Current • Practical • Peer-Reviewed

Clinical information on the management of patients with cystic fibrosis
including the latest information on new and emerging treatment options


CME Activities: New Free CME Courses

  • An Eight Module CME Series: Optimizing All Aspects of Management to Improve Outcomes in Patients with Cystic Fibrosis

    Faculty: John P. Clancy, MD (moderator); Susanna A. McColley, MD; Manu Jain MD, MSc; Felix Ratjen, MD, PhD; Adrienne P. Savant, MD, MS; Debbie S. Benitez, RN, MSN, ACNP-BC; Jennifer L. Taylor-Cousar, MD, MSCS; Carlos Milla, MD; Gregory Sawicki, MD, MPH

    This activity includes eight 30-minute modules that bring learners up to date on all aspects of cystic fibrosis (CF) treatment and management. Dr. John P. Clancy interviews eight experts in the CF field, each with their own specialization. The individual modules will focus on different areas of CF care, ranging from newborn screening to long-term real world efficacy and safety data. Each module is worth 0.5 CME/CNE credits.

    Available Credit:

    • 4.0 AMA PRA Category 1 CreditsTM
    • 4.0 Nursing contact hours
    • 4.0 Non-physician
  • Applying Recent Advances in the Science of CFTR-based Therapeutics to Improve Outcomes in Patients with Cystic Fibrosis

     

    Faculty: JP Clancy, MD; Debbie S. Benitez, RN, MSN, ACNP-BC; Isabelle Fajac, MD, PhD; Manu Jain, MD, MS; Steven M. Rowe, MD, MSPH; Gregory Sawicki, MD, MPH

    The content for this activity is based on the satellite symposium, “Applying Recent Advances in the Science of CFTR-based Therapeutics to Improve Outcomes in Patients With Cystic Fibrosis”, that was presented at the 30th Annual North American Cystic Fibrosis Conference in Orlando, Florida on October 28, 2016. The content highlights the latest advancements, particularly in CFTR-based therapeutics, for the treatment of patients with cystic fibrosis. Expert faculty discuss the most up-to-date analysis for clinical decision-making, including updates on assessment, monitoring, and management of patients treated with CFTR modulator therapies.

    Available credit:

    • 2.0 AMA PRA Category 1 CreditsTM
    • 2.0 Nursing contact hours
    • 2.0 Non-physician
  • Current Strategies for the Long-term Assessment, Monitoring, and Management of Cystic Fibrosis Patients Treated with CFTR Modulator Therapy

     

    Faculty: J. Stuart Elborn, MD (Chair), Jane Davies, MD, Marcus A. Mall, MD, Patrick A. Flume, MD, Barry Plant, MD

    The content for this activity is based on the satellite symposium, “Current Strategies for the Long-term Assessment, Monitoring, and Management for Cystic Fibrosis Patients Treated with CFTR Modulator Therapy” that was presented at the 39th European Cystic Fibrosis Society Conference on June 10, 2016. The emergence of novel targeted agents, that directly correct CFTR loss function alleles, has created new treatment opportunities for patients with cystic fibrosis with advanced disease. Knowledge of the role of these agents in the clinical setting is quickly evolving and will require physicians stay acquainted with the latest data as well as evidence-based treatment guidelines in order to achieve optimized cystic fibrosis patient care.

    Available credit:

    • 1.5 AMA PRA Category 1 CreditsTM
    • 1.5 CBRN contact hours
    • 1.5 Non-physician
  • New Insights into Disease Progression for the CFTR Modulator-Treated Cystic Fibrosis Patient
     

    Faculty: Susanna A. McColley, MD, Jane Davies, MD, Felix Ratjen, MD, PhD, Manu Jain, MD

    This educational activity is adapted from a live satellite symposium held during the 29th Annual North American Cystic Fibrosis Conference in Phoenix, Arizona. This educational symposium will update clinicians on the changes in disease progression that are now seen in CFTR modulator-treated patients. Expert faculty will present comprehensive case studies and conduct interactive panel discussions to enhance your knowledge in the advanced science of cystic fibrosis and patient management strategies.

    Available credit:

    • 2.00 AMA PRA Category 1 Credit(s)™
    • 2.00 CBRN Contact Hours
    • 2.00 Non-physician
  • The Effect of CFTR Modulation on the Disease Progression of Cystic Fibrosis in the Era of Precision Medicine
     

    Faculty: J. Stuart Elborn, MD , Jane Davies, MD,  Scott Bell, MD, Nico Derichs, MD

    This educational activity is based from a live satellite symposium from the 38th European Cystic Fibrosis Conference held in Brussels, Belgium. The expert faculty for this CME activity will present a comprehensive review of the effects of CFTR modulation therapeutics on cystic fibrosis disease progression. This clinically relevant activity also includes panel discussions with case presentations to advance your skills in caring for cystic fibrosis patients.

    Available credit: 

    • 2.00 AMA PRA Category 1 Credit(s)™
    • 2.00 Non-physician

    An application has been made to the EACCME® for CME Accreditation of this event.

  • Advanced Curriculum for Cystic Fibrosis: Integrating Genomic-Driven Data into Patient-Centered Treatment Strategies
     

    Faculty: J. Stuart Elborn, MD, Professor Isabelle Sermet-Gaudelus, MD, PhD, Patrick A. Flume, MD. Susan Madge, PhD, Frank Cerny, PhD, John P. Clancy, MD, Stacy Bichl, APN, Alison Morton

    An interactive faculty round-table discussion on the state of cystic fibrosis care and the development of strategies to manage and overcome challenges presented by variability of patient characteristics, genomic medicine, and the transition from pediatric to adult care. The goal of the webcast is to provide healthcare providers with practical information, which will update their knowledge on cystic fibrosis pathophysiology, genomics, and clinical trials relating to the rationale of therapeutic selection.

    Available credit: 

    • 1.50 AMA PRA Category 1 Credit(s)™
    • 1.50 Non-physician

Latest articles

  • End of life care for patients with cystic fibrosis

    Dorota Sands, Teresa Repetto, Lieven J. Dupont, Aleksandra Korzeniewska-Eksterowicz, Paola Catastini, Susan Madge

    Abstract


    Palliative care is an approach that improves quality of life for patients and their families facing problems associated with a life-threatening illness. Care planning is particularly important in CF, where predicting a time of death is extremely difficult. The patient and family should receive realistic information about health status and further options of care. Particularly important is the explanation that treatment does not stop during the terminal phase of the disease, instead the primary aim is to alleviate unpleasant symptoms. More invasive end of life care is becoming the norm in patients awaiting lung transplantation. Terminal care should be organised in the place chosen by the patient and their family. Ideally terminal care should not end when the patient dies, instead psychological and spiritual support should continue to bereaved families.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; End of life; Palliative care

  • Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease

    Dominique Debray, Deirdre Kelly, Roderick Houwen, Birgitta Strandvik, Carla Colombo

    Abstract


    Approximately 5–10% of cystic fibrosis (CF) patients develop multilobular cirrhosis during the first decade of life. Most CF patients later develop signs of portal hypertension with complications, mainly variceal bleeding. Liver failure usually occurs later, after the paediatric age. Annual screening for liver disease is recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt disease progression. Liver disease should be considered if at least two of the following variables are present: abnormal physical examination, persistently abnormal liver function tests and pathological ultrasonography. If there is diagnostic doubt, a liver biopsy is indicated. All CF patients with liver disease need annual follow-up to evaluate the development of cirrhosis, portal hypertension or liver failure. Management should focus on nutrition, prevention of bleeding and variceal decompression. Deterioration of pulmonary function is an important consideration for liver transplantation, particularly in children with hepatic dysfunction or advanced portal hypertension.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; Liver disease; Liver biopsy; Esophageal varices; Ultrasonography; Ursodeoxycholic acid


Resources/Guidelines

  • European Cystic Fibrosis Society Standards of Care: Best Practice guidelines

    Abstract

    Specialised CF care has led to a dramatic improvement in survival in CF: in the last four decades, well above what was seen in the general population over the same period. With the implementation of newborn screening in many European countries, centres are increasingly caring for a cohort of patients who have minimal lung disease at diagnosis and therefore have the potential to enjoy an excellent quality of life and an even greater life expectancy than was seen previously. To allow high quality care to be delivered throughout Europe, a landmark document was published in 2005 that sets standards of care. Our current document builds on this work, setting standards for best practice in key aspects of CF care. The objective of our document is to give a broad overview of the standards expected for screening, diagnosis, pre-emptive treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support. For comprehensive details of clinical care of CF, references to the most up to date European Consensus Statements, Guidelines or Position Papers are provided in Table 1 . We hope that this best practice document will be useful to clinical teams both in countries where CF care is developing and those with established CF centres.

    Keywords: Cystic fibrosis, Standards of care, Multidisciplinary management.

    1. Newborn screening and access to specialist care from early in life

    Kevin W. Southern (UK)

    Table 1 European consensus statements, guidelines or position papers.

    First author and topic Consensus (C), guideline (G) or position papers (P) Web URL
    Screening
    Castellani C [118] Benchmarks for cystic fibrosis carrier screening: A European consensus document (C) http://www.sciencedirect.com/science/article/pii/S1569199310000275
    Castellani C [2] European best practice guidelines for cystic fibrosis neonatal screening (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/Castellani_2009_Journal-of-Cystic-Fibrosis.pdf
    Sermet-Gaudelus I [3] Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening (G) http://www.sciencedirect.com/science/article/pii/S1569199310000652
     
    Diagnosis
    Mayell SJ [4] A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis (C) http://www.elsevier.com/__data/promis_misc/JCF8.pdf
    Castellani C [10] Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice (C) http://www.elsevier.com/__data/promis_misc/JCF7.pdf
    Bombieri C [119] Recommendations for the classification of diseases as CFTR-related disorders (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF%20Articles/JCF10_Sup2_S86_S102.pdf
     
    Prevention of progression of lung disease
    Döring G [120] Early intervention and prevention of lung disease in cystic fibrosis: a European consensus (C) http://www.elsevier.com/__data/promis_misc/2004.pdf
     
    Optimal nutrition and management of metabolic complications
    Sinaasappel M [49] Nutrition in patients with cystic fibrosis: a European consensus (C) http://www.elsevier.com/__data/promis_misc/2002.pdf
    Sermet-Gaudelus I [61] European cystic fibrosis bone mineralisation guidelines (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF%20Articles/JCF10_Sup2_S16_S23.pdf
     
    Treatment of the complications
    Döring G [31] Treatment of lung infection in patients with cystic fibrosis: current and future directions (P) https://www.ecfs.eu/ecfs-standards-care/references
    Colombo C [77] Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF%20Articles/JCF10_Sup2_S24_S28.pdf
    Debray D [68] Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF%20Articles/JCF10_Sup2_S29_S36.pdf
    Heijerman HJ [121] Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: A European consensus (C) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF_article.pdf
    Edenborough F [55] Guidelines for the management of pregnancy in women with cystic fibrosis (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/Pregnancy.pdf
     
    Tranplantation and end of life
    Hirche T [86] Practical guidelines: lung transplantation in patients with cystic fibrosis (G) http://dx.doi.org/10.1155/2014/621342
    Sands D [87] End of life care for patients with cystic fibrosis (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF%20Articles/JCF10_Sup2_S37_S44.pdf
     
    Psychosocial support
    Nobili R [108] Guiding principles on how to manage relevant psychological aspects within a CF team: interdisciplinary approaches (G) https://www.ecfs.eu/files/webfm/webfiles/File/documents/JCF%20Articles/JCF10_Sup2_S45_S52.pdf

    Anne Munck (F)

    Nataliya Kashirskaya (Rus)

    The ECFS Neonatal Screening Working Group (Core Committee)

    There is clear evidence to support newborn screening for CF. Early recognition provides the foundation for future management and prevents the delay in diagnosis that has affected so many families [1] . Protocols should be designed to reflect the culture and CFTR genetics of each population and minimise potential negative impacts. Please refer to the ECFS guidelines on newborn screening and on the management of young infants with CF diagnosed through screening [2] and [3].

    1.1. What population characteristics validate screening newborn infants for cystic fibrosis?

    Health authorities need to balance the benefit/risk ratio of screening newborns for CF in their population. If the incidence of CF is less than 1/7000 births, careful evaluation is required as to whether NBS is valid. The protocol must be shown to cause the minimum negative impact possible on the population.

    1.2. What health and social resources are minimally acceptable for newborn screening to be a valid undertaking?

    Infants identified with CF through a NBS programme should have prompt access to specialist CF care that achieves ECFS standards. A NBS programme may be a mechanism to better organise CF services, through the direct referral of infants for specialist CF care. Countries with limited resources should consider a pilot study to assess the validity of NBS and the adequacy of referral services for newly diagnosed infants in their population.

    1.3. What is an acceptable number of repeat tests required for inadequate dried blood samples for every 1000 infants screened?

    The number of requests for repeat dried blood samples should be monitored and should be less than 0.5%. More than 20 repeats for every 1000 infants are unacceptable (2%).

    1.4. What is an acceptable number of false positive NBS results (infants referred for clinical assessment and sweat testing)?

    Programmes should aim for a minimum positive predictive value of 0.3 (PPV is the number of infants with a true positive NBS test divided by the total number of positive NBS tests).

    1.5. What is an acceptable number of false negative NBS results? These are infants with a negative NBS test that are subsequently diagnosed with CF (a delayed diagnosis)

    Programmes should aim for a minimum sensitivity of 95%. Sensitivity is the number of true positive NBS results as a percentage of the total CF population (true positive and false negatives). Mechanisms should be in place for the collection of reliable long-term false negative data.

    1.6. What is the maximum acceptable delay between a sweat test being undertaken and the result given to the family?

    The sweat test should be analysed immediately and the result normally reported to the family on the same day.

    1.7. What is the maximum acceptable age of an infant on the day they are first reviewed by a CF specialist team following a diagnosis of CF after NBS?

    The majority of infants with a confirmed diagnosis after NBS should be seen by the CF specialist team by 35 days and no later than 58 days after birth. Programmes that are consistently missing these targets should undertake a protocol review and consider alternative strategies.

    1.8. What is the minimum acceptable information for families of an infant recognised to be a carrier of a CF causing CFTR mutation after NBS?

     

    • a) Families should receive a verbal report of the result. They should also receive written information to which they may refer later. Information should also be sent to the family primary care physician.
    • b) The information should be clear that:

    The infant does not have CF.

    The baby is a healthy carrier.

    Future pregnancies for this couple are not free of risk of CF and the parents may opt for genetic counselling.

    There are implications that could affect reproductive decision making for extended family members and the infant when they are of child bearing age.

    1.9. What are the minimum acceptable standards for reporting a CF diagnosis following NBS to the family?

     

    • a) A CF Specialist should discuss the result in person with the parents.
    • b) The family should receive written information to read after the consultation. The information should also be sent to the family primary care physician.
    • c) The family should have a clear understanding of short and long term plans with respect to the child's management.

    1.10. What are the minimal acceptable standards for the recognition and management of infants with an equivocal diagnosis lowast Definition; an infant with a repeatedly intermediate sweat test result, or an infant with two CFTR gene mutations (one of which has unclear phenotypic outcome) and a normal or intermediate sweat test result. An intermediate sweat test result is a sweat chloride value between 30 and 59 mmol/L [4]. following NBS?

     

    • a) The infant should be reviewed by a CF specialist.
    • b) This may be in a CF clinic or a non-CF clinic, if local circumstances are appropriate.
    • c) Extended gene sequencing should be undertaken when one or no mutations are recognised.
    • d) Sweat testing should be repeated in a centre with considerable experience (> 150 sweat tests per annum) and sweat chloride measured by a standard method.
    • e) Families should receive clear verbal and written information about the infant and have a clear understanding of what to expect with respect to progress and possible symptoms. Information should also be sent to the family primary care physician.

    2. Diagnosis

    Isabelle Sermet-Gaudelus (F)

    Kevin W. Southern (UK)

    Nataliya Kashirskaya (Rus)

    It is mandatory to have a high standard of care for diagnostic evaluation in cystic fibrosis. Diagnostic confirmation is required not only for children and adults presenting with suggestive clinical features, but also for infants with a positive newborn screening test or occasionally a positive family history. The following statements refer to a diagnosis outside of newborn screening.

    2.1. What are the minimal requirements to undertake the diagnosis for CF? [5] and [6]

     

    • a) To be able to undertake sweat testing to the standards described below.
    • b) To be able to perform genetic testing for the most appropriate panel for the local population. Access to extended exon DNA analysis should be available when required.
    • c) Resources to undertake clinical assessment including assessment of respiratory condition (respiratory tract culture for CF-associated pathogens, age appropriate respiratory function testing and imaging), non-invasive evaluation of exocrine pancreatic function and sperm count in male adults.

    2.2. What are the diagnostic criteria for CF? [5], [6], and [7]

    A sweat chloride above 59 mmol/L

    and/or

    two CF causing CFTR mutations in trans

    and

    at birth or clinical features, including but not restricted to diffuse bronchiectasis; positive sputum cultures for a CF-associated pathogen (especially P. aeruginosa); exocrine pancreatic insufficiency; salt loss syndrome; and obstructive azoospermia (males).

    2.3. What are the minimal standards for laboratories performing sweat tests? [8]

     

    • a) Sweat collection by experienced personnel (at least 150 sweat tests per annum) following national or international guidelines and subject to regular (at least annual) peer review. Internal quality control (usually three samples) of the sweat analysis with acceptable limits of agreement for chloride before each sample.
    • b) Use of a commercially available equipment approved for diagnostic use.
    • c) A regular external quality assurance for analytes according to national guidelines.

    2.4. What are the diagnostic standards of a sweat test? [9]

     

    • a) The quantity of sweat should indicate an adequate rate of sweat production (15 μL for Macroduct™ tube system).
    • b) A sweat chloride value greater than 59 mmol/L is consistent with a diagnosis of CF.
    • c) In the first six months of life a sweat chloride value less than 30 mmol/L makes the diagnosis of CF unlikely. There is no international agreement on the lower limit of the borderline range after that age, and thresholds of 30 or 40 mmol/L have been suggested.
    • d) Individuals with sweat chloride values in the borderline range should undergo a repeat sweat test and further evaluation in a CF specialist centre, including a detailed clinical assessment and extensive CFTR gene mutation analysis [9] and [10].

    2.5. What are the minimal standards for a laboratory performing mutation analysis for CFTR? [10]

     

    • a) The laboratory should be able to perform DNA testing using dried blood spot samples, whole blood (EDTA) and buccal swabs.
    • b) Samples should be analysed at least weekly to avoid significant delay in processing.
    • c) The laboratory should partake in an external quality assurance exercise with at least an annual certification.
    • d) The primary laboratory should be able to provide a limited CFTR mutation panel as a starting point that recognises at least one abnormal allele in more than 90% of the individuals with CF in a local population.
    • e) When only one mutation is recognised, an extended exon DNA analysis (gene sequencing) should be available in a primary laboratory or a secondary laboratory.
    • f) The disease liability of variants detected by DNA sequencing should be validated against the CFTR2.org database. Novel mutations or variants should be reported to locus specific databases (such as CFTR1 http://www.genet.sickkids.on.ca/app ) in order to facilitate future interpretation of variants of unknown clinical significance.

    2.6. What is a CF causing mutation? [10]

     

    • a) Since CF is an autosomal recessive disease the diagnosis of CF is substantiated in patients who bear two CF causing mutations (classified in the CFTR-2 database) in trans (i.e. one on each homologous chromosome). However, absence of two CF-causing mutations after extended DNA testing in the presence of other typical clinical, laboratory features of the disease or abnormal CFTR bioassays (see below) does not rule out CF.
    • b) Patients with “mutations of varying consequence” require further evaluation in a CF specialist centre.

    2.7. What are the minimal acceptable standards of care for reporting a diagnosis of CF to a symptomatic patient? [2]

     

    • a) A positive CF diagnostic test result should be reported promptly (ideally within 24 h).
    • b) The patient or parents/carers should receive clear written and verbal information about the disease and be provided with access to electronic media from the health service/national patient organisation. Contact information of the appropriate CF centre should be given (in accordance with treatment pathways for newly diagnosed CF in each country).
    • c) Genetic counselling should be offered and contacts for clinical genetic services provided. This will facilitate prevention of CF in affected families, including their relatives who may have an increased risk of the disease.
    • d) An early follow-up appointment should be arranged to assess understanding (no more than one week) and contact information of the CF centre should be given.
    • e) Patients and parents/carers should receive advice on other information resources, in particular the internet.
    • f) At the initial diagnostic meeting patients and parents/carers should receive information about the model for future clinical care.

    2.8. What are the minimal standards of care and follow-up for a newly diagnosed patient? [5]

    A patient diagnosed with CF should have immediate access to a CF specialist centre which has the multi-disciplinary capacity to provide care that complies with the ECFS standards of care.

    2.9. What are the minimal standards of care and follow-up for patients with symptoms suggestive of CF and intermediate sweat chloride values?[5] and [6]

     

    • a) A patient in whom the diagnosis is suggestive of CF and an intermediate sweat chloride concentration and only one or no mutation is identified should have access to a CF specialist centre for an appropriate assessment. It is important that such patients have long-term care. Follow-up in a clinic other than a CF clinic may be acceptable in collaboration with a CF specialist centre.
    • b) Ancillary tests may help establish a diagnosis of CF by revealing a second organ disease phenotype, such as pancreatic insufficiency (faecal pancreatic elastase), CBAVD in males, lung or sinus involvement, or by identifying an ion channel abnormality (see section 2.10 ).
    • c) These patients must be monitored carefully for development of any complications and appropriate therapy implementation.

    2.10. Should a patient with equivocal diagnosis have CFTR bioassay tests (nasal potential difference, intestinal current measurement)? [11]

    Patients with a diagnosis that is not clearly CF, should be assessed by a CF specialist. In cases with intermediate sweat test results, further electrophysiological investigations (nasal potential difference, intestinal short circuit current measurement) should be arranged if available.

    3. Prevention of progression of lung disease by ensuring all patients have access to therapies of proven effectiveness

    Felix Ratjen (Can)

    Patrick Flume (USA)

    Alan Smyth (UK)

    Life expectancy in CF has improved dramatically in the last 4 decades [12] . However, the majority of CF patients still die of respiratory failure [13] and so slowing progression of lung disease is a primary aim of CF therapy. The basic defect of CF leads to failure of mucociliary clearance, mucus plugging and secondary infection, with pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Chronic infection (with neutrophil-driven inflammation) is punctuated by acute exacerbations, following which lung function may fail to return to baseline levels [14] . Meticulous daily management of lung disease, together with prompt, aggressive treatment of exacerbations are therefore essential to preserve lung function. Best practice in this area is discussed in this section.

    3.1. Should initial or new bacterial infection with Pseudomonas aeruginosa be treated?

    Left untreated, new infection with P. aeruginosa will progress to chronic infection which is associated with worse lung function, worse nutrition, more pulmonary exacerbations and a higher mortality [15] . There is no clear evidence how quickly an eradication therapy should be commenced, but treatment should be started promptly (not more than 4 weeks from receiving a positive culture result). There is robust evidence that eradication treatment for P. aeruginosa is effective but no one regimen has yet been shown to be preferred because of superior efficacy [16] . Options include 28 days of tobramycin solution for inhalation (TIS) and up to 3 months of a combination of nebulised colistin and oral ciprofloxacin [17] . Follow-up cultures to document eradication after treatment are crucial.

    3.2. How should chronic bacterial infection with Pseudomonas aeruginosa be treated?

    When eradication therapy has failed, the diagnosis of chronic infection is made and long term inhaled antibiotic therapy should be commenced [18] . USA guidelines recommend TIS on alternate months for patients over 6 years, with chronic P. aeruginosa, irrespective of the severity of lung disease and continued indefinitely [19] . Whilst studies are lacking for children younger than 6 years, treatment at equivalent doses is also recommended in this age group. The licenced regimen is 300 mg twice daily for 28 days, alternating with 28 days off treatment. A dry powder inhalation of tobramycin (TOBI PodhalerTM) has been shown to be of equivalent efficacy [20] . Inhaled aztreonam lysine [21] is recommended as an alternative by both European and US guidelines. Colistin (2 MU twice daily) is used widely in Europe and is now also available as a dry powder preparation [22] . A specialist physiotherapist should advise on the timing of inhalational drugs and in an appropriate inhalation technique.

    3.3. Is chronic maintenance therapy indicated to treat other bacteria?

    Whilst individual patients may benefit from prolonged courses of antibiotics, there is currently little evidence to support chronic maintenance therapy for bacteria other than P. aeruginosa.

    3.4. Is prophylactic therapy indicated to treat bacteria?

    Prophylactic flucloxacillin for the first years of life to prevent infection with Staphylococcus aureus is endorsed by guidelines in some countries and recommended against in others; its use remains controversial [17] . There is no evidence to support prophylactic therapy for other bacteria.

    3.5. Is physiotherapy an essential component of chronic maintenance therapy and is any form of airway clearance superior to others?

    Chest physiotherapy, to achieve airway clearance is advocated in UK [23] and US [24] guidelines and should be available to all CF patients. A recent head-to-head trial [25] has shown that conventional positive expiratory pressure (PEP) is superior to high frequency chest wall oscillation (which relies on expensive equipment). However, in most cases there is little evidence to support the use of one technique over another. The airway clearance technique should therefore be tailored to the individual [26] . Flexibility and appreciation of patient preference are essential when prescribing a suitable airway clearance technique [27] . The CF specialist physiotherapist should have a comprehensive knowledge of all techniques: CF pathophysiology, the rationale for alternative approaches and any contraindications to specific treatment techniques [26] . Exercise and physical activity should be integral to the overall physiotherapy management suggested for every individual with CF, irrespective of age and disease severity. Reduction in exercise capacity is associated with a decline in respiratory function and survival [28] .

    3.6. What are important components of treating patients during episodes of clinical deterioration?

     

    • a) Early recognition and treatment.

    Progression of CF lung disease is characterised by periods of stability and intermittent episodes of clinical deterioration, termed pulmonary exacerbations (PEX). There is no agreed definition of a PEX but it is essential that these episodes are diagnosed and treated promptly. Patients having change in their symptoms that could represent a PEX need to have access to a specialised centre without delay. Necessary diagnostic tools for assessment of PEXs include lung function measurements, microbiological testing and radiological tests. Treatment of a PEX usually requires antibiotics which can be administered orally via inhalation or intravenously. If the patient needs hospital admission for intravenous antibiotic therapy it is important that this is not delayed.

    • b) Multidisciplinary care.

    Treatment of CF exacerbations does not rely on antibiotic therapy alone and requires a multidisciplinary approach. Patients should be reviewed regularly by a specialist physiotherapist who will adjust airway clearance and optimise aerosol regimens where appropriate. Patients often have a reduced appetite and require increased caloric intake during a PEX, due to higher metabolic demands. Access to a specialist dietician is crucial. Intravenous antibiotics should be selected with input from a pharmacist and infectious disease/microbiology specialist.

    • c) Antibiotic regimen.

    The pharmacokinetics of antibiotics differ between CF and non CF individuals and antibiotic dosages need to be adjusted according to disease specific guidelines (including higher doses in some cases) [29] . For P. aeruginosa, a combination of two or more antibiotics is recommended and, although evidence is lacking, 14 days of intravenous treatment is routine [30] . Some patients may benefit from longer therapy and this decision should be based on medical needs rather than resources and costs. Home intravenous antibiotic therapy is used in individual cases, but a home care programme needs to assure that all aspects discussed above are part of the treatment plan. Therefore hospital treatment remains the standard of care for most patients requiring intravenous antibiotic therapy.

    • d) Evaluating response to therapy.

    It is important to monitor lung function at the beginning and end of treatment of a PEX. Despite intensive treatment about 25% of patients experiencing a PEX requiring intravenous antibiotic therapy will have a persisting decline in lung function [14] , emphasising the need for maintenance therapies to prevent exacerbations.

    A comprehensive review of this topic is beyond the scope of this document and is available elsewhere [19] and [31]. Airway clearance techniques, physical activity and nutritional support are important components in maintaining lung health; here we focus on drug therapy only.

    3.7.1. Mucolytics

    The only mucus degrading agent that has proven efficacy in CF is dornase alfa. Studies have demonstrated improvements in lung function and a reduction in pulmonary exacerbations in patients regardless of disease severity [32] . Recent evidence from an analysis of a large data base suggests that dornase alfa reduces lung function decline [33] . Treatment effects are lost when treatment is ceased, therefore long term maintenance therapy is required. Other mucolytics, such as N acetyl cysteine, have not been proven to be effective in CF patients [34] .

    3.7.2. Hydrator therapy

    Airways in CF are dehydrated and increasing the airway surface liquid can be accomplished with osmotic agents that are called hydrators. The mechanism of action differs from that of dornase alfa and both approaches are complimentary. Hypertonic saline and mannitol are available as inhaled agents in Europe. Hypertonic saline (7%) has been shown to reduce pulmonary exacerbations and marginally improve lung function in a systematic review [35] . H ypertonic saline is currently used in many patients with moderate to severe lung disease and is supported by guidelines [19] . Mannitol has been introduced more recently and improves lung function [36] and [37]. The drug is available as a dry powder formulation thereby reducing treatment time. Both agents act as irritants and require pre-treatment with a bronchodilator and initial tolerability testing.

    3.7.3. Antibiotic therapy

    Airway infection in CF can be divided into early, intermittent and chronic infection. This scheme has been useful for P. aeruginosa infection (see question 1 above) and may also apply to other bacteria. If eradication fails and chronic infection with P. aeruginosa develops, inhaled antibiotic therapy has proven efficacy to reduce pulmonary exacerbations, improve lung function and respiratory symptoms [18] and is therefore part of standard of care [17] and [19]. Inhaled antibiotic therapy should be administered as long term maintenance therapy with either single agent therapy or alternating therapy of different antibiotics. The benefits of treatment outweigh the risks associated with the development of antimicrobial resistance which is often overcome by high topical antibiotic concentrations.

    3.7.4. Macrolides

    Macrolides are beneficial to CF patients likely due to their dual effect on infection and inflammation. Whilst not primarily efficacious against P. aeruginosa, there is evidence suggesting efficacy if the organism resides in biofilms which is the case in chronic P. aeruginosa infection. Maintenance therapy with azithromycin has been shown to improve lung function and reduce PEXs in chronically infected patients [38] and is part of recommended care [19] . A reduction in pulmonary exacerbations has also been observed in younger patients not infected with P. aeruginosa [39] . Some concerns remain, regarding the durability of their effect and their impact on inducing resistance for other bacteria.

    3.8. Is airway inflammation a target of chronic maintenance therapy and how should it be treated?

    Inflammation is an important component of CF lung disease. CF airway inflammation is neutrophil dominated and common anti-inflammatory drugs such as corticosteroids, either systemic or inhaled have no proven efficacy in CF patients, outside of treatment of concomitant asthma. High dose ibuprofen has been shown to reduce lung function decline [40] . Treatment requires monitoring of drug levels and despite these promising data it has not received widespread acceptance. Whilst other anti-inflammatory therapies are currently being studied, they are neither supported by sufficient evidence nor available for clinical care at the present time.

    3.9. CFTR modulator therapy — which treatments address the underlying defect in CF?

    Current treatment largely addresses the symptoms caused by the defective gene whilst CFTR pharmacotherapy aims to increase protein expression at the cell surface, or its function, with drug therapy. This treatment strategy could make a major difference in altering or even halting the disease process. Different drugs targeting specific classes of CFTR defects are currently being studied; to date only one drug has clearly demonstrated clinical efficacy. Ivacaftor, a CFTR potentiator studied in the gating mutation G551D, not only enhanced ion transport reflected by reductions in sweat chloride concentrations but also improved clinical measures such as lung function and PEXs [41] . The effect size of lung function changes exceeded that observed for any drug therapy available for CF patients to date. Whilst this mutation is found in less than 5% of patients worldwide, ivacaftor is a proof of principle demonstrating the potential impact of CFTR pharmacotherapy. In patients with the G551D mutation ivacaftor should be part of standard of care.

    3.10. How should fungal infections and severe/recurrent Allergic Bronchopulmonary Aspergillosis (ABPA) be treated?

    Aspergillus fumigatus as well as other fungi are commonly found in sputum of CF patients. Whilst their relevance is not entirely clear, more recent evidence suggests that A. fumigatus may act as a pathogen in at least in some CF patients [42] . Sputum cultures in CF patients should therefore include assessments for fungi. Allergic bronchopulmonary aspergillosis is a well characterised complication in CF patients and should be considered in any patient with clinical deterioration not responding to antibiotic therapy [17] . Diagnostic tests include allergy skin testing, measurements of serum IgE and IgE specific to Aspergillus, and serum precipitins for Aspergillus. These tests need to be available to every CF care facility. Treatment is with oral prednisolone plus/minus antifungal therapy [17] .

    3.11. How should we monitor lung disease?

     

    • A multi-disciplinary team is needed to assess and discuss all aspects of CF care.
    • Regular monitoring includes assessment of competence of airway clearance and inhalation technique and monitoring of adherence.
    • Clinical assessments that should be performed at least every 3 months and at times of symptomatic deterioration [43] .
    • As airway infection is a major driver of CF lung disease airway cultures should be obtained at every clinic visit [17] . The microbiological assessment needs to include specific culture media for the range of CF pathogens to ensure that relevant organisms are not overlooked.
    • Lung function testing guides therapy and should be performed at every clinic visit in patients old enough to cooperate (usually 5 years and older) [43] . Tests for younger children are currently under development. Routine lung function testing should include spirometry performed according to ATS/ERS criteria [44] and testing pre and post bronchodilator should be available.

    Chest X-rays are routinely performed on an annual basis in most CF centres as well as at times of clinical deterioration. Other imaging modalities such as high resolution CT scanning should be available as well and are used routinely in some CF centres.

    4. Optimal nutrition and management of metabolic complications of cystic fibrosis

    Anne Munck (F)

    Sarah Jane Schwarzenberg (US)

    Sue Wolfe (UK)

    Nutritional status has a strong positive association with pulmonary function and survival in CF. Attainment of normal growth in children and maintenance of adequate nutrition in adulthood represent major goals for the CF team.

    4.1. What are the goals for nutritional status in patients with CF?

    Infants and children should grow normally, with infants achieving normal weight and height percentiles similar to the non-CF population by two years of age. Older children and adolescents should achieve the 50th percentile for body mass index (BMI). In adults absolute BMI should be maintained above 20 kg/m2, ideally, 22 kg/m2 (females) and 23 kg/m2 (males). All patients should have normal fat soluble vitamin and micronutrient status. Essential fatty acid status should be monitored, if the assay is available. Guidelines have been published on nutritional evaluation and management [3], [5], [45], [46], [47], [48], [49], [50], and [51].

    4.2. How do we monitor nutritional status in routine care?

    Until growth ceases, accurate measurement of weight (kg), length or height (m), and head circumference (cm) (up to 2 years of age) should be made at each hospital visit. In adults, height should be measured annually. Measurements should be converted to BMI (> 2 years) and compared to national reference charts. Special attention is needed for toddlers and adolescents due to rapid growth velocity [3], [43], [45], [46], [47], [48], [49], [50], [51], [52], and [53].

    4.3. How do we determine exocrine pancreatic insufficiency (EPI) and adequate pancreatic enzyme replacement?

    Confirmation of EPI is required. Coefficient of fat absorption (CFA) is the “gold standard”, but is cumbersome. Faecal pancreatic elastase-1 (FE1) is simple and reliable from two weeks of age in the absence of liquid stools.

    Pancreatic sufficient patients should be monitored by annual FE1 during infancy and childhood and during periods of failure to thrive, weight loss or diarrhoea.

    Pancreatic enzyme replacement therapy (PERT) adequacy is determined clinically, monitoring nutritional status, signs and symptoms of malabsorption and excessive appetite with poor weight gain. Inappropriate doses of PERT may result in abdominal pain and constipation.

    Guidelines for testing for EPI and dosing of enzymes are available [3], [46], [47], [48], [49], [50], [51], and [54].

    4.4. What are the main strategies to providing preventive nutritional care?

    CF centres should be familiar with the recommendations for age-appropriate dietetic advice directed by CF dietitians [3], [5], [43], [45], [46], [47], [48], [49], [50], [51], [54], [55], and [56]. This includes:

    • Assessment of EPI and administration of PERT.
    • Selection of appropriate diet, with attention to a high fat intake.
    • Behavioural therapy to achieve positive mealtime experiences.
    • Providing sodium supplementation, when necessary, with special awareness in newborn screened infants.
    • Supplementing fat soluble vitamins, as indicated by laboratory testing.

    Women with CF who plan their pregnancies should receive pre-conception advice to improve their nutritional status [55] .

    4.5. What factors should be evaluated in patients with poor growth?

    Evaluation should be triggered by weight loss, or decline in weight or length/height percentile (< 2 years of age), or decline in BMI percentile for age and gender (> 2 years of age), or poor linear growth (< 18 years) or decline in BMI (> 18 years). Early intervention is essential to avoid significant loss of weight or growth.

    Diagnosing the cause of malnutrition relies on a careful assessment and a multidisciplinary approach. Potential causes include insufficient food intake, excessive stool energy losses (inadequate PERT or poor adherence), Giardia infection, coeliac disease, hypercatabolism from pulmonary disease, vomiting or gastroparesis, glycosuria and psychological impacts of CF.

    4.6. What are the options for interventional nutritional care?

    Interventions should be tried stepwise for a limited period of time or until nutritional status is optimised, depending on the severity of malnutrition and the age of the patient.

    • Anticipatory guidance. Reinforcement of adherence to diet, sodium and enzyme recommendations, using behavioural modification or motivational interviewing
    • Moderate malnutrition. Oral supplements should be used as additional calories in a time-limited trial or temporarily as meal replacement for ill patients. Temporary nasogastric (NG)/nasojejunal (NJ) feeds may be useful
    • Severe malnutrition. Enteral feeding via NG or gastrostomy tubes usually improves and maintains nutrition in a patient with CF

    Other therapies: Cyproheptadine and growth hormone are not part of routine management. Parenteral nutrition is only appropriate when enteral nutrition is impossible or fails.

    Nutritional rehabilitation can take 3–6 months, so if being used pre-operatively should start well ahead of an anticipated operation (e.g. organ transplantation) [45], [46], [47], [48], [49], and [56].

    4.7. When and how do we screen for diabetes mellitus?

    All CF patients who have not been diagnosed with diabetes/CFRD including those who may have had gestational diabetes should be screened during a period of clinical stability using the standard WHO protocol annually from age 10 years. A single abnormal OGTT requires confirmation with a second test. Refer to the published guidelines for additional detail.

    Published guidelines [57], [58], and [59] suggest more frequent screening with fasting/post-prandial glucose and/or OGTT in the following situations: pulmonary exacerbation, initiation of glucocorticoids, enteral tube feeding, planning for pregnancy, during pregnancy, planned organ transplantation and where there are symptoms of diabetes.

    4.8. What is the current management of CFRD?

    Care of patients with CFRD should adhere to standards of care for all individuals with diabetes; specific variations required for patients with CF are outlined below [57], [58], and [59].

    Patients with CFRD require care from a multi-disciplinary management team with experience in CFRD and in communication and consultation with the CF team. It is recommended that CFRD be treated with insulin, not oral diabetic agents. Glucose control may be challenging during pulmonary exacerbations, requiring more frequent monitoring and increased insulin. CF nutritional guidelines apply to CFRD patients. Modification of calorie, fat, protein, or salt intake as a result of the diagnosis of diabetes is not appropriate. Monitoring for complications of CFRD is similar to that for other forms of diabetes. CF patients with impaired glucose tolerance (IGT) must be monitored closely, particularly when ill, as they may need insulin therapy intermittently.

    4.9. Should patients be screened for CF bone disease and if so, how and which factors are involved in the prevention of reduced bone mineral density?

    Low bone mineral density (BMD) is a common complication in adolescent and adult patients and can occur in children as clinical status declines. Routine screening for reduced BMD using dual energy X-ray absorptiometry (DXA) scans from the age of eight to ten years is recommended, as detailed in published guidelines [60], [61], and [62].

    Centres should be familiar with the factors contributing to development of reduced BMD in CF and how to reduce these risks. The most common risk factors include: pulmonary infections, poor nutritional status and lack of weight bearing exercise, delayed puberty, glucocorticoid treatment, hypogonadism, and vitamin D, calcium and vitamin K deficiencies [60], [61], and [62].

    4.10. What is the current management of reduced bone mineral density?

    Known risk factors should be minimised and dietary intake of calcium and vitamin D should be optimised to enhance bone health. The use of bisphosphonates should be considered on an individual basis, taking bone mineral density, low trauma fracture history and transplant status into consideration [60], [61], and [62].

    5. Treatment of the complications of cystic fibrosis in a timely and effective way

    Patrick Flume (USA)

    Giovanni Taccetti (It)

    Alan Smyth (UK)

    5.1. Pulmonary complications

    Patients with cystic fibrosis (CF) may develop a variety of complications which, although infrequent, occur commonly enough that the CF centre should be well-prepared in their management. The following offers standards of diagnosis and management for these complications as well as resources for additional guidance.

    5.1.1. What is the best way to manage pneumothorax in patients with CF?

    Pneumothorax is a complication occurring more commonly in patients with more severe obstructive airways disease [63] . The CF centre should have a high suspicion for this complication in the patient with acute chest pain and shortness of breath and be able to make the diagnosis using radiologic studies (i.e. chest X-ray, CT chest). Management guidelines have been published [64] ; the Centre should be able to provide basic treatment (i.e. chest tube, pain control). For those patients who may need more complicated procedures (e.g. VATS), the Centre should have pre-agreed referral process with Thoracic Surgery Services.

    5.1.2. What is the best way to manage hemoptysis in patients with CF?

    Hemoptysis is a common complication and may range in severity from scant to massive, defined as > 240 ml/day or > 100 ml/day for several days [65] . Management guidelines have been published [64] . The Centre should give the patient and family clear guidance about when to call, if hemoptysis occurs, and should be able to provide the recommended therapies. For severe bleeding, the Centre should have access to interventional radiology (e.g. bronchial artery embolisation) and/or thoracic surgery.

    5.1.3. What is the best way to manage respiratory failure in patients with CF?

    The natural history CF lung disease is progression to advanced stage airways obstruction and eventual respiratory failure. The Centre should recognize progression to this stage and have discussions about lung transplant and advanced healthcare directives (see Section 6 ). The need for supplemental oxygen should be assessed in the patient with advanced stage lung disease (FEV1 < 40% predicted) both at rest and with exercise  [56] . Ventilatory support (e.g. non-invasive ventilation) should be provided in accordance with the patient's wishes for palliation of dyspnea [43] . The Centre should be able to assess the need for opiates to relieve dyspnea and pain associated with advanced stage disease [66] and [67].

    5.2. Liver and pancreas complications

    5.2.1. What is the best way to manage liver disease in patients with CF?

    Many pancreatic insufficient (PI) CF patients will have evidence of liver disease ranging in severity from very mild biliary fibrosis to end-stage cirrhosis. Cystic fibrosis related liver disease (CFLD) is a biliary cirrhosis that usually presents before age 20 years and can lead to portal hypertension and hepatic failure [68] and [69]. The Centre should monitor all patients with routine physical examination and periodic liver enzyme testing. Guidelines on the use of ultrasonography, ursodeoxycholic acid (“Urso”), and when to consider a liver biopsy, are available in published guidelines [68], [69], and [70].

    Patients with portal hypertension should be referred to a gastroenterologist/hepatologist for screening endoscopy and management of complications of pulmonary hypertension. Routine management of CF patients with cirrhosis should include immunisation against hepatitis A and B viruses, avoidance of NSAIDs and hepatotoxic agents (e.g. alcohol), and monitoring of the functional status of the liver (i.e. coagulation, albumin). The Centre should have a pathway for referral to a liver transplant programme, for those patients with advanced stage liver disease.

    5.2.2. What is the best way to manage cholelithiasis in patients with CF?

    Cholelithiasis is not always symptomatic [71] . The Centre should be suspicious when evaluating the patient with nonspecific abdominal pain and nausea. The Centre should have access to ultrasonography and HIDA scan for assessment of the gallbladder. For symptomatic gall stones, ursodeoxycholic acid is ineffective and surgical referral is usually necessary.

    5.2.3. What is the best way to manage pancreatitis in patients with CF?

    Pancreatitis is a less common complication in the CF population, but troublesome in some CF individuals with pancreatic sufficiency [72] . Recurrent acute pancreatitis may contribute to the transition from pancreatic sufficiency to insufficiency in CF. The presentation may be a nonspecific abdominal pain, so there should be a high suspicion when seeing a patient with a recurrent, unexplained pain and associated nausea and vomiting. The Centre must be able to evaluate with standard laboratory testing (i.e. amylase, lipase) and imaging (e.g. ultrasonography, CT, or MRI). Management principles are not different than for non-CF pancreatitis. However, acute pancreatitis is associated with severe dehydration and in the CF population, this may be more severe and attention to rehydration and electrolyte monitoring is crucial.

    5.3. Gastrointestinal complications

    5.3.1. What is the best way to manage gastroesophageal reflux disease (GORD) in patients with CF?

    GORD occurs commonly in patients with CF, affecting approximately 30% [73] . The Centre should be aware of the signs and symptoms of GORD and be able to provide appropriate diagnostic testing (i.e. impedance and pH probe, upper endoscopy) and treatment [74] .

    5.3.2. What is the best way to manage constipation in patients with CF?

    Constipation has a slow onset with reduced stool frequency [75] . It is common in CF and may be exacerbated by the use of narcotics. Most of the time constipation responds to hydration therapy, stool softeners (e.g., polyethylene glycol) or laxatives [76] . Enemas are rarely needed.

    5.3.3. What is the best way to recognize and manage distal intestinal obstruction syndrome (DIOS)?

    The symptoms of DIOS have acute onset with right lower quadrant pain [75] . The Centre should be able to recognise this complication (and its variants) and have standard protocols for diagnosis and treatment based upon published recommendations [43], [75], and [77]. Patients may respond to oral rehydration combined with stool softeners, but more severe cases may require IV hydration, nasogastric aspiration, and enemas. For patients who fail such conservative therapies, referral to a gastroenterologist with knowledge of DIOS is essential. Surgical intervention should be considered only in extreme situations and so the Centre should have surgeons who know about the gastrointestinal complications of CF.

    5.3.4. What is the best way to prevent fibrosing colonopathy (FC)?

    This is an uncommon complication. The only clear recommendation to prevent FC is to use the appropriate dose of pancreatic enzymes, not increase enzyme dose without clear indication and not exceed 10,000 lipase units/kg/day total enzyme dose [49] .

    5.3.5. What is the best treatment for appendiceal mucocele?

    Ultrasonography will aid the diagnosis [78] . In case of symptoms, appendectomy with resection of the appendix edges and resection of the caecal tip will avoid risk of recurrence.

    5.3.6. What is the best way to manage small bowel overgrowth in patients with CF?

    Small bowel overgrowth is suspected when patients have diffuse or periumbilical abdominal pain, excessive bowel gas, nausea, and malabsorption despite adequate enzyme intake. Risk is higher in patients who have had previous intestinal surgery or are using narcotics. It is recommended that diagnosis be made by clinical therapeutic trial of metronidazole [79] . An opinion from a gastroenterologist is essential.

    5.3.7. What is the best way to manage meconium ileus (MI) in patients with CF?

    MI is a neonatal emergency best handled by a pediatric surgeon (and pediatric radiologist) with expertise in MI, who should liaise promptly with the CF centre. The surgical team should be familiar with both non-surgical and surgical management [80] and [81]. Complicated MI is more severe, more difficult to treat, and may require prolonged hospitalisation. Post-operative management may require a centre familiar with nutritional management of short bowel syndrome.

    5.4. Other complications

    5.4.1. What is the best way to manage medication toxicities?

    The treatment of CF lung disease can result in complications due to the treatment and toxicity related to medications, especially aminoglycosides (e.g. nephro-, oto-, and vestibular toxicity).

    The Centre should utilise standard protocols for therapeutic drug monitoring when using aminoglycosides following recommended treatment dosing [17] . There should be strict avoidance of NSAIDs when using intravenous (IV) aminoglycosides to avoid nephrotoxicity. The Centre should perform assessment for ototoxicity using audiology testing for patients who have hearing loss or tinnitus, or as part of a routine screening assessment. The Centre should have access to a clinician experienced in vestibular assessment.

    5.4.2. What is the best way to manage nephrolithiasis in patients with CF?

    Nephrolithiasis is common in CF patients [82] . The Centre should be aware of the signs and symptoms associated with nephrolithiasis and able to evaluate by urinalysis and CT-IVP. The metabolic disorder causing kidney stones should be determined. The Centre should have access to a urology specialist and interventional radiologist for complicated nephrolithiasis.

    5.4.3. What is the best way to manage arthropathy in patients with CF?

    Arthralgias are common symptoms in CF patients [73] but arthropathy remains poorly understood. The Centre should be aware of this problem and have access to a rheumatologist who has knowledge of CF.

    5.4.4. What is the best way to manage sinus disease in patients with CF?

    Chronic sinusitis with or without nasal polyposis is common in patients with CF [73] . The Centre should routinely evaluate sinus disease and offer a recommended treatment, recognizing that this could be a source for lower airways infection [83] . The Centre should have access to diagnostic testing (i.e. CT sinus) and to an otolaryngologist experienced with CF-related sinus disease.

    5.4.5. What is the best way to manage allergic disease in patients with CF?

    With the exception of ABPA, discussed elsewhere in this document, the prevalence of allergic disease is not increased in CF patients and can be managed as for the general community. However patients can develop drug allergies (e.g. antibiotics) that can complicate treatment decisions. The Centre should be aware of the signs and symptoms of possible allergic response to treatment and should know when to stop that therapy accordingly. The Centre should have established protocols for desensitisation.

    5.4.6. What is the best way to avoid complications that result from chronic indwelling intravenous (IV) catheters in patients with CF?

    An indwelling IV catheter should be placed in accordance with the patient's wishes if difficulties exist in performing IV treatment. The Centre should have access to professionals experienced in the placement of indwelling catheters (e.g. Port-A-Cath). Only trained individuals should access the indwelling catheter, using standardized protocols in infection control and maintenance of the catheter. Common complications of catheters include vascular problems (e.g. infection, thrombus, SVC syndrome) [84] and [85]. The Centre should have a keen awareness of the signs and symptoms of catheter-related complications and be able to perform proper testing including blood cultures (to assess for infection), ultrasonography and contrast radiology studies (CT or MRI) for vascular occlusion.

    5.4.7. What is the best way to address pregnancy in a CF patient?

    Pregnancy can complicate the management of women with CF. The Centre should always inquire about possible pregnancy when assessing women who may be fertile, especially when considering additional medications that are contraindicated in pregnancy. The pregnant CF patient should always be considered as having high-risk pregnancy because of the potential pulmonary and nutritional/metabolic complications and should be seen by an obstetrician experienced in high-risk cases. Management recommendations for pregnant CF patients have been published [55] .

    5.4.8. What is the best way to address infertility in a CF patient?

    Females with CF can become pregnant and those with good lung function and nutrition are likely to complete the pregnancy. In less well females there is the possibility of reduced fertility, and they should be referred to specialists in fertility services if there is a perceived inability to become pregnant. Most (98%) CF males will be azoospermic and should be informed of this finding at an appropriate age. Sperm analysis should be offered to those patients interested in knowing their status. Patients should receive proper counselling regarding fertility options including assisted reproductive techniques.

    6. Transplantation and appropriate management of end of life issues

    Scott Bell (Aus)

    Alistair Duff (UK)

    6.1. Summary

    Transplantation is an established therapy for end-stage lung and liver disease in patients with CF. Referral to transplant services is enhanced by the CF team having an understanding of the processes leading to a success transplant. In some patients, transplant is not a suitable treatment option or does not occur. Effective management of the end of life is vital and requires attention to communication, symptom control and a multi-disciplinary approach to care, including expertise in palliative care. These standards include a series of questions about the approach to transplantation assessment and end of life care, utilising available published evidence and published transplant guidelines. For a detailed review of all facets of the topic see “Practical guidelines: Lung transplantation in patients with cystic fibrosis” prepared by the European Centres of Reference Network for Cystic Fibrosis (ECORN-CF) Study Group [86] and the ECFS End of Life Care Guidelines [87] .

    6.2. Questions

    6.2.1. What are the important determinants for the timing of listing for lung transplantation in patients with CF?

    The lead time for assessment and waiting for suitable donor lungs is variable but can be in excess of two years. Factors that are associated with increased mortality [88] and [89] and where transplantation referral [89] is recommended are in patients with:

    • FEV1% predicted of ≤ 30% predicted,
    • Rapid decline, particularly female and younger patients,
    • Oxygen therapy for hypoxaemia,
    • Hypercapnia,
    • Frequent exacerbation that responds poorly to intravenous antibiotics.

    Earlier referral should be considered in patients with refractory pneumothorax and recurrent massive haemoptysis [89] . Increased survival, limited donor availability and differences in organ allocation schemes have led to prediction models of mortality/survival which assist with decisions for prioritising patients for transplantation [90] and [91]. The complexities of timing transplantation-referral require close liaison with the Transplant Service. This will also help patients process complex information and make informed choices.

    6.2.2. What clinical features increase the risk for dying on the lung transplant waiting list?

    Priority for transplantation [88], [89], and [92] should be given to CF patients with:

    • Oxygen-dependent respiratory failure,
    • Chronic hypercapnia,
    • Pulmonary hypertension,
    • Undernutrition, especially female patients.

    The limited donor pool determines the number of possible transplants. National policies optimise the efficiency of donor-organ allocation differently, depending on donor identification systems and practical/geographical logistics. Prioritisation of urgent cases is managed at a national level.

    Regular and detailed communication with the Transplant Service is vital to allow regular updates of the clinical progress of all wait-listed patients.

    6.2.3. What are the important patient variables, which may prevent active listing for lung transplantation in CF?

    Exclusions for lung transplantation [89] include:

    • Malignancy within 2 years. A disease-free period of 5 years is generally required. Consideration for cutaneous and some urogenital cancers may be given
    • Untreatable dysfunction of another major organ (e.g. heart, liver, kidney),
    • Chronic extra-pulmonary infection (e.g. hepatitis B, hepatitis C, HIV),
    • Severe skeletal deformity,
    • Prolonged poor-adherence or irregular clinic attendance,
    • Untreatable psychological condition/s limiting ability to participate with therapies,
    • Lack of consistent social support system,
    • Substance addiction (e.g. alcohol, tobacco, within previous 6 months).

    Most transplant services do not assess patients with:

    • Chronic Burkholderia cenocepacia
    • Mycobacteria abscessus.

    Other infections (e.g. multi-resistant Pseudomonas aeruginosa, Scedorsporium species, Clostridium difficile) are influenced by local transplant unit policy and experience and require detailed discussion.

    Combined ‘liver/lung’ or ‘lung only’ transplantations require careful consideration in patients with advanced lung disease and portal hypertension.

    6.2.4. What complications of CF are important to prioritise prior to lung transplantation?

    Optimising nutritional status is a priority for wait-listed patients, but should not be a strong factor in delaying the listing process [92] .

    CFRD is present in 40–50% of patients at assessment and develops post transplant in another ~ 20% of patients. Increased mortality, infection and rejection-related hospitalisation have been reported in patients with CFRD at transplantation. Optimising control of CFRD is important whilst wait-listed [93] and [94].

    Chronic kidney disease (CKD) occurs in many adults with CF and where practical, limiting exposure to nephrotoxic drugs pre-transplant should be considered [95] . The impact of long-term systemic use of aminoglycosides before transplantation on post-transplant renal function is uncertain [96] . Calcineurin inhibitors, hypertension and CFRD have been associated with CKD following transplantation.

    Osteoporosis (24%) and osteopenia (38%) is reported in patients with CF [97] . Biphosphonate therapy may be required to maintain and improve bone health pre-transplantation.

    Systemic corticosteroids are required in some patients with advanced lung disease (e.g. APBA). Limiting daily dose of prednisolone to < 15 mg/day will assist in healing and reduce post-operative infection risk and limit further reduction in bone density.

    Psychologically it is vital to help patients maintain hope and counter demoralisation or exhaustion.

    6.2.5. Under what circumstances should invasive ventilation be considered in patients with CF?

    The role of invasive ventilation for patients with end-stage pulmonary disease is controversial and associated with poor outcomes [98] .

    Consideration should be made for patients who develop respiratory failure in the setting of an acute precipitant and where recovery is anticipated (e.g. massive haemoptysis, pneumothorax, influenza, post-operative care) [98] and [99].

    Transplantation from the ventilator is associated with higher early mortality [100] and is only offered in highly selected cases and not by all transplant services. Usually this only occurs in patients who have completed transplant work-up prior to ventilation.

    Some transplant services consider transplantation in patients who have required Extracorporeal Membrane Oxygenation (ECMO) for severe respiratory failure. Case reports have suggested excellent outcomes [101] . Close communication between the CF Team and the Transplant Service is mandatory prior to ECMO initiation.

    6.2.6. What therapeutic modalities are important in the palliative care of the patient with CF?

    Early discussions (including the potential for transplantation) to allow time to psychologically adjust and carefully consider options is required, particularly as misunderstanding is common. The physician should initiate a conversation about end of life care with the patient and family and should involve the multidisciplinary team. Significant psychological intervention can be required (e.g., management of anticipatory grief and work with family members) [102] .

    Symptoms that frequently require control include dyspnoea, chest pain, headaches, fatigue and poor sleep quality [103] . The use of narcotic analgesic, anxiolytics, airway clearance support, psychological strategies, oxygen and non-invasive ventilation support are important [67] . Teams should access support from palliative care colleagues to optimise symptom control, when required [103] and [104].

    The balance between effective active treatments whilst providing adequate symptom control can be difficult especially in patients waiting for transplant [103] and [105]. Symptom control does not preclude lung transplantation, however close communication between CF and Transplant teams is vital [103] .

    The death of a patient can have a significant effect on other patients and staff at the centre. Support of other patients with CF and staff members should be offered [103] .

    6.2.7. What factors are important in deciding on the location of care for the dying person with CF?

    Patients' and families' wishes should be the key to making decisions about where to manage the dying patient and where practical, measures taken to assist facilitating these wishes. The support available at home to optimally manage all symptoms is a key consideration (e.g., providing airway clearance support, the availability of timely symptom control).

    Patients prefer to have care by a staff that they know well in a familiar environment [106] and, in many cases, prefer to receive care in a hospital [103] and [107].

    Active management of patients to maximise symptom control often continues and potential for conflict between active management and optimising control symptoms needs to be carefully considered.

    Communication between all team members, community healthcare team (including primary care), the patient and the family are vital.

    6.2.8. How should CF-specific complications be managed following recovery from lung transplantation?

    After lung transplant, management of complications of CF remains important (e.g. CFRD, osteoporosis, DIOS). In many cases, the transplant service manages the complete care of the patient. However, the CF Centre should be available to support where assistance is desired.

    Psychosocial input is required to address psychopathology (e.g. drug-related psychosis, post-traumatic stress reactions).

    7. Psychosocial support

    Alistair Duff (UK)

    Gerald Ullrich (Ger)

    Mandy Bryon (UK)

    Living with CF can be emotionally and physically challenging for the patient with CF and their relatives. The condition and its treatment influence the ability to deal with normal tasks of daily living and unexpected life events. Good psychosocial care is now well-integrated into the medical team and there is a substantial body of literature that establishes the essential elements of the psychosocial role [5] and [108]. The focus of this paper is to prioritise key psychosocial issues and make recommendations for appropriate management.

    7.1. What are the core elements of supporting parents in the first year, post-diagnosis?

    Diagnosis of CF for the majority is by newborn screening. Screening for CF aims to minimise morbidity and mortality, yet potential disadvantages must be recognised and effects minimised [2] . Diagnosis of CF is traumatic, especially in an otherwise healthy infant. Parents can experience disbelief and dissociation from the diagnosis and baby, which can last well beyond the first few weeks [109] . Preventative counselling and emotional support must be offered to assess parents' (i) understanding of information, (ii) reactions to diagnosis and, (iii) coping style, support needs and resources.

    Parents need to engage in education about their child growing up with CF, ensuring balance between managing a complex health condition and enabling their child to grow with good self-esteem and concept. Families should be hopeful that their child will enter adulthood having a good quality of life with achievements similar to non-CF peers.

    Key tasks are to advise on:

    • Establishing treatment with baby's daily-routine
    • Helping parents accept and administer treatment
    • Communicating to family and friends about the medical condition
    • The availability of psychosocial follow-up for parents if required including couple counselling
    • Available financial support/benefits/allowances and other sources of support.

    7.2. International Depression/Anxiety Epidemiology Study (TIDES)

    European data emerging from the International Depression/Anxiety Epidemiology Study (TIDES) show that elevated depression scores are no different to general populations although higher anxiety scores have been reported, particularly amongst women. Several risk factors have emerged for increased depression and anxiety scores amongst patients. Anxiety and depression also appear particularly problematic in parents. Support for these problems should be available from the CF service. In what ways should they be identified and addressed?

    The CF team needs to assess the psychological well-being of people with CF routinely (see Centre Framework for access to psychological professionals). Surveillance for depression and anxiety in patients and parents should be conducted during annual review with psychometrics (e.g. HADS, CES-D) or discussion.

    Elevated psychometric scores require diagnostic confirmation. This should be undertaken by the CF Team psychologist via clinical interview. Where there is no integrated psychologist, referral should be considered to mental health agencies.

    Psychological intervention when required, needs to be supported with consideration of the practical, social, educational and vocational needs of the patient and their caregivers.

    7.3. How do we promote psychosocial resilience at key transition points and address potential associated psychosocial vulnerability?

    Transitions relate to significant changes in developmental and personal prospects and challenges for people with CF and the sense of responsibility these imply.

    Key transition points are:

    • i. Parental adaptation to diagnosis
    • ii. Commencement of schooling; nursery, primary and secondary
    • iii. Parental- to self-guided treatment
    • iv. Transition of care from paediatric to adult services
    • v. Entering the workplace or further education
    • vi. Loss of independence (e.g. retirement, loss of activities and functioning, increased reliance on intrusive treatments and carers, and facing transplantation or end of life).

    Psychosocial resilience is broadly an ability to recover from negative events with an absence of lasting emotional disturbance. It is multi-factorial, the elements of which are not all amenable to change [110] . The primary focus should be to increase social support and foster hope (primarily by paediatric preparation of patients for fulfilling adult lives and increasing self-efficacy and control). Emotional vulnerability should be addressed pro-actively at each transition point.

    7.4. What are the core components in addressing adherence, particularly to nebulised therapies?

    Improving adherence, particularly to nebulisers, is a key challenge for the prevention of progression of disease. Successful psychosocial intervention is determined by: (i) the Team ethos to patient care, (ii) collaboration with patients to increase their motivation and (iii) identifying barriers and actively supporting patients' efforts to increase treatment.

    • i. Teams must endorse a collaborative, nurturing and holistic approach to adherence, based on effective information-giving and empathic communication. Open discussion leads to facilitating care that is individually meaningful and accounts for needs for involvement and making informed choice. Psycho-social professionals need to support team-members' efforts to engage patients in conversation using active-listening skills
    • ii. Persuading patients with chronic sub-optimal adherence does not work. Psychosocial professionals must lead on efforts to address perceptual or emotional barriers to adherence in patients unwilling to acknowledge problems or who lack motivation [111]
    • iii. A range of psychological strategies are effective (e.g., reinforcement scheduling, problem-solving). Clinical trials of interventions are ongoing. Psychosocial professionals must achieve competence and provide leadership about techniques.

    7.5. What are the main components to supporting patients diagnosed in adolescence/adulthood?

    CF diagnosed beyond childhood may be for a range of reasons, mild or mis-diagnosed symptoms or less severe phenotype [112] . Patients often are angry and overwhelmed by information (prognosis, infertility) and ‘technical’ aspects of busy CF clinics. This leads to challenges in building a trusting alliance. A flexible and individualised approach to clinical management is needed for the particular patient which differs from the routine care provided to those diagnosed in early childhood. Emphasis must be placed on prognosis, fertility issues, personal support, and reviewing what CF knowledge patients may have acquired and from where (some sources being misleading) [113] .

    7.6. Disordered eating and body image problems in patients impact on treatment and prognosis. What are the key components in addressing these?

    Competing demands from CF management including monitoring of nutritional status emphasising weight gain within a culture emphasising thinness contribute to confused attitudes towards eating. Disordered eating and body image problems have been reported in people with CF [114] .

    The approach to nutritional management needs to take account of the patient's attitudes towards eating, shape and personal appearance, rather than focus simply on calorie intake and weight gain. Assessment of nutritional intake should include questions on the above and diet plans incorporating healthy eating idea.

    Educational programmes should be available to inform people with CF about digestion, calorie consumption and energy usage in CF. Health professionals working with people with CF should be equipped to identify disturbed eating behaviours allowing early detection and joint intervention between dietitian and psychologist is recommended.

    7.7. How should we tackle the key psychosocial issues of adulthood and growing older with CF?

    Key issues of adulthood are (i) normal tasks of adulthood being made more complex due to CF, (ii) making complex decisions (e.g. making vocational plans or making treatment decisions) and, (iii) coping with deterioration in health and loss of mobility and independence, as well as new complications diagnoses (e.g., CFRD), that can lead to, for example, increased anxiety and depression (demoralisation), low self-esteem and relationship difficulties.

    Key approaches are:

    • i. A pro-active approach during routine clinics and assessment during annual review can help identify emotional, practical and social support requirements (e.g., employment, fertility, risk-taking behaviours). Patients tend not to initiate these [115] and [116]
    • ii. Referral to a CF team's psychosocial professional or external specialist mental health services.

    CF teams must be aware of the likelihood of demoralisation occurring as a consequence of multiple health problems. This resembles, but is different from, depression in personal impact and treatment [117] .

    7.8. What are the core aspects of training and supporting the MDT in developing psychosocial skills?

    All members of the Team need to have some psychosocial skills. A 4-step skills model is described;

    • i. Team members should have training to enable recognition of psychological needs and provide information and general psychological support. Be able to access psychiatric services in an emergency.
    • ii. A team member can have additional training to: enable screening and referral for psychological distress, administer psychological first-aid following traumatic medical events (e.g., haemoptysis) and implement particular psychological techniques (e.g., desensitisation to painful procedures).
    • iii. Trained and accredited team member to assess for psychological distress and implement specific therapeutic techniques (e.g. counselling or therapy delivered according to an explicit framework). Requires supervision from a qualified mental health trained professional.
    • iv. Qualified mental health specialist (e.g. clinical psychologist), who can diagnose psychopathology and treat using specialist psychological interventions.

    Conflict of interest

    A.R. Smyth: personal fees from Gilead, other from MPEX, other from Pharmaxis, other from Vertex, grants from Forest Labs, outside the submitted work; S.C. Bell: grants and non-financial support from Vertex Pharmaceuticals, personal fees and other from Novartis, other from Gilead, personal fees and other from Rempex, outside the submitted work; P. Flume: grants and personal fees from Aptalis, grants and personal fees from Gilead Sciences, Inc, grants and personal fees from Bayer Healthcare AG, grants and personal fees from Novartis, grants and personal fees from Vertex Pharmaceuticals, Inc, grants and personal fees from Pharmaxis Limited, grants from Boehringer Ingelheim Pharmceuticals, grants from Grifols, grants from Savara Pharma, grants from KaloBios, grants from Cystic Fibrosis Foundation, grants from National Institutes of Health, grants and personal fees from Genentech, outside the submitted work; A. Munck: personal fees from Vertex, Novartis, personal fees from Vertex, outside the submitted work; F. Ratjen: personal fees from Boehringer Ingelheim, during the conduct of the study; personal fees from Vertex, personal fees from Novartis, personal fees from Bayer, personal fees from Talecris, personal fees from CSL Behring, personal fees from Roche, personal fees from Gilead, grants from Novartis, personal fees from Genetech, personal fees from Genetech, personal fees from Pari, outside the submitted work; S.J. Schwarzenberg: consulting for Spark HealthCare, outside the submitted work; G. Ullrich: personal fees from Chiesi Pharma GmbH, personal fees from Novartis Pharma GmbH, personal fees from Gilead Sciences GmbH, personal fees from GSK GmbH & Co. KG, personal fees from Activaero GmbH, personal fees from Axcan Pharma GmbH, outside the submitted work. S. Bojcin, M. Bryon, A. Duff, N. Kashirskaya, I. Sermet-Gaudelus, K.W. Southern, G. Taccetti, and S. Wolfe have no conflicts of interest to report.

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    Footnotes

    a Division of Child Health, Obstetrics & Gynaecology (COG), School of Medicine, University of Nottingham, UK

    b Department of Thoracic Medicine, The Prince Charles Hospital, Australia

    c Queensland Children's Medical Research Institute, Brisbane, Australia

    d Cystic Fibrosis Europe, Denmark

    e Cystic Fibrosis Unit, Great Ormond Street Hospital for Children, London, UK

    f Regional Paediatric CF Unit, The Leeds Children's Hospital, Belmont Grove, Leeds LS2 9NS, UK

    g Medical University of South Carolina, Charleston, SC, USA

    h Department of Cystic Fibrosis, Research Centre for Medical Genetics, RAMS, Moscow, Russia

    i Assistance publique-Hôpitaux de Paris, Hôpital Robert Debré, Paediatric Gastroenterology and Respiratory Department, CF Centre, Université Paris 7, 75019, Paris, France

    j Association française pour le dépistage et la prévention des handicaps de l'enfant (AFDPHE), France

    k Division of Respiratory Medicine, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Canada

    l Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, University of Toronto, Canada

    m Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Amplatz Children's Hospital, Minneapolis, MN, USA

    n INSERM U1151, France

    o Université René Descartes Paris 5, France

    p Unité fonctionnelle de Mucoviscidose, Service de Pneumo-Pédiatrie, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743, Paris, France

    q Department of Women's and Children's Health, University of Liverpool, UK

    r Institute of Child Health, Alder Hey Children's Hospital, Eaton Road, Liverpool L12 2AP, UK

    s Cystic Fibrosis Centre, Department of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy

    t Reutzstr. 1, 19055, Schwerin, Germany

    u Paediatric Cystic Fibrosis, Regional Paediatric CF Unit, The Leeds Children's Hospital, Belmont Grove, Leeds LS2 9NS, UK

    v Macedonian Cystic Fibrosis Association, Misko Mihajlovski 15, 1000 Skopje, Republic of Macedonia

    lowast Corresponding author.

    lowast Definition; an infant with a repeatedly intermediate sweat test result, or an infant with two CFTR gene mutations (one of which has unclear phenotypic outcome) and a normal or intermediate sweat test result. An intermediate sweat test result is a sweat chloride value between 30 and 59 mmol/L [4] .

    The term “mutation” is synonymous with “pathogenic variant”, according to the CFTR-2 database http://www.cftr2.org .

  • European Cystic Fibrosis Society Standards of Care: Framework for the Cystic Fibrosis Centre

    Abstract

    A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries.

    Keywords: CF Centre, Multidisciplinary team, Continuing professional development.

    1. Introduction

    People with cystic fibrosis (CF) have complex care needs that demand specialist, medical and allied healthcare expertise. The life expectancy has increased significantly in successive patient birth cohorts [1] as a result of more effective treatments and crucially because most patients attend CF Centres in line with the demonstration that patients who attend CF Centres for their care have better well-being and lung function than those who do not [2] and [3]. Thus, the CF Centre has become the model of care for people with CF; patients should receive full care from the Centre or have local directed care supervised by the Centre [4], [5], and [6].

    The framework of the CF Centre is formed by a multidisciplinary team (MDT), links with other medical and surgical specialties, the buildings and facilities, and the hardware and software that combined allow the MDT to provide a level of care that meets the complex medical challenges of this disease using effective diagnostics and holistic treatment programmes.

    The MDT members are at the core of the CF Centre and should be supported with continuing professional development (CPD), audit and research. Each discipline should establish its own rigorous framework, to ensure that patients' needs related to their discipline are met. The CF Centre should have adequate resources (e.g. staffing, IT equipment) and an infrastructure (inpatient and outpatient facilities) that allow the MDT to provide a level of care that is in accordance with the European Cystic Fibrosis Society (ECFS) standards recommended in this document, ensuring a safe, cost-effective and high-quality service. It is recognized that this may not be immediately achievable throughout Europe, particularly in countries with a low gross domestic product. It is crucial that where these standards cannot be met, procedures are put in place to enable them to do so within the short- to mid-term future, and that the hospital management commits to supporting CF clinicians. Without proper resources, a Centre is at risk of providing uncoordinated and substandard care. A lack of homogeneity in CF care will impact on patient outcomes [7] .

    At present, access to specialist CF services across Europe is inconsistent. Qualifications, training and roles vary considerably. Clinical practice should where possible be evidence based and reflect current research findings, clinical guidelines and consensus views. CF specialist professionals should be appropriately trained, qualified and registered by the state/national health authorities and legally recognized to practice within that country. Specialists should practice within their professional code of conduct and competency. They have a responsibility to maintain, update and enhance their knowledge, skills, efficacy and expertise through a proactive approach to continuing professional development. Participation in uni- and multi-professional audit and research, benchmarking, external quality assessment schemes, service evaluation, development and improvement, both of the specialist service and its provision as a whole is essential. As a CF Centre may be the only facility in a city or region, national and international programmes to support CPD, benchmarking and service improvement are strongly encouraged.

    The following sections describe the ECFS recommended standards for the individual specialties within the CF Centre.

    2. Framework for the paediatric and adult Centres

    Paediatric and adult CF Centres have many features in common, so that the requirements outlined below usually apply to both. As the health of children and adolescents continues to improve, the emphasis in paediatric care is on the prevention of disease progression. The morbidity and almost all of the mortality associated with CF have shifted to adults. Adult services should take into account the greater demands for inpatient provision and the higher prevalence of multisystem complications. Even before the transition from paediatric to adult care, it is most important that the two Centres work closely together. Regular meetings between the teams and shared protocols can smooth the transition process for the young adult and minimize the changes to their treatment. Effective communication between teams during this period is crucial to the success of the transition process.

    Children with CF will have their care transferred to adult services around the time of their 17th/19th birthday. Children, and their families, should understand that they will transfer to an adult Centre at this age. The paediatrician is not trained or experienced to manage the emotional, social, or medical demands of the adult patient. In the adult population, the manifestations of this multisystem disease (e.g. CF-related diabetes, osteoporosis, renal and liver complications and atypical infection) are significantly more problematic. The adult physicians are also best placed to fully inform patients about the potential risks of pregnancy and are competent in the non-obstetric care of pregnant women with CF.

    The young person with CF and his/her family must be involved in planning transfer at an early stage. The topic should be introduced when the diagnosis of CF is made and reinforced at appropriate intervals thereafter. Practical discussions should start at around 11 years of age in the context of educational, social and sexual conversations about growing up with a long-term condition. There must be close liaison with an agreed protocol for transition, and coordinators from both teams should be identified. The adolescent and his/her carers should have the opportunity to formally meet the adult team on more than one occasion. This is optimally achieved by having joint clinics with the adult team during the transition process. An opportunity to visit the adult facilities should be made available to patients and parents. Written information about each patient must be given to the adult team at the time of handover.

    2.1. The Centre

    Many of the required features are the same for adult and paediatric Centres. The CF Centre should have appropriate staff and facilities to provide comprehensive care and be capable of treating all CF-associated complications [4] . Patients should have direct access to the Centre 24 h a day.

    In order to justify and maintain an appropriate level of expertise and experience, a specialist Centre should have a minimum of 100 adults or children with CF. In some circumstances, the geographical location of a specialist CF Centre, or a low disease frequency in certain populations, may mean that the number of patients seen by a Centre is less, but never below 50. Centres with fewer than 100 patients should be linked to a larger Centre until there are sufficient patients, experience and resources to run an independent service.

    All patients with CF must have access to the Centre for routine and emergency care and advice. Patients should be reviewed regularly at a frequency appropriate to their individual needs. Routine appointments for people with stable disease should be every 2–3 months depending on the severity of their disease. Newly diagnosed infants should be seen more frequently (initially weekly).

    All patients should have an annual assessment to ensure that, as a minimum, a full medical, dietetic, physiotherapy and psychosocial review is performed once a year and that all surveillance blood tests are requested. The report should be written by a consultant who should discuss the review findings with the patient/carers, and the treatment plan should be agreed by all.

    2.2. The multidisciplinary team

    A core MDT of trained and experienced CF specialist healthcare professionals should be responsible for patient care. The MDT should be of appropriate size for the clinic population and should include the following CF specialists and support staff:

    • respiratory paediatrician/pulmonologist
    • clinical microbiologist
    • medical support from trainee(s)
    • clinical nurse specialist
    • specialist physiotherapist
    • specialist dietitian
    • clinical psychologist
    • social worker
    • pharmacist
    • clinical geneticist
    • secretarial support
    • database coordinator.

    There should be clear medical leadership of the MDT. The roles and responsibilities of all senior doctors in the team should be clearly defined.

    The ECFS concurs with the staff numbers for paediatric and adult Centres recommended by the UK CF Trust (Table 1 and Table 2) [6] . These numbers may vary according to health care organisation, geographical factors and local/regional variations in CF services. For example, the numbers of physiotherapists may vary according to the proportion of patients who self-administer intravenous antibiotics at home. Staffing numbers should reflect the model of shared care being used, taking into account time spent by staff from the specialist Centre in assessing and treating patients in a local hospital CF clinic. In addition, it is important that adequate cover is available for annual leave, study leave, and untoward events.

    Table 1 Whole-time equivalents per clinic size: full-time paediatric patients a .

    The MDT 50 patients 150 patients ≥ 250 patients b
    Consultant 1 0.5 1 1
    Consultant 2 0.3 0.5 1
    Consultant 3 0.5
    Medical trainees 0.8 1.5 2
    Specialist nurse 2 3 4
    Physiotherapist 2 3 4
    Dietitian 0.5 1 1.5
    Clinical psychologist 0.5 1 1.5
    Social worker 0.5 1 1
    Pharmacist 0.5 1 1
    Secretary 0.5 1 2
    Database coordinator 0.4 0.8 1

    a Patients with CFTR-related disorders should not be counted.

    b When clinics care for significantly more than 250 patients, additional consultants should be added to the multidisciplinary team (MDT) at a rate of approximately one additional consultant per extra 100 patients. Additional allied health professionals and support staff will also be required. There is likely to be a limit to the number of patients who can be cared for effectively in a CF Centre. This number will vary according to the facilities available in the hospital housing the Centre and the capacity of that hospital to support adequate staffing for the Centre. The MDT in individual Centres should review patient numbers annually and appreciate when resources are becoming stretched beyond the limit allowing care to be delivered to the standards recommended in guidelines. Paediatric patient numbers are likely to remain relatively stable but adult numbers are increasing every year. The need to establish a new adult Centre in any region must be considered proactively. Supply must precede, or coincide with, need.

    Table 2 Whole-time equivalents per clinic size: full-time adult patients a .

    The MDT 100 patients 150 patients ≥ 250 patients b
    Consultant 1 0.5 1 1
    Consultant 2 0.3 0.5 1
    Consultant 3 0.5
    Staff grade/fellow 0.5 1 1
    Specialist registrar 0.4 0.8 1
    Specialist nurse 2 3 5
    Physiotherapist 2 4 6
    Dietitian 0.5 1 2
    Clinical psychologist 0.5 1 2
    Social worker 0.5 1 2
    Pharmacist 0.5 1 1
    Secretary 0.5 1 2
    Database coordinator 0.4 0.8 1

    a Patients with CFTR-related disorders should not be counted.

    b See footnote in Table 1 .

    All members of the MDT must be registered with their relevant national health profession's council/body, and be a member of their national or international CF special interest group. They must have specialist knowledge and be experienced in the care of children and/or adults with CF. They must maintain CPD through attendance at local study days and national and international CF conferences.

    2.3. Access to other specialists

    It is essential that there is access to other medical and surgical specialists as needed. Essential supporting disciplines and services include: gastroenterology and hepatology (with expertise to perform emergency endoscopic ligation of oesophageal varices); diabetes and endocrinology; ear, nose and throat surgery; cardiothoracic and general surgery; specialist anaesthesia and pain control; rheumatology; nephrology; obstetrics and gynaecology; psychiatry; intensive care; and interventional radiology (with expertise to perform emergency bronchial arterial embolization, and elective percutaneous ultrasound-directed gastrostomy).

    2.4. Centre infrastructure

    The facilities at the CF Centre must be appropriate for all age groups. There should be sufficient capacity within the Centre for outpatients to be seen urgently whether this is within a clinic session, in a day-case unit or during a ward visit. The number of inpatient beds should be sufficient to allow non-urgent patients to be admitted within 7 days and urgent patients to be admitted within 24 h. The hospital ward nursing staff who are in contact with patients should have sufficient knowledge and experience of CF care. Finally, there should be resources and staffing available for home intravenous antibiotic administration supervised by trained outreach nurses.

    2.5. Segregation

    All CF Centres must have a clear policy for infection prevention and control, and facilities must allow for adequate patient segregation to prevent cross-infection. Patients should not share rooms, bathrooms or toilets during a hospital stay and should not be in contact with each other in waiting areas, such as in CF clinics, wards, the pharmacy and radiology departments.

    2.6. Access to specialist investigations

    Within the specialists CF Centre, there should be easy access to specialist investigations. These include biochemistry and haematology laboratories for routine tests as well as analysis of sweat and measurement of fat-soluble vitamin levels, aminoglycoside levels, and measures of glucose metabolism (including continuous glucose monitoring systems). The microbiology services should have the ability to process samples from people with CF and to reliably detect Burkholderia spp., non-tuberculous mycobacteria, and fungal infection. Molecular pathogen typing and immunology for allergic bronchopulmonary aspergillosis monitoring should also be available.

    Physiology must include lung function measures (both ward and outpatient spirometry), pulse oximetry including overnight O2/CO2 monitoring, exercise testing and fitness-to-fly testing.

    The radiology and nuclear medicine service should include computed tomography (CT) scanning, liver ultrasound, and dual energy X-ray absorptiometry (DXA scan) bone scanning. High-frequency pure tone audiometry and flexible bronchoscopy should also be available.

    2.7. Miscellaneous

    Facilities must exist for a parent/carer to stay with their child in hospital, and for a child to receive suitable education within the hospital if they cannot attend school due to illness. Related to these facilities should be access to appropriate play and/or recreation, with facilities for study.

    The CF Centre should be committed to active participation in clinical and translational research, and encourage patient participation in clinical trials. Each Centre should aim to be part of the expanding European Clinical Trials Network ( www.ecfs.eu/ctn ).

    2.8. European policy aspects of CF Centre care

    CF is a rare disease (i.e. < 1 in 2000), and as such belongs to the domain of several European Union (EU) policy initiatives relevant to research and healthcare. CF Centres, in compliance with the European Committee of Rare Disease Experts guidelines for Centres of Expertise for rare diseases, could operate within the frame of the newly established European Reference networks for rare diseases. As a rare disease, CF has a special status (Art. 54) in the Cross-Border Directive that facilitates exchange of expertise and eventually patients, and could thus address disparities in care. The development of CF Centre care in EU member states is supported by the EU Council Recommendation on action in the field of rare diseases (EC 2009/C 151/02). The introduction of orphan medical products into CF care also falls into such policy initiatives.

    3. Framework for the specialist doctor

    3.1. The CF consultant

    The Consultant who works in a specialist CF Centre should have received accredited training in paediatric or adult CF care, usually within the context of respiratory specialization. The knowledge and skills that the CF Consultant should have acquired are detailed below [8] .

    3.1.1. Knowledge

    The CF Consultant should have knowledge of the epidemiology and pathophysiology of CF and the aetiology of respiratory and non-respiratory manifestations and complications of CF, including massive haemoptysis, pneumothorax, respiratory failure, gastrointestinal disease, diabetes, problems of fertility and pregnancy (adult care) and psychosocial problems. The relevant investigations required, including microbiological investigations, non-invasive imaging modalities such as chest X-ray, CT imaging scans, should be familiar to the Consultant. The CF Consultant also needs to be familiar with the pharmacology of inhaled, oral and systemic drugs that are prescribed to patients and with the varied interventions employed by physiotherapists. The nutritional requirements of individual patients should be monitored and enteral tube feeding initiated when appropriate.

    Finally, the CF Consultant should know the indications for lung transplantation and be experienced in discussing this option with patients and carers.

    3.1.2. Skills

    CF Consultants should be able to apply the above knowledge to the management of respiratory and non-respiratory manifestations and complications. They should also be able to interpret the results from sputum microbiology tests and evaluate the functional status of patients. CF Consultants should also have good communication skills so that they can educate their patients and carers as the disease evolves.

    The CF Consultant's job plan should include adequate time allocation for CF patients, both for clinical tasks as well as managerial duties. This must include the capacity to maintain his/her own CPD in CF, which should involve attendance at national or international respiratory/CF meetings. In order to keep up to date with advances in treatment and research, the CF Consultant should spend a minimum of 50% of his/her working time dedicated to CF issues.

    3.2. The clinical lead

    The Director of the specialist CF Centre is usually the Clinical Lead and will be expected to lead the CF MDT. He/she should act as a link between clinical experts and the hospital management. The Clinical Lead/Centre Director will be expected to head the team and to ensure that: the needs of its members are met in terms of professional development and adequate support; that opportunities for attendance at national and international CF meetings are available; and that research is encouraged. The Director should also ensure that a team approach is maintained and that all members of the CF MDT have the opportunity to have their observations and opinions considered in patient management.

    It is essential that the Director understands the financial framework underpinning the country's healthcare system in order to develop and protect the financial support needed for the CF service. The Director should lead on staff recruitment, aiming to realize the human resource numbers as recommended in these Standards of Care. He/she should ensure that CF MDT meetings are held weekly, that Centre outcome measures are audited and that the results are reported back to the team so that standards of care are improved. In order to achieve the latter, the Director needs to oversee accurate data collection and documentation and that transfer of these data to the national and European registries is carried out.

    In some Centres there may be co-leads/directors of the service. Clear definition of responsibility and communication is essential in this situation.

    4. Framework for specialist nursing care

    4.1. The role of the CF Clinical Nurse Specialist

    The role of the CF Clinical Nurse Specialist should include [6] :

    • education, advocacy and psychosocial support, particularly at important times such as:
      • notification of a screening result and diagnosis
      • first admission to hospital
      • first course of intravenous antibiotics
      • a second diagnosis (e.g. CF-related diabetes)
      • transition from paediatric to adult care
      • reproductive issues, pre- and postnatal care
      • transplant and end-of-life issues
    • provision of support and education at home, particularly for home intravenous antibiotic therapy, nebulizer therapy, enteral feeding and non-invasive ventilation
    • provision of education to others about CF, including nurseries, schools, places of higher education and work places
    • acting as a link between the patient and family, primary care, community services and hospital
    • acting as a resource for training and education of other professionals involved in CF care.

    4.2. Access, availability and facilities

    There should be an adequate number of Clinical Nurse Specialists with expert knowledge of CF in the MDT [9] . The CF Clinical Nurse Specialist should deliver skilled support, advice and care directly to the patient and family wherever it is needed, both when attending hospital and at home. The service will vary according to differing patient populations, their needs and requirements. The role of the CF Clinical Nurse Specialist should continuously develop to meet the needs of the local CF population [4] .

    CF Clinical Nurse Specialists need sufficient time, office space, computer/printer and financial support in order to be able to provide a reliable service. They should stay in regular contact with patients and families in between clinic visits and therefore need access to technology such as email, phone and SMS texting.

    4.3. Key stages for delivery of care

    4.3.1. Diagnosis

    Diagnosis through newborn screening is now common in many countries. The CF Clinical Nurse Specialist plays an active role in talking to parents at diagnosis and providing ongoing support and continuing education following the initial discussion. Where screening is not available, the CF Clinical Nurse Specialist plays a similar role offering support, advice and education, which has to be individualized at a level and frequency to meet differing needs, whether diagnosis is within the first year of life, in older children or during adulthood. Contact between the CF Clinical Nurse Specialist and the patient/parent is therefore essential, whether this is in hospital, through home visiting, or via email or telephone.

    4.3.2. Pre-school

    For many, after coming to terms with the diagnosis and learning how to carry out treatment regimens while adjusting back to family life, the early years can seem almost normal. However, there are a few areas where the CF Clinical Nurse Specialist can provide education, practical advice and psychosocial support [10] , such as: administering medication; nutrition; adjusting pancreatic enzyme replacement therapy (judging the correct amount or offering advice when the child refuses to take the enzymes) in conjunction with the CF Dietitian; recognizing chest infections and making decisions about when to ask for advice or to start treatment; managing airway clearance and exercise in conjunction with the CF Physiotherapist; starting nursery; dealing with siblings; planning further children.

    4.3.3. School age

    When a child starts school it can be a traumatic experience for any parent. When the child has CF, parental anxiety about loss of control is likely. Many CF Clinical Nurse Specialists will visit the school (with parental permission) to educate and prepare teachers for managing CF in areas such as: maintaining good nutrition at school; administration of pancreatic enzymes and other medication (e.g. nebulizers/inhalers/oral); liaising with the school nurse; facilitating time off for hospital visits/admissions; dealing with the child's growing independence; advising on issues surrounding non-adherence, especially eating and airway clearance. The CF Clinical Nurse Specialist can help parents at this time, particularly with outreach contact as it gives parents time away from the clinical setting and allows them to discuss their anxieties in a safe and familiar environment.

    Most school-age children with CF are relatively well and take part in all academic, sporting and social activities provided by the school. Occasionally, extra treatment is necessary. Supporting treatments such as intravenous therapy or enteral feeding in the home often allows children to continue attending school. The provision of an outreach service can help, as routine checks (such as spirometry) can be performed by the CF Clinical Nurse Specialist, and problems can be identified early [11] and [12].

    4.3.4. Adolescence

    Adolescents with CF go through the same physical and emotional changes and have the same expectations as their healthy peers, irrespective of the severity of lung disease [13] . The CF Clinical Nurse Specialist should be able to have open and honest discussions about issues such as: recreational drug use and the effects on CF; sexuality, safe sex and contraception; fertility and pregnancy; further education and employment; body image and self-esteem; adherence to treatment regimens; relationships with parents; promotion of self-care, adherence and responsibility; accurate information about their disease and treatment.

    CF Clinical Nurse Specialists need to be sensitive and honest when giving information to young people with CF [14], [15], and [16]. Much of the information they (and their families) receive is from peers, the media and the Internet. Information given by the CF Clinical Nurse Specialist must therefore be correct and up to date.

    4.3.5. Transition from paediatric to adult care

    All children with CF should move from paediatric to adult care. The importance of getting this transition process right is widely recognized [17] and [18]. Transition from paediatric to adult care happens at a time when the young person with CF is moving into adulthood in other areas of their life, such as further education or employment, forming relationships and taking more responsibility for their own lifestyle. Transition can therefore be difficult for many reasons. CF Clinical Nurse Specialists involved with the transition process need to be aware of the many barriers that can prevent this process being successful [19] and [20]. Both the paediatric and adult CF Clinical Nurse Specialists play an important role in ensuring a successful transition and will manage details such as: patient and parent involvement in decision making; clear communication between paediatric and adult CF MDTs; appropriate transition clinics involving the MDT; ensuring attendance at the adult clinic with appropriate follow-up.

    Young people may find that their first admission to the adult Centre is to an unfamiliar ward where they do not know the staff. For these individuals and their families, the first inpatient admission requires an increase in awareness and sensitivity from the ward staff and further CF Clinical Nurse Specialist support to both the patient and the family. The CF Clinical Nurse Specialist should liaise between the ward and the CF MDT.

    4.4. Adult issues

    CF Clinical Nurse Specialists play a vital role in helping adults maintain a balance between adhering to treatment and their lifestyle, and recognize the need to help individuals adapt treatment regimens to suit them. This will include: educating employers and work colleagues; liaison with government agencies and the work place to ensure maximum support (financial and practical) to enable patients to stay employed or to re-train; advocacy on a patient's behalf with local social services; educating and liaising with family doctors and local pharmacists; negotiating easier access to classes at school or university; increasingly, CF Clinical Nurse Specialists will work in collaboration with the family doctor, social services and the CF team to support patients caring for their ageing parents; providing education, counselling and support around reproductive issues for both men and women with CF; practical and emotional support throughout the neonatal and postnatal periods.

    Complications occur more commonly in older patients with CF [21], [22], and [23]. An outreach service led by a CF Clinical Nurse Specialist may have to manage complex medication regimens and organise care to help maintain a lifestyle/treatment balance.

    4.5. Transplantation and end-of-life issues

    When admissions become more frequent, longer in duration and the burden of treatment increases, patients or their families may wish to raise the issue of lung transplantation. Early discussion with the team raises questions and concerns for both patients and their families. The CF Clinical Nurse Specialist's role as advocate and educator for the patient is vital in this decision process.

    CF continues to be life limiting. Death in childhood, although uncommon, does occur. Unlike other chronic diseases, the end stages of CF can be difficult to recognize. Patients often need opportunities to discuss their fears and anxieties but may feel uncomfortable or protective talking about these issues with their family for fear of upsetting them or ‘letting them down’. Advocacy allows the CF Clinical Nurse Specialist to facilitate discussion between the patient and family. Early discussion about an individual's wishes for the terminal stage of their disease is essential to aid appropriate care planning. Issues that may be raised include transplantation, wills, funeral arrangements, writing letters or diaries to the family and where they would like to be when they die [24] and [25].

    The CF Clinical Nurse Specialist plays a key role in providing individual emotional support for parents/partners. Although some families are willing to return to the hospital, many find this difficult. Visiting the family at home allows bereavement support to be offered in a safe and comfortable environment. Home visiting also allows other family members, siblings or grandparents for example, to receive support.

    4.6. Core competencies, qualifications and professional development

    4.6.1. Core competencies

    The CF Clinical Nurse Specialist should be competent in the following key areas.

    • Clinical practice
      • Diagnostic and assessment skills
      • Treatment skills
      • Recognizing and monitoring change
      • Facilitating programmes of care
      • Clinical research and audit
    • Education
      • Knowledge of CF and associated issues
      • Evidence-based practice
      • Teaching and training: patients, carers, other healthcare professionals
    • Communication
      • Patients and carers
      • MDTs
      • Liaison with clinical, social, educational, employment and other lay agencies
    • Support and advocacy
      • Social care
      • Advocacy
      • Counselling skills
      • Legal and ethical issues.
    4.6.2. Qualifications and professional development

    The CF Clinical Nurse Specialists must be registered as licensed practitioners in their country. They should also have specialist knowledge and be experienced in the care of children (including specific paediatric training) and/or adults with CF. The CF Clinical Nurse Specialist must contribute to research in all areas of CF, either through developing individual projects or participating in research carried out by the CF MDT, and maintain CPD through attendance at courses and conferences.

    CF is a demanding disease to manage for the patient, family and the CF MDT. The CF Clinical Nurse Specialist must act as a link between the patient and family, primary and community services, and the hospital. The CF Clinical Nurse Specialist has a responsibility to ensure that every patient receives appropriate care for their individual needs. Patients should receive lifelong support and good-quality treatment through the coordination of care between patient and family, community services and hospital, both practically and through support and advice.

    5. Framework for physiotherapy care

    The specialist CF Physiotherapist should take the lead in providing high-quality treatment of airway clearance, physical exercise and inhalation therapy. Physiotherapy programmes in CF care are primarily preventive, and regular input is required from the time of diagnosis. The aims of therapy are to maintain ventilation in all parts of the lungs, to postpone progression of pulmonary disease, to stimulate establishment and retention of normal physical capacity and to avoid pain and musculoskeletal complications due to pulmonary or bone disease [26] . The CF Physiotherapist should also develop strategies for the management of complications or co-morbidities experienced by the ageing patient and should optimize the respiratory physiotherapy programme, which includes highly technical equipment, non-invasive ventilation and physical exercise with oxygen supplementation. Physical rehabilitation is essential for patients on a transplant waiting list.

    5.1. The role of the CF physiotherapist

    The CF Physiotherapist should be available for regular contact and assessment of the patient for treatment, lung function testing, physical surveillance and therapy evaluation. The frequency of this will vary according to the patient's age and clinical status but as a minimum should happen at every routine outpatient clinic and daily during each hospitalization (including when patients are admitted under the care of other specialists and to intensive care). A more extensive assessment should take place annually.

    5.2. Regular assessment and therapy

    Regular lung assessments by the CF Physiotherapist should include lung function test data, respiratory signs, degree of dyspnoea, oxygenation cough characteristics and questioning about activity of everyday life. All interventions should be tailored to the individual, with consideration of their age, severity of disease, physical side-effects or complications, and social and domestic circumstances.

    5.2.1. Inhalation therapy

    As the CF Physiotherapists are responsible for inhalation therapy they should be familiar with techniques, equipment provision and appropriate maintenance of devices. There is a need for consideration of timing of inhalations in relation to airway clearance as there may be a positive interdependence between the two. Education of patients in appropriate inhalation techniques is essential for optimal deposition of inhaled drugs. The CF Physiotherapist should be familiar with the appropriate nebulizer systems proven to be safe and effective in the delivery of the medications prescribed. Cleaning and maintenance of the whole nebulizer system are essential to ensure that medications are delivered optimally and safely [26] and [27].

    5.2.2. Airway clearance therapy

    Physiotherapists are responsible for airway clearance therapy. This involves knowledge and experience of the full range of techniques available and immediate evaluation of therapy, for example by expiratory sounds, sputum volume and characteristics and by ability to control cough. Alternative physiotherapy techniques should be recognized and considered for individual patients. There are a variety of effective airway clearance techniques that allow patient independence. These are based on sound physiological concepts and allow the CF Physiotherapist to individualize treatment programmes [28] . There is no standard airway clearance regimen or conclusive evidence to promote one technique over another [6], [26], [29], [30], [31], [32], [33], [34], [35], [36], and [37].

    5.2.3. Postural and musculoskeletal assessment

    Assessment of postural and musculoskeletal function is carried out to evaluate therapy. Physical exercises aimed at the maintenance of good posture and chest mobility should be included in the treatment from the beginning. As with all physiotherapy interventions the exercises should be individually tailored to each patient [26], [38], and [39].

    5.2.4. Exercise capacity

    Exercise capacity and the opportunities for exercise prescription for the person with CF include any pre-transplantation preparation. Reduction in exercise capacity is associated with a decline in respiratory function and survival [40] and [41]. Physical exercise has been reported to improve lung function and decrease habitual inactivity in children with CF [42] . The CF Physiotherapist should perform regular exercise testing with a frequency dictated by disease progression, and in cases of specific needs like transplantation assessment or evaluation of a treatment. Care should be taken when prescribing exercise activities for patients with advanced disease, particularly when they may also experience haemoptysis, exercise-induced desaturation requiring supplementary oxygenation, pulmonary hypertension, cor pulmonale, joint arthropathies and other co-morbidities [26] . The CF Physiotherapist should also assess supplementary oxygen needs, for exercise or ambulation [26] and [43].

    5.2.5. Non-invasive ventilation

    It is recognized that non-invasive ventilation is a useful therapeutic adjunct to support airway clearance therapy and reduce the work of breathing and fatigue experienced by the severely ill patients during treatment. Non-invasive ventilation may also be useful during exercise management to decrease breathlessness, improve oxygenation and, consequently, to maintain or improve exercise tolerance [44], [45], and [46]. Additionally, non-invasive ventilation is implemented to facilitate optimal function in patients with end-stage disease and possibly as a bridge to transplantation [45] .

    5.2.6. Other considerations and assessments

    Surveillance regarding the incidence of urinary and faecal incontinence should also be the responsibility of the CF Physiotherapist. A sensitive and open approach with early recognition of symptoms should be adopted; questioning can occur as early as 10 years of age [47] and [48].

    The CF Physiotherapist should also be responsible for:

    • management of associated complications and issues with adherence while continuing to promote independence that is age appropriate
    • appropriate inhalation and airway clearance therapy and physical exercise programmes during pregnancy [49]
    • ensuring the appropriate maintenance and function of equipment provided for therapy and nebulization
    • the education of patients, carers, teachers and local physiotherapists; the physiotherapists should work closely with the other professionals for the benefit of the patients' holistic care
    • palliative care, especially in relation to relieving dyspnoea in the terminally ill, and advising on when to withdraw non-invasive ventilation.

    5.3. Service provision

    When patients are resident in hospital for the treatment of an exacerbation or for routine management they should be reviewed by the CF Physiotherapist within 24 h of admission, and a treatment plan focusing on airway clearance, inhalation therapy and exercise tolerance should be implemented. The CF Physiotherapist should have a comprehensive knowledge of all techniques, respiratory pathophysiology, the rationale for alternative approaches and any associated contraindications to the treatment techniques available [28] . CF physiotherapy services should be available 7 days a week, with an out-of-hours physiotherapy service available for those patients who may deteriorate overnight.

    5.4. Professional development, research and availability

    Education, clinical audit, research and contribution to a CF registry should be pursued. CPD is integral to the work of the CF Physiotherapist who should maintain and increase specialist knowledge by attendance at relevant postgraduate courses, lectures, and national and international conferences. They should preferably be an active member of their national CF physiotherapy group and be available to represent physiotherapy interests for their country at meetings of the International Physiotherapy Group for CF (IPG/CF) [50] . The CF Physiotherapist should contribute to research, development and evaluation by performing audits, participating in multicentre studies and contributing data to registries. They should collect annual data in order to evaluate their care [50] and [51].

    6. Framework for dietetic care

    A normal nutritional status is positively associated with better lung function [52] and [53]. Healthy body weight, height and BMI are positively associated with survival [53], [54], and [55]. Ensuring normal growth in children and adolescents and maintaining a normal BMI in adults is essential.

    Specialist CF Dietitians have an integral role to play in patient management and have overall responsibility for the delivery of expert nutritional care. They should be actively involved in the nutritional training, education, development and support of other healthcare professionals involved in CF care. Dietetic intervention should be both proactive and reactive, evolving in response to the needs of each individual patient. It is essential that the specialist CF Dietitian has expertise in managing the complex nutritional challenges and rare complications of the disease.

    6.1. The role of the specialist CF dietitian

    The specialist CF Dietitian should take the lead in providing high-quality treatment and care to ensure optimal nutritional status, including nutritional screening and surveillance, and regular patient assessment with review of all aspects of nutrition and gastrointestinal status. The frequency and type of assessment will vary with age and clinical status.

    The specialist CF Dietitian should advise and educate patients and carers about the principles of nutritional management in CF to enable them to meet their nutritional needs and achieve optimal growth, weight and body composition. Advice may be required on the management of pancreatic insufficiency, fat-soluble vitamin deficiency, altered gastric motility, gastro-oesophageal reflux, impaired glucose tolerance/diabetes, reduced bone mineral density, renal disease and liver disease.

    Age-specific individualized advice should be offered. This advice should consider psychosocial barriers (especially during adolescence) and be supported by written literature, visual, audio and/or audiovisual aids, computerized learning packages and ‘apps’. This is an ongoing and evolving process and must take into account the key times that may require more intensive dietetic intervention and support, such as diagnosis, early infancy, initiation of pancreatic enzyme replacement therapy, weaning, adolescence and self-management, pregnancy, initiation of enteral tube feeding, diagnosis of CF-related diabetes, transplantation and end-of-life care.

    It is important to remember that patients diagnosed later in life tend to present atypically and have unique educational requirements. Improving adherence to the many prescribed nutritional therapies is a key challenge. The specialist CF Dietitian should provide a collaborative approach to increase motivation to change and support patients' efforts to change. This is based on providing information and facilitating open discussion. It is important to address emotional and perceptual barriers to adherence, e.g. a reluctance for females to gain weight during adolescence.

    6.2. Clinical governance, research and quality framework

    The specialist CF Dietitian should be a member of, and an active participant in, specialist interest groups locally, nationally and internationally, (e.g. European Cystic Fibrosis Nutrition Group) in order to support their practice. They should be encouraged to be an Allied Healthcare Professional Member of the European Cystic Fibrosis Society.

    6.3. Dietary assessment

    6.3.1. The annual assessment

    Dietetic staffing should allow for a structured annual assessment of dietary intake and nutrition. Formal assessment of dietary intake using a written diet and enzyme diary should be targeted at selected individuals only; in large CF Centres, such an exercise is unsustainable if applied to all patients and is unlikely to provide additional information for patients with stable nutritional status. The annual evaluation should address all aspects of nutritional status assessment, nutritional intake, pancreatic enzyme replacement therapy, and the management of nutritional and metabolic complications. The annual assessment will help to provide the framework for future care planning and anticipatory guidance.

    The reader is referred to the document “European Cystic Fibrosis Society Standards of Care: Best Practice guidelines – Optimal Nutrition and Management of Metabolic Complications of Cystic Fibrosis” for details on the assessment of the following:

    • pancreatic status and absorption
    • growth and nutritional status
    • bone mineral density, and
    • glycaemic status.

    6.4. Service provision framework

    Traditionally the framework for service provision is divided into:

    • inpatient care
    • outpatient care
    • home care
    • shared care
    • transitional care
    • annual review.

    All patients should have access to a specialist CF Dietitian at all of these times. The same dietitians should provide inpatient and outpatient advice to ensure continuity of care and to prevent the important minutiae of care being overlooked. Advances in telecommunications and technology allow opportunities to re-evaluate service delivery.

    6.5. Key considerations of service provision

    6.5.1. Inpatients

    A clear discharge plan and follow-up arrangements should be provided for patients treated in hospital, especially for those requiring ongoing nutritional support.

    6.5.2. Home treatment

    For those being treated with intravenous antibiotic therapy at home, there should be access to a specialist CF Dietitian at the start and end of this treatment, with ongoing nutritional support provided remotely (e.g. by telephone, telemedicine) or via the CF Clinical Nurse Specialist. There should be clear channels of communication between the CF Clinical Nurse Specialist and the specialist CF Dietitian.

    Outpatients with CF-related diabetes should have access to a specialist CF Dietitian with experience in the management of this CF complication.

    6.5.4. Shared care

    In general, due to the complexity of the dietetic needs of adults with CF, shared care is not appropriate. In paediatric Centres there should be:

    • protocols for the delivery of care and lines of responsibility for nutritional management
    • an identified dietitian within the shared care hospital who will liaise with the specialist CF Dietitian at the Centre
    • review of all patients by the Centre's specialist CF Dietitian at least twice a year.
    6.5.5. Transition

    The paediatric and adult specialist CF Dietitians should work together to promote autonomy, facilitate self-management and ensure a smooth transition. At the time of transfer, the paediatric specialist CF Dietitian should provide a clear and concise summary of the nutritional management and challenges for each patient. Where possible the paediatric specialist CF Dietitian should provide a written treatment plan.

    7. Framework for microbiology

    A Clinical Microbiologist with specialist knowledge of CF infection should be part of the CF MDT. This individual may be a medically trained clinical microbiologist/infectious disease specialist; alternatively, a clinical scientist with relevant knowledge and experience may be able to undertake this role. The CF Clinical Microbiologist should work closely with the microbiology laboratory providing diagnostic services for the CF MDT and also with the local infection control and prevention team.

    In order to provide support to the CF MDT for the diagnosis and treatment of infection, the CF Clinical Microbiologist needs to know about the range of infections in CF. In particular, they need to be aware of the role of unusual micro-organisms, the risk of cross infection and the impact of long-term chronic infection on microbiological laboratory testing and treatment. In addition to a good basic knowledge, the CF Clinical Microbiologist should have evidence of CPD in CF microbiology and attend specialist CF meetings and conferences.

    7.1. The role of the CF Clinical Microbiologist

    The CF Clinical Microbiologist should ensure that appropriate laboratory microbiology provision is in place. The individual may be part of the management of the laboratory. Alternatively, these services may be provided through an external contract, in which case the CF Clinical Microbiologist should be involved with setting the terms of the contract and act as an advocate for the CF Centre.

    The CF Clinical Microbiologist should advise on the diagnosis and treatment of infection including the monitoring of antibiotics. This may be achieved by attendance at the CF MDT meetings. The CF Clinical Microbiologist should also act as an advisor on infection prevention and control in the CF Centre. This may be delegated to the designated infection control doctor if such a position exists.

    7.2. Overview of laboratory services

    The CF Clinical Microbiologist should ensure that the full range of microbiology laboratory tests needed for the CF Centre is available and that the laboratory service provided is based on published guidelines [56], [57], and [58]. The laboratory should be fully accredited by a recognized national scheme for clinical microbiology and should participate in external quality assurance, which includes CF-associated pathogens. There should be provision to send relevant samples to a reference laboratory specializing in CF microbiology when required.

    The laboratory should provide accurate and timely results to the CF Centre with an agreed system for notifying urgent and important results. The technical staff in the laboratory should have sufficient expertise and knowledge to deal with the complex microbiology of CF infections.

    There should be a framework for recording and investigating errors and other incidents, with evidence of how the lessons learned are used to inform a programme of service improvement.

    The service should be regularly audited. Examples of audits are the turn-around time (i.e. the time between the receipt of the sample in the laboratory and the time when the result is available to the CF MDT), the accuracy of identification and susceptibility testing, and the appropriate and prompt communication of urgent results to the CF MDT.

    7.3. Clinical microbiology services and the CF MDT

    The following items should be agreed between the CF MDT and the clinical microbiology service.

    • Which respiratory samples should be taken and how should they be processed (e.g. sputum, bronchoalveolar lavage, cough swab or a pharyngeal swab).
    • Which samples should be taken for the diagnosis of an infected intravascular line.
    • Diagnosis of other infections including infections of the gut (e.g. enteric viruses, when and how to test for toxigenic Clostridium difficile)
    • The level of identification of micro-organisms (e.g. genus, species, subtype) required in individual cases. This may include a discussion on the tests that can be performed in a local laboratory and what may need to be referred to a specialist laboratory with more advanced testing methodology (e.g. confirmation of first infection with Burkholderia spp. with accurate species identification).
    • Typing methods and frequency of typing (i.e. how often the CF MDT should send samples for routine surveillance and when additional typing should be done due to suspicion of cross infection)
    • Measurement of antipseudomonal antibodies where appropriate
    • Provision of diagnostic testing for fungal and mycobacterial infection together with level of identification and role of typing
    • Susceptibility testing — agreement on the antibiotics to be tested and when susceptibility testing is helpful
    • Virology services should include rapid identification of highly pathogenic viruses that may spread between patients — both familiar (e.g. influenza virus) and emerging viral pathogens (e.g. SARS, MERS coronavirus).
    • Which results need to be phoned urgently to the CF MDT (e.g. first growth of Pseudomonas aeruginosa, new isolation of Burkholderia cepacia complex and other Burkholderia species, MRSA, possible Mycobacteria seen in sputum).
    • Advice on infection prevention and control.

    In addition, a robust framework for communication between the microbiology services and the CF MDT should be agreed (e.g. telephone contact, ward rounds to review patients, participation in MDT meetings).

    7.4. Clinical advice on treatment of infection

    The CF Clinical Microbiologists should work with the CF MDT to draw up guidelines for the use of antimicrobials, including the selection of treatment for clearance of new infections, therapy for acute exacerbation and long-term suppressive antibiotics. The aim is to reduce morbidity and hospital admissions and to use antibiotics responsibly in order to limit the development of resistance.

    There must be provision of therapeutic drug monitoring of antibiotics. The CF Clinical Microbiologist should ensure that guidelines and advice are available on the maintenance of optimum antibiotic levels in the patient in order to promote effective treatment while minimizing side-effects.

    7.5. Infection prevention and control

    The CF Clinical Microbiologist should work with the CF MDT and the local infection control team to develop a local infection control and prevention policy and procedures in line with expert national and international guidelines [59], [60], [61], [62], and [63]. This policy should include:

    • how patients with transmissible infections are managed, both in the community and in hospital, in order to prevent the spread of infection
    • surveillance for transmissible infection (e.g. how often to screen and which samples to send to the laboratory)
    • antimicrobial treatment to clear carriage of potentially transmissible micro-organisms
    • guidelines for staff with infections
    • the investigation of outbreaks
    • the provision of facilities for the CF Centre and the outpatient department — this should include the cleaning and maintenance of equipment and involvement in any plans for refurbishment or re-build of the department.

    7.6. Role in clinical research and data collection

    CF Clinical Microbiologists can have an active role in CF clinical research. They may be involved with the design of innovative research but also have a role in the provision of reliable and accurate laboratory support for clinical studies. They can also help to ensure that accurate microbiological results are available for national and international database collection.

    8. Framework for medicines management

    Optimal care of people with CF requires complex multidrug treatment plans. These drugs may be administered by oral, intravenous and inhaled routes. Adverse effects and drug interactions are common.

    Many of the drugs are expensive and require specialist assessment and instruction on optimal administration. Adherence is a major challenge for patients and parents/carers. Non-adherence is associated with poor outcomes. CF Centres must have an effective medicines management programme to support patients in optimizing their therapy. The CF Clinical Pharmacist is pivotal in this process [64] . In European countries, decentralized clinical services, with a pharmacist working in the ward at least 50% of his/her time, or with pharmacists visiting wards daily, are not very common [65] . Only two countries, UK and Ireland, have developed these clinical services to a significant extent [65] .

    8.1. The role of the CF Clinical Pharmacist

    CF Clinical Pharmacists have a central role in managing medicines effectively [66] . The overall goal of clinical pharmacy activities is to promote the correct and appropriate use of medicinal products and devices [67] . These activities aim to:

    • maximize the clinical effect of medicines (i.e. using the most effective treatment for each patient)
    • minimize the risk of treatment-induced adverse events (i.e. monitoring the therapy course and the patient's compliance with therapy)
    • optimize the expenditures for pharmacological treatments borne by the national healthcare systems and by the patients.

    The principle objective of the service provided by the CF Clinical Pharmacist is to provide patient-focused pharmaceutical care, defined as the responsible provision of medication to achieve definite outcomes that improve patients' quality of life and long-term survival. The service is the process through which the pharmacist cooperates with a patient and other healthcare professional in designing, implementing and monitoring a therapeutic plan to produce these specific health outcomes [68] .

    Effective provision of a clinical pharmacy service to the CF Centre relies on the knowledge and skills of a CF Clinical Pharmacist and the quality of various support services, such as a medicine information service with experience in the problems of CF and paediatrics (if applicable), and the necessary procurement and distribution services that can provide an efficient medicine supply service for inpatients. A dispensing service should also be provided as required. Access to an on-call service for the supply of urgent medication, information and advice for inpatient care, and an aseptic dispensing service for the preparation of intravenous antibiotics including complex desensitization regimens should also be available.

    The CF Clinical Pharmacist should:

    • dispense medications to inpatients or outpatients as required in their institution
    • attend CF wards rounds and CF MDT meetings
    • support and provide information to other pharmacists in the department who may not be familiar with CF
    • liaise with paediatric and adult Centres during transition of care and transfer of patients
    • support and provide information to pharmacists working in primary care and other hospitals
    • maintain CPD through appropriate study and attendance at relevant study days, and at national and international conferences
    • network with other CF Pharmacists for advice and CPD.

    8.2. Pharmaceutical care practice for CF Clinical Pharmacists

    8.2.1. Managing formularies, clinical guidelines and treatment protocols

    The CF Clinical Pharmacist should assist in the completion of formulary applications to ensure that the appropriate medicines are introduced into clinical practice. They should also assist in the development and support of homecare services, such as home intravenous antibiotics, and manage and monitor the delivery of medication in this setting.

    Effective communication should exist between the CF Clinical Pharmacist and other members of the CF MDT. As for all clinical professionals in the CF MDT, the Clinical Pharmacist should participate in CPD and attend CF conferences and relevant study days. They should also contribute to education and training of other healthcare professionals, including those working in primary care, as appropriate. The CF Clinical Pharmacist should act as an advisor on the legal and ethical responsibilities of using medicines, including sourcing and administration of unlicensed and off-label medicines. Any problems with medication supply should be resolved by the CF Clinical Pharmacist and communicated to the CF MDT.

    The CF Clinical Pharmacist may be required to collaborate with CF research and development and assist in the completion of individual funding requests or exceptional case requests for the supply of specific medications for individual patients where no such mechanism exists to currently fund that treatment.

    8.2.2. Medication reconciliation/history taking

    The CF Clinical Pharmacists is responsible for medicines reconciliation at admission/transfer from other institutions and on discharge, including alternative over-the-counter medications, trial medications and medications used for other conditions. They should ensure that an accurate history is recorded, including previous allergic reactions/adverse drug reactions.

    8.2.3. Prescription monitoring and medication review service

    In the monitoring and review of patient medication, the CF Clinical Pharmacists should ensure that medication and the formulation are appropriate for the patient, oversee extended prescribing for allied healthcare professionals including other pharmacists, and check for drug interactions. The CF Clinical Pharmacist is also responsible for ensuring that prescriptions are complete, unambiguous and legal, and for detecting potential medication errors.

    8.2.4. Identifying patient and medication risk factors

    It is the CF Clinical Pharmacist's responsibility to ensure that patient characteristics, including age, pregnancy or breast feeding, and organ dysfunction are taken into account when medicines are prescribed, and to check the response to previous and current medication. The use of non-drug and complementary therapies should also be taken into account when managing the patient's medication.

    8.2.5. Preventing, detecting and reporting adverse drug reactions

    The CF Clinical Pharmacist needs to document and report all reactions to newer medications and serious reactions to established medications to the appropriate national body. This includes documentation of individual toxicity/allergies/hypersensitivity reactions and contraindications, and monitoring for any adverse drug reactions. The appropriate use, storage and disposal of medicines should be ensured in order to minimize adverse events.

    8.2.6. Individualizing drug and dosage requirements

    The CF Clinical Pharmacist should aim, whenever possible, to maximize the therapeutic potential and minimize the adverse effects of medicines. Therapeutic drug monitoring of specific medicines (e.g. aminoglycosides, azoles) according to an individual's pharmacokinetic variables and monitoring and reviewing the outcome of an individual's need for medication are also required. While optimizing the use of medicines the CF Clinical Pharmacist also needs to take into account the patient's wishes and lifestyle.

    The CF Clinical Pharmacist needs to keep up to date with newly available medications and therapies (e.g. new nebulized antimicrobials), and find a place for them in the treatment regimen.

    8.2.7. Educating and counselling patients and carers

    The CF Clinical Pharmacist has an important role to play in providing appropriate patient education and counselling to ensure the safe and effective use of medicines. This may include patient information leaflets about medicines and other appropriate methods of improving adherence to treatment. Pharmacists should also agree an informed plan with a patient/carer to achieve the best possible concordance with medication.

    8.2.8. Evaluating medicine use

    The CF Clinical Pharmacist's non-clinical responsibilities will include financial reporting to the CF MDT, hospital management, and other authorities, as appropriate, on CF medication usage. They should audit treatment guidelines, new therapies and homecare services.

    9. Framework for psychosocial care

    Living with CF provides many challenges for patients and their families. The CF Centre should provide adequate psychosocial care and support to help the person with CF and the families meet these challenges. In order to deliver optimal care CF Centres need a multidisciplinary framework to include access to psychosocial professionals throughout the patient's life. The core psychosocial professionals available should be a Clinical Psychologist and a Social Worker, though variations on these professions are acceptable provided core competencies are met (see below). Psychosocial professionals should be proficient in the following areas: working with children, families and adults according to the needs of the specific CF Centre; working with patients presenting with a range of clinical severity; and delivering care in all CF settings including outpatients, inpatients, community and residential care.

    The variability of patient needs and availability of expertise in CF Centres prevent the formulation of a single programme. Psychosocial care should be provided within the context of the patients' development: from infancy to toddler, childhood, adolescence, young adulthood, adult life and old age. In each stage there are age-related themes as well as CF themes [69] and [70] ( Table 3 ). Key stages include the time around diagnosis [71] , the transition to adult care [19], [72], [73], [74], [75], and [76] and the transition to end-of-life/transplantation care [77] and [78]. The disease trajectory itself also necessitates times of increased psychosocial support, for example, at diagnosis, first P. aeruginosa infection, first inpatient admission, diagnosis of CF-related diabetes, the need for gastrostomy tube feeding, supplementary oxygen, non-invasive ventilation, and assessment for lung transplantation. Psychosocial professionals should be included in the multidisciplinary care at all of these stages ( Table 3 ).

    Table 3 Examples of important life events where psychosocial support is crucial in people with cystic fibrosis.

    Childhood years Adolescent years Adult years
    Starting kindergarten/day care/pre-school Starting secondary school Starting higher education
    Starting school Being a teenager with CF Starting to work
    First awareness of being different First relationship Starting a long-term relationship
    Eating problems First sexual experience Parenthood
    Sleeping problems Death of a CF friend Death of a CF friend
    Behavioural problems (e.g. non-adherence) Behavioural problems (e.g. non-adherence) Behavioural problems (e.g. non-adherence)
     
    Examples of key medical stages
    CF diagnosis Diagnosis of infertility
    First Pseudomonas infection Treatment of infertility
    First episode of allergic bronchopulmonary aspergillosis Awareness of deteriorating disease
    Gastrostomy placement Transition to the adult clinic
    Diagnosis CF-related diabetes Transition to transplantation
    First haemoptysis and other complications Transition to end-of-life care
    Supplementary oxygen dependence Transplantation

    CF, cystic fibrosis.

    9.1. The CF social worker

    9.1.1. Role

    The CF Social Worker provides expertise in helping patients and families with their emotional and practical needs and supports patients and families in coping with CF in the different developmental and disease stages. The CF Social Worker should bridge the gap between hospital life and home life and liaise with locally available support so that local services can be accessed. The CF Social Worker is actively involved in the different transition stages, including transition to adult care and transition to transplantation care ( Table 3 ). The CF Social Worker has an expertise that complements that of the CF Clinical Psychologist.

    The CF Social Worker must have skills in the assessment of practical needs and provide a range of services that are available in the patient's country. Up-to-date knowledge of the country's system of benefits and allowances is essential. The CF Social Worker has to be able to liaise with other agencies (e.g. health insurance companies, child benefit agencies, social welfare agencies, hospital administration, school, CF patient associations) and serve as an advocate for patients and families. The CF Social Worker must have expertise in educational and career issues of the country where the patient resides. They should be skilled in the implementation of child protection procedures, and ensure effective information sharing, referral and liaison to home authority teams, where appropriate. Home visits can greatly contribute to best care and should be available where needed.

    9.1.2. Professional development

    CF Social Workers need to keep up to date with changes in healthcare systems, financial or social security matters, educational and work aspects, and patient and family welfare concerns. CF Social Workers need continuous education about CF issues. They should attend national and international conferences regularly to maintain up-to-date knowledge about CF and new scientific developments.

    9.2. The CF Clinical Psychologist

    During their life people with CF have to acquire specific CF-related healthcare behaviours in conjunction with acquiring normal developmental tasks. The CF Clinical Psychologist can help patients and families with these challenges and support them in coping with CF and its treatment throughout life.

    9.2.1. Role

    In relation to the patient and the family, the key responsibilities of the CF Clinical Psychologist are the assessment of, and intervention in, emotional, behavioural and psychological difficulties, using evidence-based treatments where indicated and making onward referrals where appropriate. The CF Clinical Psychologist is responsible for all the psychological work in the CF Centre. They should offer outpatient clinics as well as caring for hospitalized patients. Adherence, eating behavioural problems, anxiety and depression, demoralization, pain, phobias and sleep are day-to-day themes that need psychological care.

    The CF Clinical Psychologist may use mediation techniques in working with other CF MDT members. In addition, the CF Clinical Psychologist should provide a consultation and supervision service to other members of the CF MDT in their work with patients, and provide staff support in coping with ‘working in CF’.

    The CF Clinical Psychologist must be registered with their national governing body. They should have expertise in child/adolescent and/or adult clinical psychology and also in systemic psychology and the psychology of grief and bereavement. The CF Clinical Psychologist must be skilled in applying therapeutic techniques that have proven efficacy in patients and families with CF. These include, for example (cognitive) behavioural techniques [79] and [80] and motivational interviewing [81] . Finally, the CF Clinical Psychologist has to be up to date with research on psychological issues in CF, including adherence, self-management and self-care, impact of chronic illness on human development, impact of chronic illness on family and social life, end-of-life issues and palliative care. The CF Clinical Psychologist should have or should develop, skills and experience in conducting psychological research with the aim of improving the care of patients and the understanding of psychosocial issues in CF.

    9.2.2. Professional development

    CF Clinical Psychologists have a responsibility to engage in CPD and in some countries this will be assessed as part of annual registration. Clinical Psychologists working in CF have a responsibility to update their knowledge of medical aspects of CF as well as mental health. Some countries have a national body for psychosocial professionals, such as in the UK, and membership is a requirement of practising in a CF team. CF Clinical Psychologists should attend national and international conferences regularly to maintain CF knowledge and to be aware of scientific developments.

    9.3. Facilities and requirements for psychosocial care

    The CF Clinical Psychologist and the CF Social Worker need sufficient time, office space, and facilities, and the support and respect of the CF MDT. The CF Social Worker and the CF Clinical Psychologist often need to stay in regular contact with patients and families in between clinic visits and therefore need access to modern media (e.g. email, phone, texting). They both need an up-to-date interactive referral system to external psychosocial professionals and institutions in order to provide problem-specific psychosocial/mental healthcare (e.g. for attention deficit hyperactivity disorder or autism) within the vicinity of a patient's home. The CF Clinical Psychologist and CF Social Worker must participate and contribute to the MDT meetings, decision making and patient consultation.

    10. Framework for clinical genetics

    Clinical Geneticists, Medical Molecular Genetic Laboratory Specialists and Genetic Counsellors have an increasingly important role in the complex diagnosis and disease management of CF, particularly in the areas of disease diagnosis, informed reproductive choices and the assessment of disease liability of CFTR variants detected by DNA sequencing. Furthermore, the Clinical Geneticist assesses the linkage phase through family segregation analysis, and ensures that complex alleles (which may be associated with variable CF phenotype) are not under- or misdiagnosed.

    The Genetic Counsellor or the Clinical Geneticist provides counselling on reproductive options to the families of newly diagnosed children and to adult patients, and facilitates identification of at-risk family members who are genetically related to the patient.

    Clinical Geneticists, working within the CF Centre, also coordinate data sharing with specialized registries (e.g. the ECFS Registry) and submission of detected CFTR mutations to both the Cystic Fibrosis Mutation Database (CFTR1), which serves as a locus-specific database for mutations and variants identified on a world-wide scale, and the Clinical and Functional Translation of CFTR online interactive resource (CFTR2), in order to objectively substantiate the disease liability of identified CFTR gene variants.

    If administration of CFTR modulating therapies is considered, the CF Clinical Geneticist is responsible for the laboratory verification of the CFTR genotype in eligible patients (optimally by independent sampling and DNA sequencing) and that the laboratory examination is performed in an ISO 15189-accredited laboratory that assures appropriate turn-around time.

    11. Framework for data collection

    CF is a multisystem clinically heterogeneous disease with variable outcomes despite its monogenic origins. Although phenotypic variation is influenced by genotype, siblings with the same genotype differ in outcome suggesting the influence of other factors such as modifier genes, the environment, airway microbiota, social class, sex, access to healthcare and adherence to treatment [82] . Collecting data at a national and international level remains a key process to aid the understanding of the epidemiology and outcomes of the disease. It is only through accurate data collection that disease progression, outcomes, health economics and the need for change can be identified [7] . High-quality data can also be used by policy makers to focus on and prioritize future strategies and interventions.

    CF is a relatively rare disease with small patient numbers. Collecting data from a single institution limits the level at which clinical and translational research can be undertaken, and does not capture the significant variability in geographical outcome [83] . It is therefore essential that both small and large CF units submit data at least annually to national and/or European CF registries in order to ensure that appropriate longitudinal data are collected. The registry also acts as a monitor for an individual Centre's outcomes, providing an additional tool for ensuring standards of care and appropriate clinical governance.

    Healthcare professionals can find collecting and submitting data to national registries laborious and time consuming. Every effort should be made to ensure that data sets are limited to those of predictive value and that individuals can upload data through a secure intuitive interface. Funders must ensure that larger CF Centres have the resource to employ either a data clerk or alternative individual whose ring-fenced responsibilities include national data submission. To have value, such a person must have meaningful access to the management structure so that their voice counts and they can submit gold standard data.

    There is a need for the international CF community to adopt a standard coding structure. Creating uniform clinical terminologies and classifications of disease through a primary coding structure would allow clinical data to be mapped and shared between registries as well as other data sets. The changes would result in a common digital language allowing effective international collaboration and would remove key barriers to electronic connectivity.

    Addressing this issue is a matter of urgency, as a new era of medical informatics and electronic health records is upon us. Health services have started to successfully deploy electronic patient records, which automate the capture of data and have the potential to feed large continuous data sets directly into national and international registries. In Europe, a standard called XML has been adopted as a first step to harmonizing data from national registries. Almost all national organisations follow this initial standard, but this is only a first step in order to standardise the uploading; if the data collected do not adhere to common unequivocal definitions, the XML format cannot correct it. Therefore, common definitions and coding in both national registries and directly reporting individual centres are crucial.

    The European Commission has decided to start funding a European Platform on Rare Diseases Registration, which will provide services and tools for the existing and future rare diseases registries, in accordance with the Council Recommendation on action in the field of rare diseases (2009/C 151/02).

    The interconnectivity will maximize patient benefit for minimum outlay, which is a key given the difficult financial situation in healthcare. Adopting a detailed coded registry structure can have the added advantage of reducing costs and improving productivity [84] and [85]. All such European and/or international data aggregations will have to make the best possible use of local/regional/national data acquisition and storage and intelligent ways of data sharing or retrieval will have to be developed.

    Registries are here to stay and should be seen as a key part of any chronic disease management.

    12. Challenges relating to developing health services in low income countries

    The aim of the ECFS Standards of Care Guidelines is to improve the quality of care for patients with CF and to establish best practice across the whole of Europe. Immediate implementation of these guidelines may prove difficult for less economically advantaged countries where CF services are absent or inadequate. The EU EuroCareCF European Commission 6th Framework Coordination Action project identified a persisting wide difference in the standards of care across Europe, with some Eastern European countries having very basic or no recognizable CF services [7] . The likely reason for such dramatic inequalities has been the absence of appropriate funding, a lack of staff recruitment and training, and also a lack of political prioritization.

    The current situation in Eastern Europe was assessed from the responses to a questionnaire distributed to most Eastern European countries by the ECFS Standards of Care Committee. The aims were to evaluate:

    • a minimum number of patients who attend CF Centres in Eastern Europe
    • national recognition of CF Centre networks, and
    • the composition of CF MDTs and the cooperation between paediatric and adult Centres.

    Each question was answered on the basis of the current situation in the country and in relation to the ECFS Standards of Care [4] . The response rate was 44% (7/16: Czech Republic, Hungary, Latvia, Poland, Serbia, Slovakia, Ukraine).

    The major observations were as follows. While the number of patients per CF Centre is currently below 50 in some Eastern European countries, a requirement for a minimum number of 50 was seen to be an achievable goal. Centralized CF care has been endorsed by government authorities in only three of seven Eastern European countries. A paediatrician/pulmonologist, a physiotherapist and a CF nurse specialist were agreed to be essential team members. Many CF Centres lack a full-time CF nurse specialist, a dietitian, a microbiologist, a psychologist, a social worker or secretarial support. Collaboration between paediatric Centres and those for adults with CF had not been established in two of the countries that replied to the survey.

    It is imperative that all European countries should strive to implement best practice in accordance with the ECFS recommendations. An initial stepwise approach may be needed in some low income countries where there are no established services and CF MDTs virtually do not exist. For example, initial recruitment of core medical, nursing and physiotherapy staff may be the most appropriate initial investment on the way to establishing a service that meets all ECFS standards. It is no longer acceptable to have such dramatic variation in the survival of people with CF across European nations, and every effort must be made to deliver equality and high standards of care.

    CF care in low income countries should be centralized in well-established CF Centres that can guarantee a reasonable standard of complex care for both paediatric and adult patients. The Centre should care for at least 100 patients, although a minimum of 50 may be temporarily considered acceptable. Because of the financial and staffing limitations in Eastern Europe, shared care with local hospitals is not a preferred model of care. Resources should be directed at establishing state-of-the-art CF care at a national level by the development of specialized CF Centres at major hospitals, and where possible at the level of University Hospitals. The minimum staff requirements for a specialist CF team include a physician and a specialist nurse (one each for children and adults in Centres that care for all age groups), and a CF specialist physiotherapist. The goal is to develop teams that include a microbiologist, dietitian, psychologist, social worker and clinical geneticist. Meanwhile the absence of these specialists should not delay the setting up of regional CF Centres. Their roles may be temporarily performed by specialist consultants of the hospital who can be accessed by the CF service, even though not primarily allocated to a CF team and therefore not able, for instance, to participate in regular CF MDT meetings.

    13. Perspective from European CF associations

    13.1. The function and role of national CF patient organisations in Europe

    Most European countries have their own national CF patient organisation. These vary in size and methodology but have one thing in common: they fight for the interests of people with CF, in the broadest sense of the word. They work together with volunteers, who are often experts in CF but who may be non-medical. In Europe patient organisations are developing their own in-house expertise and employing professional staff, for example in the area of healthcare quality, scientific research, communication, fund raising, information provision, and the legal and psychosocial aspects of CF. The organisations aim to support patients and their parents, both individually and collectively, and to define research agenda, to finance scientific research and to test healthcare quality. They are often closely involved in the setting up and maintenance of guidelines for the diagnosis and treatment of CF.

    The national CF organisation can play an important role in the national CF registry. Many have helped found these registries and continue to support and finance them. In a number of countries, the CF organisation plays a role in the set-up and organisation of research networks and healthcare quality improvement programmes for people with CF.

    Fund raising is an important prerequisite to enable the organisations to successfully achieve the above aims. Over the past few years, CF organisations in countries such as the UK, Germany, Belgium, France, Italy and The Netherlands have invested millions of Euros in scientific research and healthcare quality. As a result, they have made important contributions to the progress that has been made in many healthcare areas of CF.

    Patient participation is an important part of the work achieved by patient organisations, as it is exactly the patients' perspective that can and should be expressed by the national CF organisations.

    13.2. National organisations

    The national CF organisations have responsibilities to provide information. This material, which is made available to people with CF and their parents/carers, is often developed in collaboration with the CF Centres and covers all aspects of life with CF: diagnosis, treatment, growing up with CF, raising a child with CF, going to school with CF and building a life with CF. National CF groups should work closely with CF Centres in the organisation of healthcare, a cooperation that may vary in its infrastructure in different countries. However, in all cases, representatives of those Centres should be present on medical advisory boards and scientific councils.

    CF organisations should organise meetings for parents and, with the use of information technology to safeguard against cross-infection risks, for the patients themselves. E-health has many advantages and is a subject that is being researched and developed.

    CF organisations are the obvious parties to represent and protect the interests of patients and their parents/carers, for example by supporting ready availability of new medications, securing reimbursements for medication and access to high-quality healthcare. CF organisations should lobby and exert pressure on the authorities, government and insurance companies in this regard. They should also organise congresses, symposia and other meetings (in collaboration with or under the supervision of the healthcare organisations), in which the specific (scientific) aspects of CF are discussed.

    CF patient organisations are non-medical yet through close cooperation with CF Centres have developed a lot of CF expertise. It is important that the Centres and the organisation exchange information on a regular basis in order to facilitate a proactive approach to developments in the healthcare industry and scientific research. This collaboration will help to improve communication with patients, facilitating their inclusion in scientific studies and solving problems on a national level more swiftly.

    13.3. European organisations

    The European CF patient organisations are united in a single European society — CF Europe (CFE). The importance of collaboration in Europe is growing, especially with regard to healthcare access, which is not uniform, or even available, in all European countries. As a result, collaboration in the fields of research, research financing and fund raising is continually increasing.

    The European collaboration should lead to the CF organisations in countries where CF healthcare is already at a high level accepting their responsibility and offering their expertise to countries in which adequate healthcare, access to healthcare and the ready availability of medication are not universal. This should take place in close collaboration with the CF Centres. Collaboration through CF Europe has made it easier to lobby effectively on a European level with regard to subjects such as organ donation, accessibility, quality and affordability in healthcare.

    Another level of European collaboration is partnering with the European overarching patient support organisation (Eurordis), which is representing the majority of rare disease national and regional organisations (including CF) in e.g. terms of awareness building, access to care, reimbursement policies, development of European guidelines for centre care fundraising, introduction of orphan medicinal products into therapy, including training courses on various aspects of patient advocacy.

    CF patient organisations are working increasingly with the ECFS, for example by participating in the executive boards of the EFCS Patient Registry and the EFCS Clinical Trials Network. The latter is financially supported by a number of patient organisations. Through the CF patient organisations, patients and parents have become more involved recently in the assessment of the ECFS Clinical Trials Network research protocols.

    Conflict of interest

    S. Conway, K. De Rijcke, P. Drevinek, J. Foweraker, T. Havermans, H. Heijerman, L. Lannefors, A. Lindblad, M. Macek, S. Madge, M. Moran, L. Morrison, A. Morton, J. Noordhoek, D. Sands, A. Vertommen, and D. Peckham have no conflicts of interest to report. I. M. Balfour-Lynn declares personal fees from Vertex, outside the submitted work.

    Acknowledgements

    We would like to thank Drs Preston Campbell, Carla Colombo, Ed McKone, Anil Mehta, Hanne Olesen and Thomas Wagner for their advice and Mrs Tina Payne-Gath for administrative support.

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    Footnotes

    a Paediatric and Adult CF Units, Leeds Teaching Hospitals Trust, UK

    b Royal Brompton Hospital, Sydney Street, London, UK

    c Cystic Fibrosis Europe, Belgium

    d Department of Medical Microbiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

    e Department of Paediatrics, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic

    f University Hospital Motol, Prague, Czech Republic

    g Department of Microbiology, Papworth Hospital NHS Foundation Trust, Papworth Everard, Cambridge, UK

    h Cystic Fibrosis Centre, University Hospital Leuven, Belgium

    i HagaZiekenhuis, Department of Pulmonology & Cystic Fibrosis, The Hague, The Netherlands

    j Copenhagen CF Centre, Rigshospitalet, University Hospital, Copenhagen, Denmark

    k Gothenburg CF Centre, Queen Silvia Children's Hospital, Göteborg, Sweden

    l Department of Biology and Medical Genetics, University Hospital Motol, Prague, Czech Republic

    m Second School of Medicine, Charles University Prague, Prague, Czech Republic

    n Department of Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London, UK

    o National Referral Centre for Adult Cystic Fibrosis, Pharmacy Department, St. Vincent's University Hospital, Ireland

    p Gartnavel General Hospital, West of Scotland Adult CF Unit, Glasgow, UK

    q Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, UK

    r Dutch Cystic Fibrosis Foundation, The Netherlands

    s Department of Pediatrics, Institute of Mother and Child, Warsaw, Poland

    t Cystic Fibrosis Centre, University Hospital Leuven, Belgium

    u Adult Cystic Fibrosis Unit, St James's Hospital, Leeds, UK

    lowast Corresponding author.


Journal of Cystic Fibrosis

Guest Editor
John P. Clancy, MD

Professor of Pediatrics and the Research Director of Division of Pulmonary Medicine at the Cincinnati Children’s Hospital and Medical Center and Guest Editor, welcomes you to the Cystic Fibrosis Resource Center.


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