference ± SD, %FEV1 = 1.69 ± 11.93; %FVC = 0.58 ± 10.04; FEV1: FVC = 0.01 ± 0.09), LCI (mean difference ± SD, 0.08 ± 1.13), six-minute walk test, and CFQ-R were unchanged post-intervention. Participant-reported experiences of the device were predominantly positive. CONCLUSIONS: The disposable OPEP device maintained patients' lung function during short term use (≤ 1 month), and was the subject of positive feedback regarding functionality while reducing the risk of airway contamination associated with ineffective cleaning. REGISTRATION: The study was approved as a Clinical Investigation by the Irish Health Products Regulatory Authority (CRN-2209025-CI0085).

The Lung Microbiome in Young Children with Cystic Fibrosis: A Prospective Cohort Study.

The cystic fibrosis (CF) lung harbours a diverse microbiome and reduced diversity in the CF lung has been associated with advancing age, increased inflammation and poorer lung function. Data suggest that the window for intervention is early in CF, yet there is a paucity of studies on the lung microbiome in children with CF. The objective of this study was to thoroughly characterise the lower airway microbiome in pre-school children with CF. Bronchoalveolar lavage (BAL) samples were collected annually from children attending the three clinical centres. Clinical and demographic data were collated on all subjects alongside BAL inflammatory markers. 16S rRNA gene sequencing was performed on the Illumina MiSeq platform. Bioinformatics and data analysis were performed using Qiime and R project software. Data on 292 sequenced BALs from 101 children with CF and 51 without CF show the CF lung microbiome, while broadly similar to that in non-CF children, is distinct. Alpha diversity between the two cohorts was indistinguishable at this early age. The CF diagnosis explained only 1.1% of the variation between the cohort microbiomes. However, several key genera were significantly differentially abundant between the groups. While the non-CF lung microbiome diversity increased with age, diversity reduced in CF with age. Pseudomonas and Staphylococcus were more abundant with age, while genera such as Streptococcus, Porphyromonas and Veillonella were less abundant with age. There was a negative correlation between alpha diversity and interleukin-8 and neutrophil elastase in the CF population. Neither current flucloxacillin or azithromycin prophylaxis, nor previous oral or IV antibiotic exposure, was correlated with microbiome diversity. Consecutive annual BAL samples over 5 years from a subgroup of children demonstrated diverse patterns of development in the first years of life.

Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID).

Over the past two decades there has been considerable progress with the evaluation and management of infants with an inconclusive diagnosis following Newborn Screening (NBS) for cystic Fibrosis (CF). In addition, we have an increasing amount of evidence on which to base guidance on the management of these infants and, importantly, we have a consistent designation being used across the globe of CRMS/CFSPID. There is still work to be undertaken and research questions to answer, but these infants now receive more consistent and appropriate care pathways than previously. It is clear that the majority of these infants remain healthy, do not convert to a diagnosis of CF in childhood, and advice on management should reflect this. However, it is also clear that some will convert to a CF diagnosis and monitoring of these infants should facilitate their early recognition. Those infants that do not convert to a CF diagnosis have some potential of developing a CFTR-RD later in life. At present, it is not possible to quantify this risk, but families need to be provided with clear information of what to look out for. This paper contains a number of changes from previous guidance in light of developing evidence, but the major change is the recommendation of a detailed assessment of the child with CRMS/CFSPID in the sixth year of age, including respiratory function assessment and imaging. With these data, the CF team can discuss future care arrangements with the family and come to a shared decision on the best way forward, which may include discharge to primary care with appropriate information. Information is key for these families, and we recommend consideration of a further appointment when the individual is a young adult to directly communicate the implications of the CRMS/CFSPID designation.

National Newborn Screening for cystic fibrosis in the Republic of Ireland: genetic data from the first 6.5 years.

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in the Republic of Ireland (ROI), with a previously quoted incidence of 1 in 1353 and carrier rate of 1 in 19. The National Newborn Screening (NBS) for CF was incorporated in July 2011 in the ROI. A cut-off point of the top 1% Immunoreactive Trypsinogen (IRT) was taken as an indication for 38 CFTR variant panel to maximise identification of affected CF cases and to minimise detection of carriers. All neonates from July 2011 to Dec 2017 with an elevated IRT on NBS were tested with 38 CFTR mutation panel and included. Clinical and laboratory database were analysed. In the first 6.5 years a total of 5,053 newborns (1.16% of total births) were screened with 38 CFTR panel. 170 CF affected cases, 320 unaffected carriers, 32 CF Screening Positive Inconclusive Diagnosis (CFSPID) were identified. There was one missed diagnosis. The most common disease-causing variant was c.1521_1523delCTT (p.(Phe508del)) followed by c.1652G>A (p.(Gly551Asp)). 95 out of 170 (55%) affected newborns were homozygous for c.1521_1523delCTT (p.(Phe08del)) and 25 (15%) carried at least one copy of c.1652G>A (p.(Gly551Asp)). Hence, 70% of affected newborns were eligible for CFTR modulator treatment. The NBS programme has identified almost triple the number of affected newborn with c.1652G>A (p.(Gly551Asp)) than previously quoted figures and identified less than 50% of carriers than predicted. The revised incidence and carrier frequency of CF in the ROI is 1 in 2570 and 1 in 25, respectively.

Neonatal screening programme for CF: Results from the Irish Comparative Outcomes Study (ICOS).

The introduction of NBS in Ireland in July 2011, provided a unique opportunity to investigate clinical outcomes using a comparative historical cohort study. Clinical cohort: children clinically diagnosed with CF born 1 July 2008 to 30 June 2011, and NBS cohort: children diagnosed with CF through NBS born 1 July 2011 to 30 June 2016. Clinical data were collected from the CF Registry of Ireland, medical charts, and data on weight/height before diagnosis from public health nurses and family doctors. SPSS was used for analysis. A total of 232 patients were recruited (response 93%) (93 clinically diagnosed, 139 NBS-detected). Following exclusions of meconium ileus (MI) (40), diagnosis outside Ireland (4), and being designated as CFSPID (2), a total of 77 clinically diagnosed patients and 109 NBS detected children were included in analysis. Over half were homozygous for F508del mutation. Being clinically diagnosed was independently associated with hospitalization for infective exacerbation of CF < 36 months (OR, 2.80; 95%CI 1.24-6.29). Diagnosis to first acquisition of Pseudomonas aeruginosa was significantly longer in NBS than clinically detected; from birth there was no significant difference. Weight and length/height were significantly greater in NBS cohort at 6 and 12 months. We provide evidence of improved growth, reduced hospitalization for acute exacerbations, and delayed P. aeruginosa acquisition (from diagnosis) to age 3 for the NBS cohort. Screening practices likely account for the non-significant difference in P. aeruginosa acquisition from birth.