Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID).

Newborn bloodspot screening (NBS) for cystic fibrosis (CF) is an effective strategy for the early recognition of infants with a CF diagnosis. Some infants with a positive NBS result for CF have an inconclusive diagnosis and evidence suggests the number of these infants is increasing, as more extensive gene analysis is integrated into screening protocols. There is an internationally agreed, but complex, designation for infants with an unclear diagnosis after a positive screening result: cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). Infants with a CRMS/CFSPID designation have no clinical evidence of disease and do not meet the criteria for a CF diagnosis, but the NBS result indicates some risk of developing CF or a CFTR-related disorder. In this review, we describe the accurate designation of these and reflect on emerging management pathways, with particular attention given to clear and consistent communication.Educational aimsTo clarify the definition of the global harmonised designation: cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive, inconclusive diagnosis (CFSPID).To understand what impact a CRMS/CFSPID result has for the patient and their family

Why Do We Screen Newborn Infants for Cystic Fibrosis?

The introduction and widespread implementation of newborn bloodspot screening (NBS) for cystic fibrosis (CF) has offered earlier diagnosis and better outcomes for children with CF in many countries of the world [...]

Psychological Impact on Parents of an Inconclusive Diagnosis Following Newborn Bloodspot Screening for Cystic Fibrosis: A Qualitative Study.

Genetic results of uncertain clinical significance are being returned to parents following newborn screening, representing a paradigm change in how society considers health and illness. 'Cystic Fibrosis screen positive, inconclusive diagnosis' (CFSPID) is a designation given to newborns with a positive screening result for, but not a definitive diagnosis of, cystic fibrosis. We explored the psychological impact of receiving a CFSPID result on parents. Five semi-structured interviews were conducted with eight parents whose children have CFSPID. Interpretative phenomenological analysis identified these themes: "The way we were told": 'diagnosis as a traumatic event' focused on how parents were distressed and dissatisfied by the initial screening result communication, 'Facing and challenging traditional ideas about health and illness' explored the emerging problem of how CFSPID does not fit the commonly accepted medical model, and 'Making certainty out of uncertainty' explored the varying strategies parents developed to adapt to the uncertainty regarding their child's prognosis. Findings suggest that CFSPID results caused parents' distress, initiated with the first communication of the result and persisting thereafter. Our data suggests approaches to the delivery of CFSPID results that may reduce the impact. Work is needed to close the gap between healthcare advances and societies commonly held medical model

Topical cystic fibrosis transmembrane conductance regulator gene replacement for cystic fibrosis-related lung disease

BACKGROUND: Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy. OBJECTIVES: To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. Date of most recent search: 05 May 2016. An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2015. Date of most recent search: 20 April 2016. SELECTION CRITERIA: Randomised controlled studies comparing topical CFTR gene delivery to the lung, using either viral or non‐viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta‐analysis was limited due to differing study designs. MAIN RESULTS: Four randomised controlled studies met the inclusion criteria for this review, involving a total of 302 participants lasting from 29 days to 13 months; 14 studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta‐analysis. One study only enrolled adult males, the remaining studies included both males and females aged 12 years and over. Risk of bias in the studies was moderate. Random sequence generation and allocation concealment was only described in the more recent study; the remaining three studies were judged to have an unclear risk of bias. All four studies documented double‐blinding to the intervention, but there is some uncertainty with regards to participant blinding in one study. Some outcome data were missing from all four studies. There were no differences in either the number of respiratory exacerbations or the number of participants with an exacerbation between replacement therapy or placebo groups at any time point. Meta‐analysis of most respiratory function tests showed no difference between treatment and placebo groups, but the smallest study (n = 16) reported forced vital capacity (litres) increased more in the placebo group at up to 24 hours. A further study reported a significant improvement in forced expiratory volume at one second (litres) at 30 days after participants had received their first dose of favouring the gene therapy agent, but this finding was not confirmed when combined with at second study in the meta‐analysis. The more recent study (n = 140) demonstrated a small improvement in forced vital capacity (per cent predicted) at two and three months and again at 11 and 12 months for participants receiving CFTR gene replacement therapy compared to those receiving placebo. The same study reported a significant difference in the relative change in forced expiratory volume at one second (per cent predicted) at two months, three months and 12 months. One small study reported significant concerns with "influenza‐like" symptoms in participants treated with CFTR gene replacement therapy; this was not reported on repeated use of the same agent in a larger recent study. There was no other evidence of positive impact on outcomes, in particular improved quality of life or reduced treatment burden. Two studies measured ion transport in the lower airways; one (n = 16) demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). The second study (n = 140) also reported significant changes toward normal values (P = 0.032); however, aggregate data were not available for analysis. In the most recent study, there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance. AUTHORS' CONCLUSIONS: One study of liposome‐based CFTR gene transfer therapy demonstrated some improvements in respiratory function in people with CF, but this limited evidence of efficacy does not support this treatment as a routine therapy at present. There was no evidence of efficacy for viral‐mediated gene delivery. Future studies need to investigate clinically important outcome measures

A mixed methods study of the administration of flucloxacillin oral liquid; identifying strategies to overcome administration issues of medicines with poor palatability.

BackgroundThe palatability of flucloxacillin oral liquid is poor. Parents/carers use strategies to aid the administration of poorly palatable medicines.AimTo assess views on the palatability of flucloxacillin oral liquid and identify factors associated with successful administration.MethodsA mixed methods study which included a structured review of online forums and a survey of parent/carers of children with cystic fibrosis (CF) to obtain parent/carer views on the administration of flucloxacillin oral liquid.ResultsA total of 18 strategies to aid the administration of flucloxacillin suspension to children were identified on 10 different public online forums. A total of 255 responses to the open online survey were received with 47% of respondents reporting that administration of flucloxacillin was more problematic compared to other medicines and 38% reporting the need to improve the palatability. The brand of flucloxacillin oral liquid significantly influenced the degree of difficulty associated with administration to children. A significant relationship was found between the concentration of flucloxacillin and the reported number of doses successfully administered. The use of food and drink to aid administration was more commonly stated in online forums (44%) compared to the survey data of parents/carers of children with CF (15.9%).ConclusionThe administration of flucloxacillin oral liquid is perceived as a challenge by parent/carers because of palatability. For chronic use, a more concentrated oral liquid and certain brands are likely to improve acceptability

Exhaled breath hydrogen cyanide as a marker of early Pseudomonas aeruginosa infection in children with cystic fibrosis

Hydrogen cyanide is readily detected in the headspace above Pseudomonas aeruginosa cultures and in the breath of cystic fibrosis (CF) patients with chronic (P. aeruginosa) infection. We investigated if exhaled breath HCN is an early marker of P. aeruginosa infection. 233 children with CF who were free from P. aeruginosa infection were followed for 2 years. Their median (interquartile range) age was 8.0 (5.0–12.2) years. At each study visit, an exhaled breath sample was collected for hydrogen cyanide analysis. In total, 2055 breath samples were analysed. At the end of the study, the hydrogen cyanide concentrations were compared to the results of routine microbiology surveillance. P. aeruginosa was isolated from 71 children during the study with an incidence (95% CI) of 0.19 (0.15–0.23) cases per patient-year. Using a random-effects logistic model, the estimated odds ratio (95% CI) was 3.1 (2.6–3.6), which showed that for a 1- ppbv increase in exhaled breath hydrogen cyanide, we expected a 212% increase in the odds of P. aeruginosa infection. The sensitivity and specificity were estimated at 33% and 99%, respectively. Exhaled breath hydrogen cyanide is a specific biomarker of new P. aeruginosa infection in children with CF. Its low sensitivity means that at present, hydrogen cyanide cannot be used as a screening test for this infection

Receiving results of uncertain clinical relevance from population genetic screening: systematic review & meta-synthesis of qualitative research

Genetic screening can be hugely beneficial, yet its expansion poses clinical and ethical challenges due to results of uncertain clinical relevance (such as ‘cystic fibrosis screen positive, inconclusive diagnosis’/CFSPID). This review systematically identifies, appraises, and synthesises the qualitative research on experiences of receiving results of uncertain clinical relevance from population genetic screening. Eight databases were systematically searched for original qualitative research using the SPIDER framework, and checked against inclusion criteria by the research team and an independent researcher. Nine papers were included (from USA, Canada, UK, New Zealand). PRISMA, ENTREQ, and EMERGE guidance were used to report. Quality was appraised using criteria for qualitative research. All papers focused on parental responses to uncertain results from newborn screening. Data were synthesised using meta-ethnography and first- and second-order constructs. Findings suggest that results of uncertain clinical relevance are often experienced in the same way as a ‘full-blown’ diagnosis. This has significant emotional and behavioural impact, for example adoption of lifestyle-altering disease-focused behaviours. Analysis suggests this may be due to the results not fitting a common medical model, leading recipients to interpret the significance of the result maladaptively. Findings suggest scope for professionals to negotiate and reframe uncertain screening results. Clearer initial communication is needed to reassure recipients there is no immediate severe health risk from these types of results. Public understanding of an appropriate medical model, that accounts for uncertain genetic screening results in a non-threatening way, may be key to maximising the benefits of genomic medicine and minimising potential psychological harm

Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del)

BACKGROUND: Cystic fibrosis (CF) is a common life‐shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF‐causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators. OBJECTIVES: To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data. MAIN RESULTS: We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor‐ivacaftor studies provided additional 96‐week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual‐therapy RCTs (1840 participants) (lumacaftor‐ivacaftor or tezacaftor‐ivacaftor) and five triple‐therapy RCTs (775 participants) (elexacaftor‐tezacaftor‐ivacaftor or VX‐659‐tezacaftor‐ivacaftor); below we report only the data from elexacaftor‐tezacaftor‐ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non‐standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically‐relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo‐controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate‐ to high‐quality evidence). QoL scores (respiratory domain) favoured both lumacaftor‐ivacaftor and tezacaftor‐ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high‐quality evidence). A similar effect was observed for twice‐daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low‐quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice‐daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate‐quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV(1)) % predicted improved with combination therapies compared to placebo by: 5.21% with once‐daily lumacaftor‐ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high‐quality evidence); 2.40% with twice‐daily lumacaftor‐ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low‐quality evidence); and 6.80% with tezacaftor‐ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate‐quality evidence). More pwCF reported early transient breathlessness with lumacaftor‐ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high‐quality evidence). Over 120 weeks (initial study period and follow‐up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice‐daily 400 mg lumacaftor‐ivacaftor (80 participants; high‐quality evidence). The tezacaftor‐ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate‐quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor‐ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high‐quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor‐tezacaftor‐ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV(1) (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor‐tezacaftor‐ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV(1) (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor‐ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor‐tezacaftor‐ivacaftor and placebo or control (moderate‐quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol‐defined pulmonary exacerbation with elexacaftor‐tezacaftor‐ivacaftor over 24 weeks (moderate‐quality evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor‐ivacaftor, tezacaftor‐ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor‐ivacaftor was associated with an increase in early transient shortness of breath and longer‐term increases in blood pressure (not observed for tezacaftor‐ivacaftor). Tezacaftor‐ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor‐ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer‐term adult data when considering lumacaftor‐ivacaftor. There is high‐quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor‐tezacaftor‐ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function