ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.

ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria.

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved. The definition of a CFTR-RD remains "a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF". Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.

Standards of care guidance for sweat testing; phase two of the ECFS quality improvement programme.

More than five decades after the introduction of the quantitative pilocarpine iontophoresis technique, surveys still highlight inconsistencies in the performance and reporting of sweat tests in Europe. The sweat test remains key for the Cystic Fibrosis (CF) diagnostic pathway for all age groups, as it reflects the basic pathophysiological defect in the sweat gland. It is also critical following newborn screening as a confirmatory diagnostic step. Despite its importance, sweat test quality is variable whether performed in the laboratory or as a point of care test. The ECFS DNWG aims to improve sweat test performance, taking into account the barriers and issues identified in the European survey; the previous step in the ECFS sweat test project. This manuscript proposes a grading of sweat test guidance from "acceptable" to "optimal", aiming to pragmatically improve quality while taking into account local situations, especially in resource-limited settings.

International approaches for delivery of positive newborn bloodspot screening results for CF.

BACKGROUND: Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is a well-established public health strategy with international standards. A European survey demonstrated considerable variability in approach to delivering a positive NBS result. We used a mixed methods approach to explore healthcare systems and beliefs around this process. METHODS: We used semi-structured interviews and online questionnaires with a purposive, international sample of health professionals involved in communicating positive NBS results to parents. Data were analysed using thematic analysis and Qualtrics Survey Software. RESULTS: In total, 63 healthcare professionals were approached; 25 interviews were conducted with delegates at the 2017 ECFS conference, 4 online questionnaires were subsequently completed by participants in the EU, 1 from Australia and 33 from the US. Methods used to communicate positive NBS results to families varied considerably. This influenced the quality and quantity of information provided which had the potential to heighten anxiety and affect timely diagnostic testing. Participants identified positive practices including systems to improve the timeliness of screening and processing of results, as well as areas for improvement. Respondents stated that knowledge of CF and familiarity with the family were both important when deciding who should communicate positive NBS results. CONCLUSIONS: Guidance and practice regarding communication of positive NBS results for CF to families varies considerably internationally. Further research is needed to ensure information received is accurate, up-to-date and from the most appropriate person. Also, that all children are followed up in a timely manner to minimise potential negative outcomes for the child and family.

Real life practice of sweat testing in Europe.

Evidence based guidelines exist for sweat testing, which remains a key component of a diagnosis of cystic fibrosis (CF), especially following newborn bloodspot screening (NBS). There are emerging challenges with respect to maintaining a valid sweat test service, notably a smaller number of sweat tests ordered in regions with established NBS programmes where Pediatricians refer less children for sweat testing, younger patients and equipment becoming obsolete. The ECFS Diagnostic Network Working Group has undertaken a comprehensive survey to better define sweat test practice across Europe. The survey was completed by 136 European respondents representing a CF center or laboratory providing a sweat test service (65% from regions with NBS for CF). There was considerable variance in practice, often not consistent with guidelines. In particular collection of sweat from two sites was rarely reported in European centres in contrast to US guidelines. There was a range of different references quoted for cut-off for both a positive and intermediate test. Most responses suggest cost is becoming an increasing issue and is not sufficiently reimbursed. This work will inform best practice guidelines and resources to sustain and improve sweat testing in Europe.

Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) results in the recognition of a number of infants with a positive NBS result, but an inconclusive diagnosis. Varied practice exists with respect to the management of these infants. METHODS: A Delphi consensus approach was used to determine agreement on statements generated by a core group of specialists. A designation (naming) exercise was required after Round 1 and further expert opinion was sought to guide that process. After Round 2, a sensitivity analysis was undertaken to assess the impact of attrition on subsequent agreement levels. RESULTS: Infants were divided into group A (normal sweat chloride and two CFTR mutations, at least one of which has unclear phenotypic consequences) and group B (intermediate sweat chloride and one or no CFTR mutations). 32 statements were produced for Round 1 and 24 achieved consensus. After Round 1, a designation exercise was undertaken and the term "CF Screen Positive, Inconclusive Diagnosis (CFSPID)" was suggested for Round 2. Agreement was achieved for this statement and for all other statements aside from the need for routine respiratory culture, on which there was divided opinion. The core group advocated local practice for this issue. A sensitivity analysis demonstrated that consensus for Round 2 was achieved by change in opinion rather than attrition. CONCLUSION: We have generated a new designation and statements to guide the management of infants with CFSPID through a robust international Delphi process. These statements will be a valuable tool for CF teams and will improve the consistency of management of these infants.

Comparison of real time diagnostic chemistries to detect Pseudomonas aeruginosa in respiratory samples from cystic fibrosis patients.

BACKGROUND: Early eradication therapy is key to keeping the airways Pseudomonas aeruginosa infection-free and rapid identification is essential. METHODS: We used rapid DNA extraction and qPCR assays to detect bacterial, P. aeruginosa and strain-specific targets in samples using two qPCR chemistries. Using 459 respiratory samples from adult and children CF patients, we compared two qPCR methods to culture-based methods in terms of sensitivity and time to result. RESULTS: For adult samples, there was 100% concordance between methods. There was no clear pattern in fluctuations in P. aeruginosa number during exacerbation. In child samples, qPCR methods identified additional P. aeruginosa positive samples. The time-to-result was reduced by over 24h and copy number and colony forming unit could differ dramatically in some samples. CONCLUSION: If adopted, these methods could significantly improve early P. aeruginosa detection in diagnostic laboratories and therefore play a pivotal role in prolonging infection-free airways in CF patients.

CFTR biomarkers: time for promotion to surrogate end-point.

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

Parental information use in the context of newborn bloodspot screening. An exploratory mixed methods study.

The aim of this study was to investigate how parents select and use information sources when considering newborn bloodspot screening. Mixed methods approach using semi-structured interviews (n = 18) and a self-completion postal questionnaire (n = 154) conducted with parents of children who had undergone newborn bloodspot screening. Qualitative data was assessed using a thematic analysis approach with quantitative data analyzed using multinomial logistic regression. Parents used a limited range of information. In the UK, maternity services are largely delivered by the midwife and the healthcare practitioner was the main information source for parents, with only half of parents using official health service leaflets. Barriers included the provision of information post-natally and with other non-healthcare materials. Neither number of children, age group, education level, nor income were significantly associated with the number of information sources used. Nor were they associated with the information source indicated as most important. The midwife is well placed to act as a gatekeeper for parents seeking information about newborn bloodspot screening. Even when additional sources are used, the midwife remains a prominent source of information. Furthermore, the use of written materials is dependent upon appropriate delivery and consequently delivery is essential to information use.

Assessing the Liverpool Respiratory Symptom Questionnaire in children with cystic fibrosis.

Monitoring respiratory status in cystic fibrosis (CF) is challenging, particularly in young children. We aimed to test whether the Liverpool Respiratory Symptom Questionnaire (LRSQ) could distinguish well, pre-school and older children with and without CF, whether it could distinguish well and unwell children with CF and, finally, whether LRSQ scores in older children with CF correlated with established measures of disease severity. 20 stable pre-school children with CF had significantly higher total LRSQ scores than 51 pre-school controls, and higher scores in two out of eight domains. Similarly, 21 stable 6- to 12-yr-old children with CF had higher total scores than 97 6- to 12-yr-old controls, and higher scores in seven out of eight domains. In older children with CF, LRSQ scores correlated negatively with Shwachman score and forced expiratory volume in 1 s (r = -0.58, p < 0.001, n = 31; and r = -0.46, p < 0.010, n = 34, respectively). Within the CF group, patients who cultured Pseudomonas aeruginosa, who used more "back-up" antibiotics or whose school attendance was lower also had higher LRSQ scores. The LRSQ differentiates well children from those with CF in both pre-school and the 6- to 12-yr-old age group, even at a point of stability. It also differentiates stable from unwell children with CF, and scores correlate with other measures of respiratory disease, highlighting its potential as a clinical monitoring tool in paediatric CF.

Recommendations for the classification of diseases as CFTR-related disorders.

Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.

Oxygen saturation profile in healthy preterm infants.

AIM: To establish a reference range for oxygen saturation (SpO(2)) in well preterm infants to guide home oxygen therapy using a pulse oximeter and Pulse Oximetry Data Analysis Software (PODS). METHODS: SpO(2) and heart-rate profiles of healthy preterm infants receiving mechanical ventilation for less than 6 h and supplemental oxygen for less than 48 h were monitored using a pulse oximeter. The stored data were downloaded from the monitor to a personal computer as individual files. Each infant's files of SpO(2) were subsequently displayed in graphic form, and a reference range was constructed using dedicated software, PODS. RESULTS: 43 infants were studied. The median value of all infants mean SpO(2) values was 95% (range 92-99%). The median duration of saturations less than 85% and between 85% and 90 % were 1% and 2% respectively. Using the study group median, 5th and 95th percentiles, a cumulative frequency curve of time against SpO(2) value was constructed (representing the reference range of SpO(2) profiles in healthy preterm infants). CONCLUSION: The SpO(2) reference range can be used as an easy and practical guide to compare SpO(2) profiles of infants on home oxygen therapy and guide their oxygen therapy.