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.

Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations.

There is now increased knowledge and experience of newborn screening around the world. There is also a better understanding of CF gene analysis, informed by international databases. This has resulted in a small number of children and adults having their diagnosis of CF reversed. This article illustrates this issue with three cases. It considers how best to tell children and adults with their families, and the reactions that may be encountered. It also discusses practical issues of removing the diagnosis.

Optimising equity of access: how should we allocate slots to the most competitive trials in Cystic Fibrosis (CF)?

BACKGROUND: Trial participation can allow people with CF early access to CFTR modulator therapies, with high potential for clinical benefit. Therefore, the number of people wishing to participate can substantially exceed the number of slots available. We aimed to understand how the CF community thinks slots to competitive trials should be allocated across the UK and whether this should be driven by clinical need, patients' engagement/adherence or be random. For the latter, we explored site-level versus registry-based, national randomisation processes. METHODS: We developed an online survey, recruiting UK-based stakeholders through social media, newsletters and personal contacts. Closed questions were analysed for frequencies and percentages of responses. Free-text questions were analysed using thematic analysis. RESULTS: We received 203 eligible responses. Overall, 75% of stakeholders favoured allocation of slots to individual sites based on patient population size, although pharma favoured allocation based on previous metrics. Currently, few centres have defined strategies for allocating slots locally. At face-value, stakeholders believe all eligible participants should have an equal chance of getting a slot. However, further questioning reveals preference for prioritisation strategies, primarily perceived treatment adherence, although healthcare professionals were less likely to favour this strategy than other stakeholder groups. The majority of stakeholders would prefer to allocate slots and participate in trials locally but 80% said if necessary, they would engage in a system of national allocation. CONCLUSIONS: Fair allocation to highly competitive trials does not appear to have a universally acceptable solution. Therefore, transparency and empathy remain critical to negotiate this uncertain territory.

Tablet and web-based audiometry to screen for hearing loss in adults with cystic fibrosis.

INTRODUCTION: Individuals with chronic lung disease (eg, cystic fibrosis (CF)) often receive antimicrobial therapy including aminoglycosides resulting in ototoxicity. Extended high-frequency audiometry has increased sensitivity for ototoxicity detection, but diagnostic audiometry in a sound-booth is costly, time-consuming and requires a trained audiologist. This cross-sectional study analysed tablet-based audiometry (Shoebox MD) performed by non-audiologists in an outpatient setting, alongside home web-based audiometry (3D Tune-In) to screen for hearing loss in adults with CF. METHODS: Hearing was analysed in 126 CF adults using validated questionnaires, a web self-hearing test (0.5 to 4 kHz), tablet (0.25 to 12 kHz) and sound-booth audiometry (0.25 to 12 kHz). A threshold of ≥25 dB hearing loss at ≥1 audiometric frequency was considered abnormal. Demographics and mitochondrial DNA sequencing were used to analyse risk factors, and accuracy and usability of hearing tests determined. RESULTS: Prevalence of hearing loss within any frequency band tested was 48%. Multivariate analysis showed age (OR 1.127; (95% CI: 1.07 to 1.18; p value<0.0001) per year older) and total intravenous antibiotic days over 10 years (OR 1.006; (95% CI: 1.002 to 1.010; p value=0.004) per further intravenous day) were significantly associated with increased risk of hearing loss. Tablet audiometry had good usability, was 93% sensitive, 88% specific with 94% negative predictive value to screen for hearing loss compared with web self-test audiometry and questionnaires which had poor sensitivity (17% and 13%, respectively). Intraclass correlation (ICC) of tablet versus sound-booth audiometry showed high correlation (ICC >0.9) at all frequencies ≥4 kHz. CONCLUSIONS: Adults with CF have a high prevalence of drug-related hearing loss and tablet-based audiometry can be a practical, accurate screening tool within integrated ototoxicity monitoring programmes for early detection.

Is it cystic fibrosis? The challenges of diagnosing cystic fibrosis.

The spectrum of conditions caused by abnormal CFTR function is broad - from 'classic' cystic fibrosis (CF) to single organ conditions termed CFTR-related disorders. Defining and securing the diagnosis in an important minority of patients can be a challenge as the sweat test is equivocal or normal; the impact this has on the patient (at different stages of their life) can be very significant as it has the potential to lead to misdiagnosis and over (or under) treatment with associated psychological burden. The nasal potential difference test and intestinal current measurements are physiological measurements of CFTR function and thus can provide important diagnostic information. This article provides an overview of the latest developments in CF diagnostics, outlining the approach to be taken when the diagnosis is unclear and some of the areas of uncertainty.

The emerging burden of liver disease in cystic fibrosis patients: A UK nationwide study.

OBJECTIVE: Cystic fibrosis associated liver disease (CFLD) is the third largest cause of mortality in CF. Our aim was to define the burden of CFLD in the UK using national registry data and identify risk factors for progressive disease. METHODS: A longitudinal population-based cohort study was conducted. Cases were defined as all patients with CFLD identified from the UK CF Registry, 2008-2013 (n = 3417). Denominator data were derived from the entire UK CF Registry. The burden of CFLD was characterised. Regression analysis was undertaken to identify risk factors for cirrhosis and progression. RESULTS: Prevalence of CFLD increased from 203.4 to 228.3 per 1000 patients during 2008-2013. Mortality in CF patients with CFLD was more than double those without; cirrhotic patients had higher all-cause mortality (HR 1.54, 95% CI 1.09 to 2.18, p = 0.015). Median recorded age of cirrhosis diagnosis was 19 (range 5-53) years. Male sex, Pseudomonas airway infection and CF related diabetes were independent risk factors for cirrhosis. Ursodeoxycholic acid use was associated with prolonged survival in patients without cirrhosis. CONCLUSIONS: This study highlights an important changing disease burden of CFLD. The prevalence is slowly increasing and, importantly, the disease is not just being diagnosed in childhood. Although the role of ursodeoxycholic acid remains controversial, this study identified a positive association with survival.

Eradication of respiratory tract MRSA at a large adult cystic fibrosis centre.

INTRODUCTION: The prevalence of MRSA in patients with CF is increasing. There is no consensus as to the optimum treatment. METHOD: An observational cohort study of all patients with MRSA positive sputum, 2007-2012. All eradication attempts with subsequent culture results were reviewed. Single vs dual antibiotic regimens were compared for both new and chronic infections. RESULTS: 37 patients (median FEV1 58.7 (27.6-111.5)% predicted) were identified, of which 67.6% (n = 25) had newly acquired MRSA. Compared with single regimens, a high proportion of dual regimens achieved MRSA eradication (84.6% vs 50%; p = 0.1) for new infections. Rifampicin/Fusidic acid was associated with high success rates (100% vs 60% for other dual regimens (p = 0.13)). Compared with new infections, chronic MRSA was much less likely to be eradicated (18.2%, p = 0.01). CONCLUSION: Combined antibiotic therapy, particularly Rifampicin/Fusidic acid, is a well-tolerated and effective means of eradicating MRSA in patients with cystic fibrosis.

Ageing in cystic fibrosis and long-term survival.

The demographics of cystic fibrosis continue to change with adults outnumbering children in most developed countries. Median predicted survival is now over 40 years and 7.6% are aged >40 years. Patients surviving beyond 40 cover the full spectrum of disease from homozygous F508del to single organ disease. Differences in the characteristics of older patients are recognised, but generally patients diagnosed in adulthood are still at risk of accelerated lung function decline. Improved survival brings new challenges, including a rising rate of CF co-morbidities such as diabetes, in addition to other medical problems such as renal impairment and ototoxicity.

Cystic fibrosis: management of haemoptysis.

Haemoptysis is a common complication in cystic fibrosis (CF), occurring in approximately 9% of the population. Massive haemoptysis is associated with older patients, more severe disease and carries a high mortality rate. Despite this there are few robust published studies of effective treatments and knowledge of the precise pathogenesis is limited. Current guidelines for treatment from the Cystic Fibrosis Foundation (CFF) are based on consensus opinion of experts. Patients with massive haemoptysis who do not respond to initial medical treatments should undergo bronchial artery embolization. This will control the bleeding in the majority of cases but recurrence rates are high and there are little data to support long-term improved outcomes. Surgery is a last resort in patients with CF.

Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007.

OBJECTIVES: To evaluate the survival of patients with cystic fibrosis whose lung function has deteriorated to a forced expiratory volume in one second (FEV(1)) below 30% predicted in the recent treatment era and to explore factors associated with any change in survival. Design Cohort study. SETTING: Adult cystic fibrosis unit in London. PARTICIPANTS: 276 patients (147 (53%) male) whose FEV(1) was first observed to be less than 30% predicted between 1 January 1990 and 31 December 2003. MAIN OUTCOME MEASURE: Survival during follow-up to 31 December 2007 in two year sub-cohorts. RESULTS: Median survival improved from 1.2 years in the 1990-1 group to 5.3 years in the 2002-3 group, with a marked improvement in survival from 1994. The use of nebulised recombinant human DNase was significantly associated with a reduced risk of death (hazard ratio 0.59, 95% confidence interval 0.44 to 0.79). Significantly increased risks were associated with a body mass index under 19 (hazard ratio 1.52, 1.10 to 2.10), long term oxygen therapy (3.52, 2.49 to 4.99), and nebulised antibiotics (1.84, 1.05 to 3.22). CONCLUSION: A marked improvement has occurred in the survival of patients with cystic fibrosis with an FEV(1) less than 30% predicted. Secondary analyses suggest that some of this improvement may be due to use of recombinant human DNase.

Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function.

Significant survival heterogeneity exists in cystic fibrosis. Our aim was to determine whether residual function of the cystic fibrosis transmembrane conductance regulator (CFTR) is present in long-term survivors with severe mutations. Nasal potential difference (PD) and sweat chloride were measured in 34 long-term survivors (aged ≥ 40 yrs) and compared with young patients (18-23 yrs) with severe (n = 30) and mild (n = 31) lung disease. Baseline PD was not significantly different across the three groups (long-term survivors, -42.8 (range -71.0- -20.5) mV; young/mild, -40.5 (-58.8- -19.5) mV; young/severe,-46.3 (-74.0- -20.0) mV). Response to amiloride (ΔAmil) was significantly different across the three groups (p = 0.01); long-term survivors had values (27.8 (range 8.5-46) mV) which were not different to either young group, but the young/severe group had significantly higher values (29.5 (11-47) mV) than those in the young/mild group (22.0 (7-39) mV; p<0.01). Baseline PD and ΔAmil were associated with forced expiratory volume in 1 s (FEV1) (co-efficient (95% CI) -0.13 (-0.23- -0.03); p = 0.009 and -0.12 (-0.20- -0.04); p = 0.003, respectively). Sweat chloride was lowest (p <0.05) in the young/severe group (93.5 (74-111) mmol·L⁻¹ versus 98.8 (76.5-116.0) mmol·L⁻¹; long-term survivors; and 99.5 (80.0-113.5) mmol·L⁻¹; young/mild). Δ Amil is associated with FEV1 but our findings indicate that long-term survival cannot be explained by residual CFTR function when measurements are taken in later life.

Cystic fibrosis and survival to 40 years: a case-control study.

The clinical course of patients with cystic fibrosis (CF) is variable and probably determined by many interacting factors. We aimed to examine the influence of early social and clinical factors on long-term survival. A case-control study of adult CF patients was used to compare long-term survivors (aged ≥ 40 yrs) with patients who died before reaching 30 yrs of age. Each case (n = 78) was matched by birth date with at least one control (n = 152), after exclusion of "late diagnosis" patients. Probability-weighted logistic regression models were used to identify influences on survival. Factors resulting in increased probabilities of survival included high body mass index (OR 1.76, 95% CI 1.40-2.22), forced expiratory volume in 1 s (OR per 5% increase 1.54, 95% CI 1.32-1.80), and forced vital capacity (OR per 5% increase 1.54, 95% CI 1.33-1.78) at transfer to the adult clinic and the exclusive use of oral antibiotics (OR 8.31, 95% CI 3.02-22.88). Factors resulting in decreased probabilities of survival were Pseudomonas aeruginosa acquisition (OR 0.18, 95% 0.05-0.65) or pneumothorax before transfer to the adult clinic (OR 0.02, 95% CI 0.004-0.08) and referral from a paediatric clinic in a deprived area (OR 0.13, 95% CI 0.04-0.38). Long-term survival is associated with the clinical features present by the time of referral to an adult clinic. Even "early-diagnosis" disease appears to have different phenotypes, possibly independent of CF gene function, that have different survival patterns.

Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985-2005.

INTRODUCTION: The treatment of patients with CF has continued to evolve. We hypothesised that sputum microbiology may have changed as a result of this. METHOD: Retrospective analysis of sputum microbiology from adult CF patients (1985 to 2005) using the Royal Brompton Hospital CF database. RESULTS: Colonisation with Pseudomonas aeruginosa or Staphylococcus aureus between 1985 and 2005 remained stable (77 to 82%, p=0.159; 54 to 47%, p=0.108; respectively). Haemophilus influenzae (48 to 6%; p<0.001), Aspergillus species (18 to 9%; p=0.002) and Burkholderia cepacia complex (9 to 4%; p=0.041) prevalence decreased. Stenotrophomonas maltophilia and MRSA increased (1 to 4%, p=0.02; 1 to 6%, p=0.002, respectively). CONCLUSION: P. aeruginosa colonisation has remained stable; there has been a decline in B. cepacia complex, H. influenzae and Aspergillus sp., and only a small increase in S. maltophilia and MRSA. Intensive antibiotic strategies have been employed, which, so far, have not resulted in clinically significant emergence of new pathogens.