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ECFS best practice guidelines: the 2018 revision

Open AccessPublished:March 03, 2018DOI:https://doi.org/10.1016/j.jcf.2018.02.006

      Abstract

      Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field.
      In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe.

      Keywords

      1. Introduction

      The clinical management of cystic fibrosis (CF) has long been of paediatric dominance. In the 1940s and 50s, when knowledge of the disease pathogenesis and availability of treatments were scarce, few patients entered adulthood [
      • Lewis P.A.
      • Morison S.
      • Dodge J.A.
      • Geddes D.
      • Coles E.C.
      • Russell G.
      • et al.
      Survival estimates for adults with cystic fibrosis born in the United Kingdom between 1947 and 1967. The UK Cystic Fibrosis Survey Management Committee.
      ]. Today this is no longer the case. In many countries, children account for less than half of the CF population, with the focus and burden of care gradually shifting towards adult care. This partly results from the understanding that the clinical spectrum of CF is wider than originally believed and the greater diagnostic consideration of phenotypes presenting in adulthood. However, there is no doubt that the outstanding attainments in survival predominantly stem from improvements in care. The establishment of multi-disciplinary centres, creation of large epidemiological datasets, emphasis on early diagnosis, together with important new treatments originated by dynamic pre-clinical and clinical research, have all been instrumental in the evolution of terrific care. Many adults with CF, some of whom have now lived beyond their own expectations, enjoy good quality of life and have jobs or are in further education. Some have families of their own. Yet despite this positive outlook, there remains considerable morbidity and early mortality in this group of patients - a situation particularly manifest in parts of Europe where available resources and facilities are limited [
      • Burgel P.R.
      • Bellis G.
      • Olesen H.V.
      • Viviani L.
      • Zolin A.
      • Blasi F.
      • et al.
      ERS/ECFS Task Force on Provision of Care for Adults with Cystic Fibrosis in Europe. Future trends in cystic fibrosis demography in 34 European countries.
      ,
      • Elborn J.S.
      • Bell S.C.
      • Madge S.L.
      • Burgel P.R.
      • Castellani C.
      • Conway S.
      • et al.
      Report of the European Respiratory Society/European Cystic Fibrosis Society task force on the care of adults with cystic fibrosis.
      ,
      • Madge S.
      • Bell S.C.
      • Burgel P.
      • De Rijcke K.
      • Blasi F.
      • Elborn J.S.
      Limitations to providing adult cystic fibrosis care in Europe: results of a care centre survey.
      ]. Standards of care and campaigning for their implementation remain of capital significance.
      The European CF Society (ECFS) has always held that delivering high quality care is paramount and published standards of care documents in 2005 [
      • Kerem E.
      • Conway S.
      • Elborn S.
      • Heijerman H.
      • Consensus Committee
      Standards of care for patients with cystic fibrosis: a European consensus.
      ] and 2014 [
      • Castellani C.
      • Conway S.
      • Smyth A.R.
      • Stern M.
      • Elborn J.S.
      Standards of care for cystic fibrosis ten years later.
      ]. The latter version introduced three distinct work packages; the requisite framework of the CF center [
      • Conway S.
      • Balfour-Lynn I.M.
      • De Rijcke K.
      • Drevinek P.
      • Foweraker J.
      • Havermans T.
      • et al.
      European Cystic Fibrosis Society Standards of Care: framework for the Cystic Fibrosis Centre.
      ], best clinical practice [
      • Stern M.
      • Bertrand D.P.
      • Bignamini E.
      • Corey M.
      • Dembski B.
      • Goss C.H.
      • et al.
      European Cystic Fibrosis Society Standards of Care: quality management in cystic fibrosis.
      ] and quality management in CF care [
      • Smyth A.R.
      • Bell S.C.
      • Bojcin S.
      • Bryon M.
      • Duff A.
      • Flume P.
      • et al.
      European Cystic Fibrosis Society Standards of Care: best practice guidelines.
      ]. Standards were established by achieving consensus amongst a broad spectrum of CF professional and stakeholders with the project being designed and coordinated by a dedicated ECFS core working group.
      The 2014 publications were intrinsic to a larger project and in the subsequent years the Standards of Care Working Group brought forward other initiatives, including a survey on CF facilities across Eastern Europe [
      • Madge S.
      • Bell S.C.
      • Burgel P.
      • De Rijcke K.
      • Blasi F.
      • Elborn J.S.
      Limitations to providing adult cystic fibrosis care in Europe: results of a care centre survey.
      ] and two courses on quality improvement. It also recognized the importance of continually updating best practice standards. The time interval since the previous best practice document reflects fast-moving and dynamic developments in the field, for example, recommendations for adult CF care [
      • Elborn J.S.
      • Bell S.C.
      • Madge S.L.
      • Burgel P.R.
      • Castellani C.
      • Conway S.
      • et al.
      Report of the European Respiratory Society/European Cystic Fibrosis Society task force on the care of adults with cystic fibrosis.
      ] and the expanded use of CFTR modulators [
      • Quon B.S.
      • Rowe S.M.
      New and emerging targeted therapies for cystic fibrosis.
      ].
      In this revision and update of the 2014 Best Practice Standards [
      • Stern M.
      • Bertrand D.P.
      • Bignamini E.
      • Corey M.
      • Dembski B.
      • Goss C.H.
      • et al.
      European Cystic Fibrosis Society Standards of Care: quality management in cystic fibrosis.
      ] many of the original authors contributed together with new collaborators. A systematic review of the existing evidence available from the literature was performed. Whenever consistent results from well designed, well conducted clinical studies in CF populations were not available, recommendations developed by knowledgeable, multidisciplinary panels of experts and patient representatives were considered, discussed and where appropriate included in the document. The lead authors of the Newborn Screening and Early Specialist Care Chapter adopted a Delphi consensus methodology amongst the ECFS Neonatal Screening Working Group. Here, initial statements produced by the authors, were adapted in response to comments from the Delphi process. After several iterations, complete consensus was established for all statements.
      The manuscript was ratified by the ECFS Board and patient representatives from CF Europe, and evaluated by three independent reviewers.
      Whilst much of the structure and content of the 2014 version remains unchanged, there are important modifications including new areas and subjects covered, set out across seven chapters and précised in an executive summary.

      2. Executive summary of major revisions and additions

      2.1 Newborn screening and early specialist care

      • Incidence declines, resulting from population carrier screening, should not impair the indication for a newborn screening programme.
      • Factors in making the decision on whether to implement newborn screening should include available healthcare resources and the ability to provide a clear pathway to treatment.
      • Infants with meconium ileus have an increased rate of false-negative newborn screening test results.
      • Families of screened infants with a positive result should be informed of the function and achievements of CF research and made aware of opportunities for participation in clinical trials.

      2.2 Diagnosis

      • For mutations not characterized by CFTR2, other evidence to establish diagnosis may be considered, all requiring accompanying sweat chloride confirmation.
      • Electrophysiological investigations (nasal potential difference, intestinal short circuit current measurement) should be undertaken in a centre with considerable experience of the procedure.

      2.3 Treatment of lung disease

      • Ivacaftor should be considered as part of the standard of care in patients with gating mutations.
      • Ivacaftor has also shown efficacy in mutations with residual CFTR function.
      • Lumacaftor combined with ivacaftor should be available as a treatment option for 508del/508del patients.

      2.4 Nutrition and metabolic complications

      • Fat soluble vitamin levels should be measured at least annually.
      • Excessive doses of PERT may result in abdominal pain or constipation.
      • When considering glucose assessment, a single abnormal oral glucose tolerance test requires confirmation with a second test. Some centres use continuous glucose monitoring as part of the diagnostic process.

      2.5 Treatment of complications

      • CF centers should have established protocols for desensitisation to allergies to antibiotics.
      • Ivacaftor and the combination of lumacaftor/ivacaftor may cause hepatic impairment. When liver disease is present the dosing of these drugs may need adjustment.
      • Drug-drug interactions, especially after the introduction of CFTR correctors and modulators, are complications clinicians should be aware of and when possible prevent by dose adjustment.
      • Gastrointestinal malignancies are more prevalent in patients with CF than in the healthy population, with a higher yearly incidence in colorectal cancer and progression of adenomatous colorectal polyps to colorectal cancer. Screening for colorectal cancer is cost-effective, and should be started at an age of 40 years.

      2.6 Transplantation and end-of-life issues

      • Assessment and prioritisation of younger children with CF requires careful consideration with transplant teams who have a specific paediatric expertise.
      • Ongoing regular contact should be established between the referring CF centre and the lung transplantation service about the health status of actively wait-listed patients.
      • Potential risks of post-transplant complications in patients with active Mycobacterium abscessus infection need to be highlighted.
      • The stress that transplantation assessment and being “wait-listed” can place on the patient and their family must be pro-actively assessed and managed.

      2.7 Psychosocial care

      • Recommendations for mental health screening, assessment and treatment are made in alignment with mental health guidelines in CF.
      • The standard on “growing older with CF” has been expanded to consider living with end-stage disease to balance identifying and treating psychosocial problems with promoting psychological resilience.
      • There are expanded details on supporting the CF Team and identifying key times of vulnerability.

      3. Newborn screening and early specialist care

      Kevin Southern (UK), Jurg Barben (CH), Anne Munck (FR).
      There is clear evidence to support newborn screening (NBS) for CF. Early recognition provides the foundation for future management and prevents the delay in diagnosis that has affected many families in areas that do not screen [
      • Southern K.W.
      • Mérelle M.M.E.
      • Dankert-Roelse J.E.
      • Nagelkerke A.
      Newborn screening for cystic fibrosis.
      ]. Protocols should be designed to reflect the health service infrastructure and CFTR genetics of each population and minimise potential negative impacts. Please refer to the ECFS best practice guidelines on NBS and on the management of young infants with CF diagnosed through screening [
      • Castellani C.
      • Southern K.W.
      • Brownlee K.
      • Dankert Roelse J.
      • Duff A.
      • Farrell M.
      • et al.
      European best practice guidelines for cystic fibrosis neonatal screening.
      ,
      • Sermet-Gaudelus I.
      • Mayell S.J.
      • Southern K.W.
      Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
      ].

      3.1 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 <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.
      Incidence declines due to population carrier screening should not impair the indication for an early diagnosis programme as CF NBS and carrier screening have complementary roles and neither can replace the other [
      • Castellani C.
      • Massie J.
      Newborn screening and carrier screening for cystic fibrosis: alternative or complementary?.
      ]. Other factors in making the decision on whether to implement screening should include available healthcare resources and the ability to provide a clear pathway to treatment (see next question).

      3.2 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.

      3.3 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 <0.5%. More than 20 repeats for every 1000 infants, is unacceptable (2%).

      3.4 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).

      3.5 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)

      • a.
        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 not including meconium ileus, see below).
      • b.
        Infants with meconium ileus (MI) have an increased rate of false negative NBS test results. This should have little impact on the timing of diagnosis which should be made clinically. However paediatric surgeons need to be aware of this situation. Sensitivity should be calculated and reported including with and without MI false negative infants.
      • c.
        Mechanisms should be in place for the collection of reliable long-term false negative data.

      3.6 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 reported to the family on the same day.

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

      The majority of infants with a confirmed diagnosis after NBS should be seen by a specialist CF 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.

      3.8 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 refer to. Information should also be sent to the family Primary Care Physician.
      • b.
        The information should be clear that:
        • i.
          The infant does not have CF.
        • ii.
          The baby is a healthy carrier.
        • iii.
          Future pregnancies for this couple are not free of risk of CF and the parents may opt for genetic counselling.
        • iv.
          There are implications that could affect reproductive decision making for extended family members and the infant when they are of child bearing age.

      3.9 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. 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.
      • d.
        Families of screened infants with a positive result should be informed of the function and achievements of CF research and made aware of opportunities for participation in clinical trials.

      3.10 What are the minimal acceptable standards for the recognition and management of infants with an unclear diagnosis
      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 [
      • Mayell S.J.
      • Munck A.
      • Craig J.V.
      • Sermet I.
      • Brownlee K.G.
      • Schwarz M.J.
      • et al.
      A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.
      ]. The term CF Screen Positive, Inconclusive Diagnosis (CFSPID) is recommended as the designation for infants with an unclear diagnosis after NBS [
      • Mayell S.J.
      • Munck A.
      • Craig J.V.
      • Sermet I.
      • Brownlee K.G.
      • Schwarz M.J.
      • et al.
      A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.
      ].
      1Definition; 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 [
      • Mayell S.J.
      • Munck A.
      • Craig J.V.
      • Sermet I.
      • Brownlee K.G.
      • Schwarz M.J.
      • et al.
      A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.
      ]. The term CF Screen Positive, Inconclusive Diagnosis (CFSPID) is recommended as the designation for infants with an unclear diagnosis after NBS [
      • Mayell S.J.
      • Munck A.
      • Craig J.V.
      • Sermet I.
      • Brownlee K.G.
      • Schwarz M.J.
      • et al.
      A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis.
      ].
      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 current clinical status of the infant, as well as the plans for follow-up and assessments. It should be acknowledged that for many of these infants there may be uncertainty regarding clinical progress and possible future symptoms. Information should also be sent to the family Primary Care Physician. Infants should be managed as per the ECFS guidelines [
        • Munck A.
        • Mayell S.J.
        • Winters V.
        • Shawcross A.
        • Derichs N.
        • Parad R.
        • et al.
        Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): a new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening.
        ].

      4. Diagnosis

      Isabelle Sermet-Gaudelus (FR), Nataliya Kashirskaya (RU), Kevin Southern (UK).
      It is mandatory to have a high standard of care for diagnostic evaluation in CF. Diagnostic confirmation is required for children and adults presenting with suggestive clinical features, but also in specific situations such as asymptomatic infants with a positive NBS test or a positive family history.

      4.1 What are the requirements to undertake the diagnosis for CF? [
      • Farrell P.M.
      • Rosenstein B.J.
      • White T.B.
      • Accurso F.J.
      • Castellani C.
      • Cutting G.R.
      • et al.
      Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.
      ]

      • a.
        To be able to undertake sweat testing according to the standards described below.
      • b.
        To be able to perform genetic testing for the most appropriate panel of CFTR mutations 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.

      4.2 What are the diagnostic criteria for CF? [
      • Farrell P.M.
      • Rosenstein B.J.
      • White T.B.
      • Accurso F.J.
      • Castellani C.
      • Cutting G.R.
      • et al.
      Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.
      ,
      • De Boeck K.
      • Wilschanski M.
      • Castellani C.
      • Taylor C.
      • Cuppens H.
      • Dodge J.
      • et al.
      Cystic fibrosis: terminology and diagnostic algorithms.
      ]

      A positive NBS test resultorclinical features suggestive of CF, 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 in malesanda sweat chloride > 59 mmol/Land/ortwo CF causing CFTR mutations in trans
      On rare occasions two mutations can occur on the same chromosome (called in cis). For this reason, it is important to check the parental origin of the mutations to ensure the mutations occur on separate chromosomes (in trans).
      2On rare occasions two mutations can occur on the same chromosome (called in cis). For this reason, it is important to check the parental origin of the mutations to ensure the mutations occur on separate chromosomes (in trans).
      The term “mutation” is referred as a “pathogenic variant”, according to the CFTR-2 database (http://www.CFTR2.org). For mutations not characterised by CFTR-2, other evidence may be considered, such as bibliographic data and other genetic databases (also see paragraph 4.6), all requiring accompanying sweat chloride confirmation.

      4.3 What are the minimal standards for laboratories performing sweat tests? [
      • Southern K.
      • Kent L.
      • Nguyen-Khoa T.
      • Sermet I.
      Sweat induction and collection V2.0. European Cystic Fibrosis Society clinical trial network ECFS-CTN/2.2/001 standard operating procedure.
      ]

      • 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.
      • b.
        Use of commercially available equipment approved for diagnostic use according to the national regulatory requirements or EU standards if no local ones are available.
      • c.
        Internal quality control (usually three samples) with acceptable limits of agreement for chloride before each sweat analysis.
      • d.
        Regular external quality assurance for the analyses according to national guidelines.
      • e.
        A high number of QNS (Quantity Not Sufficient) rates is a marker of technical issue. This necessitates renewing training for personnel experiencing sweat tests.

      4.4 What are the diagnostic standards of a sweat test?

      • a.
        The quantity of sweat should indicate an adequate rate of sweat production (15μL for Macroduct™ tube system).
      • b.
        The sweat sample should be processed immediately after sweat collection.
      • c.
        A sweat chloride value >59 mmol/L is consistent with a diagnosis of CF.
      • d.
        A sweat chloride value <30 mmol/L makes the diagnosis of CF unlikely. However, specific CF causing mutations can be associated with a sweat test below 30 mmol/L. These include c.3718-2477C > T (3849 + 10kbC > T) and mutations associated with varied clinical consequence such as c.617T > G (L206W), c.1040G > A (R347H), and c.3454G > C (D1152H) [
        • Feldmann D.
        • Couderc R.
        • Audrezet M.P.
        • Ferec C.
        • Bienvenu T.
        • Desgeorges M.
        • et al.
        CFTR genotypes in patients with normal or borderline sweat chloride levels.
        ].
      • e.
        Individuals with sweat chloride values in the borderline range (30–59 mmol/L) should undergo a repeat sweat test and further evaluation in a specialist CF Centre, including detailed clinical assessment and extensive CFTR gene mutation analysis [
        • Collie J.
        • Massie J.
        • Jones O.
        • LeGrys V.
        • Greaves F.
        Sixty-five years since the New York heat wave: advances in sweat testing for cystic fibrosis.
        ].

      4.5 What are the minimal standards for a laboratory performing mutation analysis for CFTR?

      • a.
        The laboratory should be able to reliably extract DNA from dried blood spot samples, whole blood (EDTA) or buccal swabs.
      • b.
        Samples should be analysed on a weekly basis to avoid significant delay.
      • c.
        The laboratory should partake in an external quality assurance exercise with at least 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 >96% of the individuals with CF in the local population [
        • Audrézet M.
        • Munck A.
        • Scotet V.
        • Claustres M.
        • Roussey M.
        • Delmas D.
        • et al.
        Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy.
        ].
      • e.
        When only one mutation is recognised, extended exon DNA analysis (gene sequencing) should be available in the primary laboratory or a secondary laboratory to detect rare mutations and major deletions or duplications should be sought. The disease liability of variants detected by DNA sequencing should be validated against the CFTR-2 database.
      • f.
        Novel mutations or variants should be reported to locus specific databases in order to facilitate future interpretation of variants of unknown clinical significance.

      4.6 What is a CF causing mutation?

      • a.
        A CF-causing mutation is a mutation that causes CF disease when found in trans with a known CF-causing mutation [
        • Sosnay P.R.
        • Siklosi K.R.
        • Van Goor F.
        • Kaniecki K.
        • Yu H.
        • Sharma N.
        • et al.
        Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.
        ]. The diagnosis of CF is confirmed in patients with two CF-causing mutations identified in trans and classified in the CFTR-2 database (https://www.CFTR2.org) or other relevant information base. However, the absence of two CF-causing mutations after extended DNA testing in the presence of typical clinical or laboratory features of the disease, or abnormal CFTR bioassays (see paragraph 4.10), does not rule out CF.
      • b.
        Patients with “mutations of varying clinical consequence” require further evaluation in a Specialist CF Centre. Those include the mutations that result either in CF or in a CFTR-related disorder such as diffuse bronchiectasis, congenital bilateral absence of vas deferens (CBAVD), recurrent/chronic idiopathic pancreatitis.
      • c.
        Patients carrying mutations of unproven or uncertain clinical consequence also require further evaluation in a Specialist CF Centre.

      4.7 What are the minimal acceptable standards of care for reporting a diagnosis of CF to a symptomatic patient?

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

      4.8 What are the minimal standards of care and follow-up for a newly diagnosed patient?

      A patient diagnosed with CF should have immediate access to a Specialist CF Centre that has the multi-disciplinary capacity to provide care that complies with the ECFS Standards of Care.

      4.9 What are the minimal standards of care and follow-up for patients with symptoms suggestive of CF and intermediate sweat chloride values? [
      • Farrell P.M.
      • Rosenstein B.J.
      • White T.B.
      • Accurso F.J.
      • Castellani C.
      • Cutting G.R.
      • et al.
      Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report.
      ]

      • a.
        A patient, with symptoms suggestive of CF of CF, with a sweat chloride concentration between 30 and 59 mmol/L, and either one or no CF causing mutations, should have access to a Specialist CF Centre for 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 Specialist CF Centre.
      • b.
        Ancillary tests should be performed to detect pancreatic insufficiency (faecal pancreatic elastase), CBAVD in males, lung or sinus involvement, or by identifying an ion channel abnormality (see question 4.10).
      • c.
        These patients must be monitored carefully for development of any complications and appropriate therapy implemented.

      4.10 Should a patient with unclear diagnosis have CFTR bioassay tests (nasal potential difference, intestinal current measurement)? [
      • Goubau C.
      • Wilschanski M.
      • Skalicka V.
      • Lebecque P.
      • Southern K.W.
      • Sermet I.
      • et al.
      Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis.
      ]

      Patients with an unclear diagnosis should be assessed by a Specialist CF centre. In cases with intermediate sweat test results, further electrophysiological investigations (nasal potential difference and intestinal short circuit current measurement), should be arranged if available. The analyses should be undertaken in a centre with considerable experience of these procedures.

      5. Treatment of lung disease

      Felix Ratjen (CA), Patrick Flume (US), Alan Smyth (UK).
      Life expectancy in CF has improved dramatically in the last 4 decades [
      • MacKenzie T.
      • Gifford A.H.
      • Sabadosa K.A.
      • Quinton H.B.
      • Knapp E.A.
      • Goss C.H.
      • et al.
      Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the Cystic Fibrosis Foundation patient registry.
      ]. However, the majority of CF patients still die of respiratory failure [
      • Cystic Fibrosis Foundation
      Patient Registry Annual Data Report 2015.
      ] 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 [
      • Sanders D.B.
      • Bittner R.C.
      • Rosenfeld M.
      • Hoffman L.R.
      • Redding G.J.
      • Goss C.H.
      Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation.
      ]. 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.

      5.1 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 [
      • Emerson J.
      • Rosenfeld M.
      • McNamara S.
      • Ramsey B.
      • Gibson R.L.
      • Emerson J.
      • et al.
      Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis.
      ]. There is no clear evidence how quickly an eradication therapy should be commenced, but treatment should be started promptly (not >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 [
      • Langton-Hewer S.C.
      • Smyth A.R.
      Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.
      ]. Options include 28 days of tobramycin solution for inhalation (TIS) and up to 3 months of a combination of nebulised colistimethate and oral ciprofloxacin [
      Antibiotic treatment for cystic fibrosis.
      ]. Follow-up cultures to document eradication after treatment are crucial.

      5.2 How should chronic bacterial infection with P. aeruginosa be treated?

      When eradication therapy has failed, the diagnosis of chronic infection is made and long term inhaled antibiotic therapy should be commenced [
      • Ryan G.
      • Singh M.
      • KD
      Inhaled antibiotics for long-term therapy in cystic fibrosis.
      ]. 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 [
      • Mogayzel P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Cystic fibrosis pulmonary guidelines.
      ]. Whilst studies are lacking for children younger than 6 years, treatment at equivalent doses is also recommended in this age group. The licensed regimen is 300 mg twice daily for 28 days, alternating with 28 days off treatment. A dry powder inhalation of tobramycin (TOBI Podhaler™) has been shown to be of equivalent efficacy [
      • Konstan M.W.
      • Flume P.A.
      • Kappler M.
      • Chiron R.
      • Higgins M.
      • Brockhaus F.
      • et al.
      Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial.
      ]. Inhaled aztreonam lysine [
      • Oermann C.M.
      • Retsch-Bogart G.Z.
      • Quittner A.L.
      • Gibson R.L.
      • McCoy K.S.
      • Montgomery A.B.
      • et al.
      An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.
      ] is recommended as an alternative by both European and US guidelines. Colistimethate (2 MU twice daily) is used widely in Europe and is now also available as a dry powder preparation [
      • Schuster A.
      • Haliburn C.
      • Döring G.
      • Goldman M.H.
      Safety, efficacy and convenience of colistimethate sodium dry powder for inhalation (Colobreathe DPI) in patients with cystic fibrosis: a randomised study.
      ]. A specialist physiotherapist should advise on the timing of inhalational drugs and on appropriate inhalation techniques.

      5.3 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.

      5.4 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 [
      Antibiotic treatment for cystic fibrosis.
      ]. There is no evidence to support prophylactic therapy for other bacteria.

      5.5 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 [
      • Association of Chartered Physiotherapists in Cystic Fibrosis
      Standards of care and good clinical practice for the physiotherapy management of cystic fibrosis.
      ] and US [
      • Flume P.A.
      • Robinson K.A.
      • O'Sullivan B.P.
      • Finder J.D.
      • Vender R.L.
      • Willey-Courand D.-B.
      • et al.
      Cystic fibrosis pulmonary guidelines: airway clearance therapies.
      ] guidelines and should be available to all CF patients. A recent head-to-head trial [
      • McIlwaine M.P.
      • Alarie N.
      • Davidson G.F.
      • Lands L.C.
      • Ratjen F.
      • Milner R.
      • et al.
      Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis.
      ] 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 [
      • International Physiotherapy Group for Cystic Fibrosis
      Physiotherapy for people with cystic fibrosis: from infant to adult.
      ]. Flexibility and appreciation of patient preference are essential when prescribing a suitable airway clearance technique [
      • Homnick D.N.
      Making airway clearance successful.
      ]. 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 [
      • International Physiotherapy Group for Cystic Fibrosis
      Physiotherapy for people with cystic fibrosis: from infant to adult.
      ]. 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 [
      • Wilkes D.L.
      • Schneiderman J.E.
      • Nguyen T.
      • Heale L.
      • Moola F.
      • Ratjen F.
      • et al.
      Exercise and physical activity in children with cystic fibrosis.
      ].

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

      5.6.1 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 PEX but it is essential that these episodes are diagnosed and treated promptly. Patients experiencing a 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 PEX include lung function measurements, microbiological testing and radiological tests. Treatment of a PEX usually requires antibiotics which can be administered orally, via inhalation and/or intravenously. If the patient needs hospital admission for intravenous antibiotic therapy it is important that this is not delayed.

      5.6.2 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.

      5.6.3 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) [
      • de Groot R.
      • Smith A.L.
      Antibiotic pharmacokinetics in cystic fibrosis. Differences and clinical significance.
      ]. For P. aeruginosa, a combination of two or more antibiotics is recommended and, although evidence for choice of antibiotics and optimal treatment duration is lacking, 14 days of intravenous treatment is routine [
      • Flume P.A.
      • Mogayzel P.J.
      • Robinson K.A.
      • Goss C.H.
      • Rosenblatt R.L.
      • Kuhn R.J.
      • et al.
      Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations.
      ]. 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.

      5.6.4 Evaluating response to therapy

      It is important to monitor lung function at the beginning and end of treatment of a PEX to guide decisions regarding treatment and its duration. Despite intensive treatment about 25% of patients experiencing a PEX requiring intravenous antibiotic therapy will have a persisting decline in lung function [
      • Sanders D.B.
      • Bittner R.C.
      • Rosenfeld M.
      • Hoffman L.R.
      • Redding G.J.
      • Goss C.H.
      Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation.
      ], emphasising the need for maintenance therapies to prevent exacerbations.

      5.7 What are the recommended chronic maintenance therapies to maintain lung health?

      A comprehensive review of this topic is beyond the scope of this document and is available elsewhere [
      • Mogayzel P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Cystic fibrosis pulmonary guidelines.
      ,
      • Döring G.
      • Flume P.
      • Heijerman H.
      • Elborn J.S.
      Treatment of lung infection in patients with cystic fibrosis: current and future strategies.
      ]. Airway clearance techniques, physical activity and nutritional support are important components in maintaining lung health; here we focus on drug therapy only.

      5.7.1 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 PEX in patients regardless of disease severity [
      • Jones A.P.
      • Wallis C.E.
      Dornase alfa for cystic fibrosis.
      ]. Recent evidence from an analysis of a large data base suggests that dornase alfa reduces lung function decline [
      • Konstan M.W.
      • Wagener J.S.
      • Pasta D.J.
      • Millar S.J.
      • Jacobs J.R.
      • Yegin A.
      • et al.
      Clinical use of dornase alfa is associated with a slower rate of FEV1 decline in cystic fibrosis.
      ]. 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 [
      • Nash E.
      • Stephenson A.
      • Ratjen F.
      • Tullis E.
      Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis.
      ].

      5.7.2 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 complementary. Hypertonic saline and mannitol are available as inhaled agents in Europe. Hypertonic saline (7%) has been shown to reduce PEX and marginally improve lung function in a systematic review [
      • Wark P.
      • McDonald V.M.
      Nebulised hypertonic saline for cystic fibrosis.
      ]. Hypertonic saline is currently used in many patients with moderate to severe lung disease and is supported by guidelines [
      • Mogayzel P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Cystic fibrosis pulmonary guidelines.
      ]. Mannitol has been introduced more recently and improves lung function [
      • Bilton D.
      • Robinson P.
      • Cooper P.
      • Gallagher C.G.
      • Kolbe J.
      • Fox H.
      • et al.
      Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study.
      ,
      • Aitken M.L.
      • Bellon G.
      • De Boeck K.
      • Flume P.A.
      • Fox H.G.
      • Geller D.E.
      • et al.
      Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study.
      ]. 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.

      5.7.3 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 paragraph 5.1) 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 [
      • Ryan G.
      • Singh M.
      • KD
      Inhaled antibiotics for long-term therapy in cystic fibrosis.
      ] and is therefore part of standards of care [
      Antibiotic treatment for cystic fibrosis.
      ,
      • Mogayzel P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Cystic fibrosis pulmonary guidelines.
      ]. Inhaled antibiotic therapy should be administered as long term maintenance therapy with either single agent therapy or alternating therapy. Alternating different antibiotics is also used in patients deteriorating during months off antibiotics, even though the evidence for the efficacy of this approach is limited. The benefits of treatment outweigh the risks associated with the development of antimicrobial resistance which is often overcome by high topical antibiotic concentrations.

      5.7.4 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 PEX in chronically infected patients [
      • Southern K.W.
      • Barker P.M.
      • Solis-Moya A.
      • Patel L.
      Macrolide antibiotics for cystic fibrosis.
      ] and is part of recommended care [
      • Mogayzel P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Cystic fibrosis pulmonary guidelines.
      ]. A reduction in PEX has also been observed in younger patients not infected with P. aeruginosa [
      • Saiman L.
      • Anstead M.
      • Mayer-Hamblett N.
      • Lands L.C.
      • Kloster M.
      • Hocevar-Trnka J.
      • et al.
      Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial.
      ]. Some concerns remain, regarding the durability of their effect and their impact on inducing resistance for other bacteria.

      5.8 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 in pediatric patients with preserved lung function [
      • Lands L.C.
      • Stanojevic S.
      Oral non-steroidal anti-inflammatory therapy for cystic fibrosis.
      ]. 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.

      5.9 CFTR modulator therapy - which treatments address the underlying defect in CF?

      Current treatment largely addresses the symptoms caused by the defective gene while CFTR pharmacotherapy aims to increase protein expression at the cell surface or its function with drug therapy [
      • Mogayzel P.J.
      • Naureckas E.T.
      • Robinson K.A.
      • Mueller G.
      • Hadjiliadis D.
      • Hoag J.B.
      • et al.
      Cystic fibrosis pulmonary guidelines.
      ]. Potentially this treatment strategy could make a difference in altering or even halting the disease process. Several drugs targeting specific classes of CFTR defects are currently being studied; to date two drugs have demonstrated clinical efficacy. Ivacaftor, a CFTR potentiatior studied initially in patients with the gating mutation G551D, showed enhanced ion transport reflected by reductions in sweat chloride concentrations but also improved clinical measures such as lung function and frequency of PEX [
      • Ramsey B.W.
      • Davies J.
      • McElvaney N.G.
      • Tullis E.
      • Bell S.C.
      • Dřevínek P.
      • et al.
      A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.
      ]. A subsequent study including patients with other gating mutations confirmed these positive results [
      • De Boeck K.
      • Munck A.
      • Walker S.
      • Faro A.
      • Hiatt P.
      • Gilmartin G.
      • et al.
      Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation.
      ]. The effect size of lung function changes exceeded that observed for any drug therapy available for CF patients to date. While gating mutations are only found in <5% of patients worldwide, ivacaftor is also a proof of principle demonstrating the potential impact of CFTR pharmacotherapy. In patients with gating mutations approved by regulatory agencies ivacaftor should be considered as part of the standard of care. Ivacaftor has also shown efficacy in mutations with residual CFTR function [
      • Moss R.B.
      • Flume P.A.
      • Elborn J.S.
      • Cooke J.
      • Rowe S.M.
      • McColley S.A.
      • et al.
      Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial.
      ]. Lumacaftor, a corrector of intracellular trafficking of CFTR, when combined with the potentiator ivacaftor, has been demonstrated to improve lung function and reduce PEX in patients homozygous for the most common (508del) mutation [
      • Wainwright C.E.
      • Elborn J.S.
      • Ramsey B.W.
      • Marigowda G.
      • Huang X.
      • Cipolli M.
      • et al.
      Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR.
      ]. The initial studies included patients 12 years and older, but positive treatment effects have also been reported in children 6 to 11 year of age [
      • Milla C.E.
      • Ratjen F.
      • Marigowda G.
      • Liu F.
      • Waltz D.
      • Rosenfeld M.
      Lumacaftor/ivacaftor in patients aged 6–11 years with cystic fibrosis and homozygous for F508del-CFTR.
      ]. While the observed effect size of treatment was smaller than for ivacaftor in gating mutations, this therapy should be available as a treatment option for 508del/508del CF patients.

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

      ABPA is a well-characterised complication in CF patients and should be considered in any patient with clinical deterioration not responding to antibiotic therapy [
      Antibiotic treatment for cystic fibrosis.
      ]. 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 [
      Antibiotic treatment for cystic fibrosis.
      ].
      Aspergillus fumigatus, as well as other fungi, are commonly found in sputum of CF patients. The majority of these patients will not develop ABPA and the relevance of fungi beyond APBA in CF is not entirely clear. More recent evidence suggests that A. fumigatus may act as a pathogen in at least some CF patients [
      • Amin R.
      • Dupuis A.
      • Aaron S.D.
      • Ratjen F.
      The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis.
      ]. Therefore, assessments of cultures in CF patients for fungi should be available.

      5.11 How should we monitor lung disease?

      • a.
        A multi-disciplinary team is needed to assess and discuss all aspects of CF care.
      • b.
        Regular monitoring includes assessment of competence of airway clearance and inhalation technique and monitoring of adherence (see paragraph 9.4).
      • c.
        Clinical assessments should be performed at least every 3 months and at times of symptomatic deterioration [
        ].
      • d.
        As airway infection is a major driver of CF lung disease airway cultures should be obtained at every clinic visit [
        Antibiotic treatment for cystic fibrosis.
        ].
      • e.
        The microbiological assessment needs to include specific culture media for the range of CF pathogens to ensure that relevant organisms are not overlooked.
      • f.
        CFTR modulator therapy requires safety monitoring that include liver function testing as the most commonly found laboratory abnormality, but also assessment for cataracts in children as well as monitoring of potential drug/drug interactions.
      • g.
        Lung function testing guides therapy and should be performed at every clinic visit in patients old enough to cooperate (usually 5 years and older) [
        ]. Tests for younger children are currently under development. Routine lung function testing should include spirometry performed according to ATS/ERS criteria [
        • Miller M.R.
        • Hankinson J.
        • Brusasco V.
        • Burgos F.
        • Casaburi R.
        • Coates A.
        • et al.
        Standardisation of spirometry.
        ] and testing pre- and post-bronchodilator should be available.
      • h.
        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.

      6. Nutrition and metabolic complications

      Anne Munck (FR), Sarah Jane Schwarzenberg (US), Sue Wolfe (UK).
      Nutritional status has a strong positive association with pulmonary function and survival in CF [
      • Kerem E.
      • et al.
      Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry.
      ]. Attainment of normal growth in children and maintenance of adequate nutrition in adulthood, represent major goals for the CF team.

      6.1 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 grow like healthy peers, with the aim of being at 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 [
      • Kerem E.
      • Conway S.
      • Elborn S.
      • Heijerman H.
      • Consensus Committee
      Standards of care for patients with cystic fibrosis: a European consensus.
      ,
      • Sermet-Gaudelus I.
      • Mayell S.J.
      • Southern K.W.
      Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
      ,
      • Borowitz D.
      • Baker R.D.
      • Stallings V.
      Consensus report on nutrition for pediatric patients with cystic fibrosis.
      ,
      ,
      ,
      • Stallings V.A.
      • Stark L.J.
      • Robinson K.A.
      • Feranchak A.P.
      • Quinton H.
      Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.
      ,
      • Borowitz D.
      • Robinson K.A.
      • Rosenfeld M.
      • Davis S.D.
      • Sabadosa K.A.
      • Spear S.L.
      • et al.
      Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
      ,
      • Robinson K.A.
      • Saldanha I.J.
      • McKoy N.A.
      Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis.
      ,
      • Schwarzenberg S.J.
      • Hempstead S.E.
      • McDonald C.M.
      • Powers S.W.
      • Wooldridge J.
      • Blair S.
      • et al.
      Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
      ,
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ,
      • Kuczmarski R.J.
      • Ogden C.L.
      • Guo S.S.
      • Grummer-Strawn L.M.
      • Flegal K.M.
      • Mei Z.
      • et al.
      2000 CDC growth charts for the United States: methods and development.
      ].

      6.2 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. Fat soluble vitamins should be measured at least yearly to permit early detection of deficiency or excess [
      • Sermet-Gaudelus I.
      • Mayell S.J.
      • Southern K.W.
      Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
      ,
      ,
      • Borowitz D.
      • Baker R.D.
      • Stallings V.
      Consensus report on nutrition for pediatric patients with cystic fibrosis.
      ,
      ,
      ,
      • Stallings V.A.
      • Stark L.J.
      • Robinson K.A.
      • Feranchak A.P.
      • Quinton H.
      Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.
      ,
      • Borowitz D.
      • Robinson K.A.
      • Rosenfeld M.
      • Davis S.D.
      • Sabadosa K.A.
      • Spear S.L.
      • et al.
      Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
      ,
      • Robinson K.A.
      • Saldanha I.J.
      • McKoy N.A.
      Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis.
      ,
      • Schwarzenberg S.J.
      • Hempstead S.E.
      • McDonald C.M.
      • Powers S.W.
      • Wooldridge J.
      • Blair S.
      • et al.
      Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
      ,
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ,
      • Kuczmarski R.J.
      • Ogden C.L.
      • Guo S.S.
      • Grummer-Strawn L.M.
      • Flegal K.M.
      • Mei Z.
      • et al.
      2000 CDC growth charts for the United States: methods and development.
      ,
      • Multicentre Growth Reference Study Group WHO
      WHO child growth standards: methods and development: length/height-for-age, weight-forage, weight-for-length, weight-for-height and body mass index-for-age.
      ,
      • Zhang Z.
      • Shoff S.M.
      • Lai H.J.
      Comparing the use of centers for disease control and prevention and World Health Organization growth charts in children with cystic fibrosis through 2 years of age.
      ].

      6.3 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 a simple and reliable marker 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. Excessive doses of PERT may result in abdominal pain and constipation. Guidelines for testing for EPI and dosing of enzymes are available [
      • Sermet-Gaudelus I.
      • Mayell S.J.
      • Southern K.W.
      Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
      ,
      • Borowitz D.
      • Baker R.D.
      • Stallings V.
      Consensus report on nutrition for pediatric patients with cystic fibrosis.
      ,
      ,
      ,
      • Borowitz D.
      • Robinson K.A.
      • Rosenfeld M.
      • Davis S.D.
      • Sabadosa K.A.
      • Spear S.L.
      • et al.
      Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
      ,
      • Robinson K.A.
      • Saldanha I.J.
      • McKoy N.A.
      Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis.
      ,
      • Schwarzenberg S.J.
      • Hempstead S.E.
      • McDonald C.M.
      • Powers S.W.
      • Wooldridge J.
      • Blair S.
      • et al.
      Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
      ,
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ,
      • Anthony H.
      • Collins C.E.
      • Davidson G.
      • Mews C.
      • Robinson P.
      • Shepherd R.
      • et al.
      Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia.
      ].

      6.4 What are the main strategies to provide preventive nutritional care?

      CF centres should be familiar with the recommendations for age-appropriate dietetic advice to be directed by CF dietitians [
      • Kerem E.
      • Conway S.
      • Elborn S.
      • Heijerman H.
      • Consensus Committee
      Standards of care for patients with cystic fibrosis: a European consensus.
      ,
      • Sermet-Gaudelus I.
      • Mayell S.J.
      • Southern K.W.
      Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
      ,
      ,
      • Borowitz D.
      • Baker R.D.
      • Stallings V.
      Consensus report on nutrition for pediatric patients with cystic fibrosis.
      ,
      ,
      ,
      • Stallings V.A.
      • Stark L.J.
      • Robinson K.A.
      • Feranchak A.P.
      • Quinton H.
      Evidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.
      ,
      • Borowitz D.
      • Robinson K.A.
      • Rosenfeld M.
      • Davis S.D.
      • Sabadosa K.A.
      • Spear S.L.
      • et al.
      Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
      ,
      • Robinson K.A.
      • Saldanha I.J.
      • McKoy N.A.
      Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis.
      ,
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ,
      • Anthony H.
      • Collins C.E.
      • Davidson G.
      • Mews C.
      • Robinson P.
      • Shepherd R.
      • et al.
      Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia.
      ,
      • Edenborough F.P.
      • Borgo G.
      • Knoop C.
      • Lannefors L.
      • Mackenzie W.E.
      • Madge S.
      • et al.
      Guidelines for the management of pregnancy in women with cystic fibrosis.
      ,
      • Yankaskas J.R.
      • Marshall B.C.
      • Sufian B.
      • Simon R.H.
      • Rodman D.
      Cystic fibrosis adult care: consensus conference report.
      ,
      • Lahiri T.
      • Hempstead S.E.
      • Brady C.
      • Cannon C.L.
      • Clark K.
      • Condren M.E.
      • et al.
      Clinical practice guidelines from the Cystic Fibrosis Foundation for preschoolers with cystic fibrosis.
      ]. This includes:
      • a.
        Assessment of EPI and administration of PERT.
      • b.
        Selection of appropriate diet, with attention to a high fat intake.
      • c.
        Behavioural therapy to achieve positive mealtime experiences.
      • d.
        Providing sodium supplementation, when necessary, with special awareness in newborn screened infants.
      • e.
        Supplementing fat soluble vitamins, as indicated by laboratory testing.
      • f.
        Women with CF who plan their pregnancies should receive pre-conception advice to improve their nutritional status [
        • Edenborough F.P.
        • Borgo G.
        • Knoop C.
        • Lannefors L.
        • Mackenzie W.E.
        • Madge S.
        • et al.
        Guidelines for the management of pregnancy in women with cystic fibrosis.
        ].

      6.5 What factors should be evaluated in patients with poor growth?

      Evaluation should be triggered by weight loss, decline in weight or length/height percentile (<2 years of age), decline in BMI percentile for age and gender (>2 years of age), 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 [
      • Sermet-Gaudelus I.
      • Mayell S.J.
      • Southern K.W.
      Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening.
      ,
      • Borowitz D.
      • Baker R.D.
      • Stallings V.
      Consensus report on nutrition for pediatric patients with cystic fibrosis.
      ,
      ,
      ,
      • Borowitz D.
      • Robinson K.A.
      • Rosenfeld M.
      • Davis S.D.
      • Sabadosa K.A.
      • Spear S.L.
      • et al.
      Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis.
      ,
      • Robinson K.A.
      • Saldanha I.J.
      • McKoy N.A.
      Management of infants with cystic fibrosis: a summary of the evidence for the Cystic Fibrosis Foundation Working Group on care of infants with cystic fibrosis.
      ,
      • Schwarzenberg S.J.
      • Hempstead S.E.
      • McDonald C.M.
      • Powers S.W.
      • Wooldridge J.
      • Blair S.
      • et al.
      Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
      ,
      • Turck D.
      • Braegger C.P.
      • Colombo C.
      • Declercq D.
      • Morton A.
      • Pancheva R.
      • et al.
      ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
      ,
      • Anthony H.
      • Collins C.E.
      • Davidson G.
      • Mews C.
      • Robinson P.
      • Shepherd R.
      • et al.
      Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia.
      ].

      6.6 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. Avoid spending too much time on a single strategy if it is not producing results.
      • a.
        Anticipatory guidance. Reinforcement of adherence to diet, sodium and enzyme recommendations, using behavioral intervention for dysfunctional feeding issues in toddlers and young children [
        • Powers S.W.
        • Stark L.J.
        • Chamberlin L.A.
        • Filigno S.S.
        • Sullivan S.M.
        • Lemanek K.L.
        • et al.
        Behavioral and nutritional treatment for preschool-aged children with cystic fibrosis: a randomized clinical trial.
        ] or motivational interviewing in older patients.
      • b.
        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.
      • c.
        Severe malnutrition. Enteral feeding via NG or gastrostomy tubes usually improves and maintains nutrition in a patient with CF.
      • d.
        Other therapies: Cyproheptadine and growth hormone are not part of routine management. Parenteral nutrition is only appropriate when enteral nutrition is impossible or fails.
      • e.
        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)
        [
        • Borowitz D.
        • Baker R.D.
        • Stallings V.
        Consensus report on nutrition for pediatric patients with cystic fibrosis.
        ,
        ,
        ,
        • Schwarzenberg S.J.
        • Hempstead S.E.
        • McDonald C.M.
        • Powers S.W.
        • Wooldridge J.
        • Blair S.
        • et al.
        Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.
        ,
        • Turck D.
        • Braegger C.P.
        • Colombo C.
        • Declercq D.
        • Morton A.
        • Pancheva R.
        • et al.
        ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with cystic fibrosis.
        ,
        • Yankaskas J.R.
        • Marshall B.C.
        • Sufian B.
        • Simon R.H.
        • Rodman D.
        Cystic fibrosis adult care: consensus conference report.
        ].

      6.7 When and how do we screen for diabetes mellitus?

      All CF patients who have not been diagnosed with diabetes/CF-related 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 oral glucose tolerance test (OGTT), requires confirmation with a second test. Some centres now use continuous glucose monitoring as part of the diagnostic process [
      • Moran A.
      • Pillay K.
      • Becker D.J.
      • Acerini C.L.
      • International Society for Pediatric and Adolescent Diabetes
      ISPAD Clinical Practice Consensus Guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
      ,
      • Prentice B.
      • Hameed S.
      • Verge C.F.
      • Ooi C.Y.
      • Jaffe A.
      • Widger J.
      Diagnosing cystic fibrosis-related diabetes: current methods and challenges.
      ]. Refer to the published guidelines for additional detail. Published guidelines [
      • Moran A.
      • Brunzell C.
      • Cohen R.C.
      • Katz M.
      • Marshall B.C.
      • Onady G.
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      ,
      • Middleton P.G.
      • Wagenaar M.
      • Matson A.G.
      • Craig M.E.
      • Holmes-Walker D.J.
      • Katz T.
      • et al.
      Australian standards of care for cystic fibrosis-related diabetes.
      ,
      • American Diabetes Association
      Clinical practice recommendations.
      ] 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.

      6.8 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 [
      • Moran A.
      • Brunzell C.
      • Cohen R.C.
      • Katz M.
      • Marshall B.C.
      • Onady G.
      • et al.
      Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society.
      ,
      • Middleton P.G.
      • Wagenaar M.
      • Matson A.G.
      • Craig M.E.
      • Holmes-Walker D.J.
      • Katz T.
      • et al.
      Australian standards of care for cystic fibrosis-related diabetes.
      ,
      • American Diabetes Association
      Clinical practice recommendations.
      ]. 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 [
      • Moran A.
      • Pillay K.
      • Becker D.J.
      • Acerini C.L.
      • International Society for Pediatric and Adolescent Diabetes
      ISPAD Clinical Practice Consensus Guidelines 2014. Management of cystic fibrosis-related diabetes in children and adolescents.
      ].

      6.9 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 [
      • Aris R.M.
      • Merkel P.A.
      • Bachrach L.K.
      • Borowitz D.S.
      • Boyle M.P.
      • Elkin S.L.
      • et al.
      Guide to bone health and disease in cystic fibrosis.
      ,
      • Sermet-Gaudelus I.
      • Bianchi M.L.
      • Garabedian M.
      • Aris R.M.
      • Morton A.
      • Hardin D.S.
      • et al.
      European cystic fibrosis bone mineralisation guidelines.
      ,
      • Marquette M.
      • Haworth C.S.
      Bone health and disease in cystic fibrosis.
      ].
      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 [
      • Aris R.M.
      • Merkel P.A.
      • Bachrach L.K.
      • Borowitz D.S.
      • Boyle M.P.
      • Elkin S.L.
      • et al.
      Guide to bone health and disease in cystic fibrosis.
      ,
      • Sermet-Gaudelus I.
      • Bianchi M.L.
      • Garabedian M.
      • Aris R.M.
      • Morton A.
      • Hardin D.S.
      • et al.
      European cystic fibrosis bone mineralisation guidelines.
      ,
      • Marquette M.
      • Haworth C.S.
      Bone health and disease in cystic fibrosis.
      ].

      6.10 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 [
      • Aris R.M.
      • Merkel P.A.
      • Bachrach L.K.
      • Borowitz D.S.
      • Boyle M.P.
      • Elkin S.L.
      • et al.
      Guide to bone health and disease in cystic fibrosis.
      ,
      • Sermet-Gaudelus I.
      • Bianchi M.L.
      • Garabedian M.
      • Aris R.M.
      • Morton A.
      • Hardin D.S.
      • et al.
      European cystic fibrosis bone mineralisation guidelines.
      ,
      • Marquette M.
      • Haworth C.S.
      Bone health and disease in cystic fibrosis.
      ].

      7. Treatment of complications

      Harry Heijerman (NL), Barry Plant (ROI), Giovanni Taccetti (IT).

      7.1 Pulmonary complications

      Patients with CF may develop a variety of complications which, although infrequent, occur commonly. 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.

      7.1.1 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 [
      • Flume P.A.
      • Strange C.
      • Ye X.
      • Ebeling M.
      • Hulsey T.
      • Clark L.L.
      • et al.
      Pneumothorax in cystic fibrosis.
      ]. 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, chest CT). Management guidelines have been published [
      • Flume P.A.
      • Mogayzel P.J.
      • Robinson K.A.
      • Rosenblatt R.L.
      • Quittell L.
      • Marshall B.C.
      • et al.
      Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax.
      ]; 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 where additional novel strategies may also need to be considered [
      • Lord R.W.
      • Jones A.M.
      • Webb A.K.
      • Barry P.J.
      Pneumothorax in cystic fibrosis: beyond the guidelines.
      ].

      7.1.2 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/d or >100 mL/d for several days [
      • Flume P.A.
      • Yankaskas J.R.
      • Ebeling M.
      • Hulsey T.
      • Clark L.L.
      Massive hemoptysis in cystic fibrosis.
      ]. Management guidelines have been published [
      • Flume P.A.
      • Mogayzel P.J.
      • Robinson K.A.
      • Rosenblatt R.L.
      • Quittell L.
      • Marshall B.C.
      • et al.
      Cystic fibrosis pulmonary guidelines: pulmonary complications: hemoptysis and pneumothorax.
      ]. 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 embolization) and/or thoracic surgery.

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

      The natural history of CF lung disease is progression to advanced stage airways obstruction and eventual respiratory failure. The centre should recognise progression to this stage and have discussions about lung transplant and advanced healthcare directives (see Chapter 8). 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 [
      • Yankaskas J.R.
      • Marshall B.C.
      • Sufian B.
      • Simon R.H.
      • Rodman D.
      Cystic fibrosis adult care: consensus conference report.
      ]. Ventilatory support (e.g. non-invasive ventilation) should be provided in accordance with the patient's wishes for palliation of dyspnea [
      ]. The centre should be able to assess symptoms and the need for opiates to relieve dyspnea and pain associated with advanced stage disease [
      • Robinson W.M.
      • Ravilly S.
      • Berde C.
      • Wohl M.E.
      End-of-life care in cystic fibrosis.
      ,
      • Clayton J.M.
      • Hancock K.M.
      • Butow P.N.
      • Tattersall M.H.
      • Currow D.C.
      • Adler J.
      • et al.
      Clinical practice guidelines for communicating prognosis and end-of-life issues with adults in the advanced stages of a life-limiting illness, and their caregivers.
      ,
      • Dellon E.P.
      • Shores M.D.
      • Nelson K.I.
      • Wolfe J.
      • Noah T.L.
      • Hanson L.C.
      Family caregiver perspectives on symptoms and treatments for patients dying from complications of cystic fibrosis.
      ].

      7.2 Liver and pancreas complications

      7.2.1 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. CF related liver disease (CFLD) is a biliary cirrhosis that usually presents before age 20 years and can lead to portal hypertension and hepatic failure [
      • Debray D.
      • Kelly D.
      • Houwen R.
      • Strandvik B.
      • Colombo C.
      Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.
      ]. 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 [
      • Debray D.
      • Kelly D.
      • Houwen R.
      • Strandvik B.
      • Colombo C.
      Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.
      ,
      • Sokol R.J.
      • Durie P.R.
      Recommendations for management of liver and biliary tract disease in cystic fibrosis.
      ,
      • van der Feen C.
      • van der Doef H.P.
      • van der Ent C.K.
      • Houwen R.H.
      Ursodeoxycholic acid treatment is associated with improvement of liver stiffness in cystic fibrosis patients.
      ,
      • Sadler M.D.
      • Crotty P.
      • Fatovich L.
      • Wilson S.
      • Rabin H.R.
      • Myers R.P.
      Non-invasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.
      ].
      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 immunization 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). Recently, CFTR modulators and correctors have been introduced. Ivacaftor and the combination of lumacaftor/ivacaftor may cause hepatic impairment. When liver disease is present the dosing of these drugs needs adjustment [
      • Talamo Guevara M.
      • McColley S.A.
      The safety of lumacaftor and ivacaftor for the treatment of cystic fibrosis.
      ]. The centre should have a pathway for referral to a liver transplant program, for those patients with advanced stage liver disease leading to hepatic failure.

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

      Cholelithiasis is not always symptomatic [
      • Modolell I.
      • Alvarez A.
      • Guarner L.
      • De Gracia J.
      • Malagelada J.-R.
      Gastrointestinal, liver, and pancreatic involvement in adult patients with cystic fibrosis.
      ]. 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 [
      • Colombo C.
      • Bertolini E.
      • Assaisso M.L.
      • Bettinardi N.
      • Giunta A.
      • Podda M.
      Failure of ursodeoxycholic acid to dissolve radiolucent gallstones in patients with cystic fibrosis.
      ].

      7.2.3 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 [
      • Ooi C.Y.
      • Durie P.R.
      Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis.
      ]. Recurrent acute pancreatitis may contribute to the transition from pancreatic sufficiency to insufficiency in CF. The presentation may be a non-specific abdominal pain, so there should be high suspicion when seeing a patient with 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 no different than those for non-CF pancreatitis. However, acute pancreatitis is associated with severe dehydration and in the CF population this may be more severe, demanding attention to rehydration and electrolyte monitoring. Recently developed CFTR correctors and potentiators may play a role in the treatment of recurrent pancreatitis as they stimulate bicarbonate and fluid secretion in the pancreas [
      • Hegyi P.
      • Wilschanski M.
      • Muallem S.
      • Lukacs G.L.
      • Sahin-Tóth M.
      • Uc A.
      • et al.
      CFTR: a new horizon in the pathomechanism and treatment of pancreatitis.
      ].

      7.3 Gastrointestinal complications

      7.3.1 What is the best way to manage gastro-oesophageal reflux disease (GORD) in patients with CF?

      GORD occurs commonly in patients with CF, affecting over 36% [
      • Cystic Fibrosis Foundation
      Patient Registry Annual Data Report 2015.
      ]. The centre should be aware of the signs and symptoms of GORD and be able to provide, if necessary, appropriate diagnostic testing (i.e., impedance and pH probe, upper endoscopy) and treatment [
      • Vandenplas Y.
      • Rudolph C.D.
      • Di Lorenzo C.
      • Hassall E.
      • Liptak G.
      • Mazur L.
      • et al.
      Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN).
      ,
      • Mousa H.M.
      • Woodley F.W.
      Gastroesophageal reflux in cystic fibrosis: current understandings of mechanisms and management.
      ,
      • Borowitz D.
      • Gelfond D.
      Intestinal complications of cystic fibrosis.
      ,
      • Kelly T.
      • Buxbaum J.
      Gastrointestinal manifestations of cystic fibrosis.
      ,
      • Demeyer S.
      • De Boeck K.
      • Witters P.
      • Cosaert K.
      Beyond pancreatic insufficiency and liver disease in cystic fibrosis.
      ].

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

      Constipation has a slow onset with reduced frequency of stooling [
      • Houwen R.H.
      • van der Doef H.P.
      • Sermet I.
      • Munck A.
      • Hauser B.
      • Walkowiak J.
      • et al.
      Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.
      ]. It is common in CF and may be exacerbated by use of narcotics. Most of the time constipation responds to hydration therapy, stool softeners or laxatives (e.g., polyethylene glycol). Enemas are rarely needed [
      • Kelly T.
      • Buxbaum J.
      Gastrointestinal manifestations of cystic fibrosis.
      ,
      • Demeyer S.
      • De Boeck K.
      • Witters P.
      • Cosaert K.
      Beyond pancreatic insufficiency and liver disease in cystic fibrosis.
      ,
      Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.
      ].

      7.3.3 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 [
      • Houwen R.H.
      • van der Doef H.P.
      • Sermet I.
      • Munck A.
      • Hauser B.
      • Walkowiak J.
      • et al.
      Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.
      ]. Complete and incomplete DIOS have been described [
      Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.
      ]. The centre should be able to recognize these complications and have standard protocols for diagnosis and treatment based upon published recommendations [
      ,
      • Demeyer S.
      • De Boeck K.
      • Witters P.
      • Cosaert K.
      Beyond pancreatic insufficiency and liver disease in cystic fibrosis.
      ,
      • Houwen R.H.
      • van der Doef H.P.
      • Sermet I.
      • Munck A.
      • Hauser B.
      • Walkowiak J.
      • et al.
      Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.
      ,
      • Colombo C.
      • Ellemunter H.
      • Houwen R.
      • Munck A.
      • Taylor C.
      • Wilschanski M.
      • et al.
      Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients.
      ]. 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. Pancreatic enzyme replacement therapy should be re-evaluated in patients with DIOS [
      • Kelly T.
      • Buxbaum J.
      Gastrointestinal manifestations of cystic fibrosis.
      ,
      • Demeyer S.
      • De Boeck K.
      • Witters P.
      • Cosaert K.
      Beyond pancreatic insufficiency and liver disease in cystic fibrosis.
      ]. Delayed arrival at hospital after the initial symptoms causes significant morbidity. Medical treatment may fail only in cases of complete DIOS. Although surgery is the ultimate resource [
      • Munck A.
      • Alberti C.
      • Colombo C.
      • Kashirskaya N.
      • Ellemunter H.
      • Fotoulaki M.
      • et al.
      International prospective study of distal intestinal obstruction syndrome in cystic fibrosis: associated factors and outcome.
      ] the centre should have surgeons who know about this CF complication.

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

      This is an uncommon complication. At present, 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 [
      • Sinaasappel M.
      • Stern M.
      • Littlewood J.
      • Wolfe S.
      • Steinkamp G.
      • Heijerman H.G.
      • et al.
      Nutrition in patients with cystic fibrosis: a European Consensus.
      ,
      • Peckham D.
      • Whitaker P.
      Drug induced complications; can we do more?.
      ,
      • Peckham D.
      • Whitaker P.
      Reply to professor Taylor.
      ,
      • Dodge J.A.
      Pancreatic enzymes and fibrosing colonopathy.
      ].

      7.3.5 What is the best treatment for appendiceal mucocele?

      Ultrasonography will aid the diagnosis [
      • Munck A.
      • Belbari N.
      • de Lagausie P.
      • Peuchmaur M.
      • Navarro J.
      Ultrasonography detects appendicular mucocele in cystic fibrosis patients suffering recurrent abdominal pain.
      ]. In case of symptoms, appendectomy with resection of the appendix edges and resection of the caecal tip will avoid risk of recurrence.

      7.3.6 What is the best way to manage small intestinal bacterial overgrowth (SIBO) in patients with CF?

      SIBO is suspected when patients have diffuse or peri-umbilical abdominal pain, excessive bowel gas, diarrhea, nausea and malabsorption despite adequate enzyme intake. Risk is higher in patients who have had previous intestinal surgery or are using narcotics. Although many non-invasive diagnostic procedures have been used, there is no golden standard test to demonstrate SIBO [
      • Demeyer S.
      • De Boeck K.
      • Witters P.
      • Cosaert K.
      Beyond pancreatic insufficiency and liver disease in cystic fibrosis.
      ,
      • Miazga A.
      • Osiński M.
      • Cichy W.
      • Żaba R.
      Current views on the etiopathogenesis, clinical manifestation, diagnostics, treatment and correlation with other nosological entities of SIBO.
      ]. It is recommended that diagnosis be made by a clinical therapeutic trial of metronidazole [
      • Quigley E.M.
      • Abu-Shanab A.
      Small intestinal bacterial overgrowth.
      ]. Treatment includes cyclical administration of oral antibiotics effective in the GI lumen, pre- and probiotics, laxatives and prokinetic drugs [
      • Demeyer S.
      • De Boeck K.
      • Witters P.
      • Cosaert K.
      Beyond pancreatic insufficiency and liver disease in cystic fibrosis.
      ]. Due to differences in studies design and outcome measures, scanty evidence exists on the effects of probiotics supplementation in SIBO [
      • Ananthan A.
      • Balasubramanian H.
      • Rao S.
      • Patole S.
      Probiotic supplementation in children with cystic fibrosis-a systematic review.
      ].

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

      MI is a neonatal emergency best handled at a centre familiar with CF and where a pediatric surgeon with expertise in MI is available. Early referral to a centre familiar with both non-surgical and surgical management is essential [
      • Karimi A.
      • Gorter R.R.
      • Sleeboom C.
      • Kneepkens C.M.
      • Heij H.A.
      Issues in the management of simple and complex meconium ileus.
      ,
      • Carlyle B.E.
      • Borowitz D.S.
      • Glick P.L.
      A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon.
      ,
      • Farrelly P.J.
      • Charlesworth C.
      • Lee S.
      • Southern K.W.
      • Baillie C.T.
      Gastrointestinal surgery in cystic fibrosis: a 20-year review.
      ]. Complicated MI is more severe, more difficult to treat, and may require prolonged hospitalization. Post-operative management may require a centre familiar with management of short bowel. MI does not predispose to later development of DIOS, however children with MI have a higher rate of surgery for DIOS [
      • Munck A.
      • Alberti C.
      • Colombo C.
      • Kashirskaya N.
      • Ellemunter H.
      • Fotoulaki M.
      • et al.
      International prospective study of distal intestinal obstruction syndrome in cystic fibrosis: associated factors and outcome.
      ].

      7.3.8 Is there an increased risk for GI malignancies in patients with CF?

      In patients with CF, gastrointestinal malignancies are more prevalent compared to the healthy population. Several studies show a higher yearly incidence in colorectal cancer and progression of adenomatous colorectal polyps to colorectal cancer [
      • Meyer K.C.
      • Francois M.L.
      • Thomas H.K.
      • Radford K.L.
      • Hawes D.L.
      • Mack T.L.
      • et al.
      Colon cancer in lung transplant recipients with CF: increased risk and results of screening.
      ,
      • Maisonneuve P.
      • Marshall B.C.
      • Knapp E.A.
      • et al.
      Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States.
      ,
      • Billings J.L.
      • Dunitz J.M.
      • McAllister S.
      • et al.
      Early colon screening of adult patients with cystic fibrosis reveals high incidence of adenomatous colon polyps.
      ,
      • Niccum D.E.
      • Billings J.L.
      • Dunitz J.M.
      • et al.
      Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis.
      ]. A recent study shows that screening for colorectal cancer is cost-effective and should be started at an age of 40 years [
      • Gini A.
      • Zauber A.G.
      • Cenin D.R.
      • Omidvari A.
      • Hemstead S.E.
      • Fink A.K.
      • et al.
      Cost effectiveness of screening individuals with cystic fibrosis for colorectal cancer.
      ].

      7.4 Other complications

      7.4.1 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) [
      • Prayle A.
      • Watson A.
      • Fortnum H.
      • Smyth A.R.
      Side effects of aminoglycosides on the kidney, ear and balance in cystic fibrosis.
      ]. Drug-drug interactions, especially after the introduction of CFTR correctors and modulators, are complications clinicians should be aware of and when possible, be prevented by dose adjustment. The inclusion of a specialized pharmacist in the CF team is important. The centre should utilise standard protocols for therapeutic drug monitoring when using aminoglycosides and follow recommended treatment dosing [
      Antibiotic treatment for cystic fibrosis.
      ]. When using intravenous (IV) aminoglycosides, there should be strict avoidance of NSAIDs 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 also have access to a clinician experienced in vestibular assessment.

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

      Nephrolithiasis is common in CF patients [
      • Gibney E.M.
      • Goldfarb D.S.
      The association of nephrolithiasis with cystic fibrosis.
      ]. The centre should be aware of the signs and symptoms associated with nephrolithiasis and be able to evaluate by urinalysis and CT-IVP. The metabolic disorder causing kidney stones should be determined, given the high frequency of enteric hyperoxaluria [
      • Plant B.J.
      • Goss C.H.
      • Plant W.D.
      • Bell S.C.
      Management of comorbidities in older patients with cystic fibrosis.
      ]. Fluid intake to maintain a high urine output combined with a low-oxalate and high-calcium diet is appropriate for patients with kidney stones [
      • Plant B.J.
      • Goss C.H.
      • Plant W.D.
      • Bell S.C.
      Management of comorbidities in older patients with cystic fibrosis.
      ,
      • Sidhu H.
      • Hoppe B.
      • Hesse A.
      • Tenbrock K.
      • Brömme S.
      • Rietschel E.
      • et al.
      Absence of Oxalobacter formigenes in cystic fibrosis patients: a risk factor for hyperoxaluria.
      ]. The centre should have access to a specialist nephrologist, urologist and interventional radiologist for complicated nephrolithiasis.

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

      Arthralgias are common symptoms in CF patients [
      • Cystic Fibrosis Foundation
      Patient Registry Annual Data Report 2015.
      ] but arthropathy remains poorly understood. The centre should be aware of this problem. Treatment with analgesics and anti-inflammatory agents may be needed. Glucocorticoids and disease-modifying anti-rheumatic drugs may be considered in refractory cases in consultation with a rheumatologist who has knowledge of CF [
      • Plant B.J.
      • Parkins M.D.
      Extrapulmonary manifestations of cystic fibrosis.
      ].

      7.4.4 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 and occurs already in early childhood [
      • Cystic Fibrosis Foundation
      Patient Registry Annual Data Report 2015.
      ,
      • Berkhout M.C.
      • Klerx-Melis F.
      • Fokkens W.J.
      • Nuijsink M.
      • van Aalderen W.M.
      • Heijerman H.G.
      CT-abnormalities, bacteriology and symptoms of sinonasal disease in children with cystic fibrosis.
      ]. The centre should routinely evaluate sinus disease and offer recommended treatment, recognizing that this could be a source for lower airways infection [
      • Bonestroo H.J.C.
      • de Winter-de Groot K.M.
      • van der Ent C.K.
      • Arets H.G.M.
      Upper and lower airway cultures in children with cystic fibrosis: do not neglect the upper airways.
      ]. It should have access to diagnostic testing (i.e., CT sinus) and an otolaryngologist experienced with CF-related sinus disease. Recently developed CFTR correctors and potentiators may ameliorate sinonasal disease [
      • Vreede C.L.
      • Berkhout M.C.
      • Sprij A.J.
      • Fokkens W.J.
      • Heijerman H.G.
      Ivacaftor and sinonasal pathology in a cystic fibrosis patient with genotype deltaF508/S1215N.
      ].

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

      With the exception of ABPA (discussed in paragraph 3.10), allergic disease is not increased in CF patients and can be managed similarly to non-CF patients with allergies. Patients can develop allergies to antibiotics (especially beta-lactams) that increase the risk of potentially life-threatening reactions and can complicate medical treatment in patients with advanced lung disease and frequent exposure to parenteral antibiotics [
      • Matar R.
      • Le Bourgeois M.
      • Scheinmann P.
      • de Blic J.
      • Ponvert C.
      Beta-lactam hypersensitivity in children with cystic fibrosis: a study in a specialized pediatric center for cystic fibrosis and drug allergy.
      ,
      • Whitaker P.
      • Shaw N.
      • Gooi J.
      • Etherington C.
      • Conway S.
      • Peckham D.
      Rapid desensitization for non-immediate reactions in patients with cystic fibrosis.
      ]. Hospitalisation at the start of treatment in patients ‘at risk’, should be considered to improve safety [
      • Roehmel J.F.
      • Schwarz C.
      • Mehl A.
      • Stock P.
      • Staab D.
      Hypersensitivity to antibiotics in patients with cystic fibrosis.
      ]. The centre should be aware of signs and symptoms of possible allergic response to treatment and stop that therapy accordingly. Following allergologists' advice, the centre should have established protocols for desensitization should that therapy be important and with no other treatment options [
      • Whitaker P.
      • Shaw N.
      • Gooi J.
      • Etherington C.
      • Conway S.
      • Peckham D.
      Rapid desensitization for non-immediate reactions in patients with cystic fibrosis.
      ,
      • Parmar J.S.
      • Nasser S.
      Antibiotic allergy in cystic fibrosis.
      ,
      • Legere III, H.J.
      • Palis R.I.
      • Rodriguez Bouza T.
      • Uluer A.Z.
      • Castells M.C.
      A safe protocol for rapid desensitization in patients with cystic fibrosis and antibiotic hypersensitivity.
      ,
      • de Groot H.
      • Mulder W.M.
      Clinical practice: drug desensitization in children.
      ,
      • Cernadas J.R.
      Desensitization to antibiotics in children.
      ]. Written instructions on the emergency treatment of allergic reactions should be provided to patients self-administering intravenous antibiotics at home [
      • Parmar J.S.
      • Nasser S.
      Antibiotic allergy in cystic fibrosis.
      ].

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

      An indwelling 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. Midline catheters, peripherally inserted central catheters [PICCs], Port-A-Cath). Only trained individuals should be able to 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) [
      • Garwood S.
      • Flume P.A.
      • Ravenel J.
      Superior vena cava syndrome related to indwelling intravenous catheters in patients with cystic fibrosis.
      ,
      • Munck A.
      • Kheniche A.
      • Alberti C.
      • Hubert D.
      • Martine R.G.
      • Nove-Josserand R.
      • et al.
      Central venous thrombosis and thrombophilia in cystic fibrosis: a prospective study.
      ]. The centre should be keenly aware of the signs and symptoms of catheter-related complications and be able to perform proper testing including blood cultures, ultrasonography and contrasted radiology studies to assess infections and vascular occlusion. Intravascular catheter-related infections should be managed according to published guidelines [
      • Mermel L.A.
      • Allon M.
      • Bouza E.
      • Craven D.E.
      • Flynn P.
      • O'Grady N.P.
      • et al.
      Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America.
      ,
      • O'Grady N.
      • Alexander M.
      • Burns L.A.
      • Dellinger E.P.
      • Garland J.
      • Heard S.O.
      • et al.
      Guidelines for the prevention of intravascular catheter-related infections.
      ].

      7.4.7 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 a 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 [
      • Edenborough F.P.
      • Borgo G.
      • Knoop C.
      • Lannefors L.
      • Mackenzie W.E.
      • Madge S.
      • et al.
      Guidelines for the management of pregnancy in women with cystic fibrosis.
      ].

      7.4.8 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 counseling regarding fertility options including assisted reproductive techniques.

      8. Transplantation and end-of-life issues

      Scott Bell (AU), Alistair Duff (UK), Su Madge (UK), Thomas Wagner (DE).
      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 successful transplant. In some patients, transplant is not a suitable treatment option or does not occur for various reasons such as death occurring prior to suitable donor organs becoming available. 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.
      Outcomes for people with CF undergoing lung transplantation have continued to improve and with 10-year survival rates approaching 50% [
      • Stephenson A.L.
      • Sykes J.
      • Berthiaume Y.
      • Singer L.G.
      • Aaron S.D.
      • Whitmore G.A.
      • et al.
      Clinical and demographic factors associated with post-lung transplantation survival in individuals with cystic fibrosis.
      ] and even exceeding this in single-centre reports [
      • Robin Vos R.
      • Verleden G.M.
      • Dupont L.J.
      Long-term survival after lung transplantation among cystic fibrosis patients: moving away from mere palliation.
      ]. These standards include a series of questions about the approach to transplantation assessment and end-of-life care, utilising available published evidence and 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 [
      • Hirche T.O.
      • Knoop C.
      • Hebestreit H.
      • Shimmin D.
      • Sole A.
      • Elborn J.S.
      • et al.
      Practical guidelines: lung transplantation in patients with cystic fibrosis.
      ] and the ECFS End-of-life Care Guidelines [
      • Sands D.
      • Repetto T.
      • Dupont L.J.
      • Korzeniewska-Eksterowicz A.
      • Catastini P.
      • Madge S.
      End of life care for patients with cystic fibrosis.
      ].

      8.1 What are the important determinants for 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 associated with increased mortality, and where referral for transplantation assessment is recommended [
      • Weill D.
      • Benden C.
      • Corris P.A.
      • Dark J.H.
      • Davis R.D.
      • Keshavjee S.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.
      ] are:
      • a.
        FEV1% of ≤30 predicted
      • b.
        Rapid decline, particularly female and younger patients.
      • c.
        Oxygen therapy for hypoxaemia.
      • d.
        Hypercapnia.
      • e.
        Frequent exacerbation that respond poorly to intravenous antibiotics.
      Earlier referral should be considered in patients with refractory pneumothorax and recurrent massive haemoptysis [
      • Orens J.B.
      • Estenne M.
      • Arcasoy S.
      • Conte J.V.
      • Corris P.
      • Egan J.J.
      • et al.
      International guidelines for the selection of lung transplant candidates: 2006 update–a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation.
      ]. 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 [
      • Liou T.G.
      • Adler F.R.
      • Cahill B.C.
      • FitzSimmons S.C.
      • Huang D.
      • Hibbs J.R.
      • et al.
      Survival effect of lung transplantation among patients with cystic fibrosis.
      ,
      • Mayer-Hamblett N.
      • Rosenfeld M.
      • Emerson J.
      • Goss C.H.
      • Aitken M.L.
      • Mayer-Hamblett N.
      • et al.
      Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality.
      ]. There remain barriers to referral for transplant assessment including physicians' perception of suitability and difficulty in predicting timing of assessment, and socioeconomic factors [
      • Ramos K.J.
      • Quon B.S.
      • Psoter K.J.
      • Lease E.D.
      • Mayer-Hamblett N.
      • Aitken M.L.
      • et al.
      Predictors of non-referral of patients with cystic fibrosis for lung transplant evaluation in the United States.
      ,
      • Martin C.
      • Hamard C.
      • Kanaan R.
      • Boussaud V.
      • Grenet D.
      • Abely M.
      • et al.
      Causes of death in French cystic fibrosis patients: the need for improvement in transplantation referral strategies!.
      ,
      • Quon B.S.
      • Psoter K.
      • Mayer-Hamblett N.
      • Aitken M.L.
      • Li C.I.
      • Goss C.H.
      Disparities in access to lung transplantation for patients with cystic fibrosis by socioeconomic status.
      ]. 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. If in doubt about the optimal timing for referral for an individual patient it is better to consider an earlier referral.
      Regular and detailed communication with the Transplant Service is vital to allow regular updates of the clinical progress of all wait-listed patients. One recent analysis based on the US CF Foundation Patient Registry of predictors of non-referral for transplant assessment included low socioeconomic status, older age and B. cepacia complex sputum culture [
      • Ramos K.J.
      • Quon B.S.
      • Psoter K.J.
      • Lease E.D.
      • Mayer-Hamblett N.
      • Aitken M.L.
      • et al.
      Predictors of non-referral of patients with cystic fibrosis for lung transplant evaluation in the United States.
      ].
      Assessment and prioritisation of younger children with CF requires careful consideration with transplant teams who have a specific paediatric expertise [
      • Hayes Jr., D.
      • McCoy K.S.
      • Whitson B.A.
      • Mansour H.M.
      • Tobias J.D.
      High-risk age window for mortality in children with cystic fibrosis after lung transplantation.
      ]. Children often have poorer pre-transplant clinical status and have a higher incidence of post-transplant infections and diabetes [
      • Moreno P.
      • Alvarez A.
      • Carrasco G.
      • Redel J.
      • Guaman H.D.
      • Baamonde C.
      • et al.
      Lung transplantation for cystic fibrosis: differential characteristics and outcomes between children and adults.
      ].

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

      Priority for transplantation [
      • Orens J.B.
      • Estenne M.
      • Arcasoy S.
      • Conte J.V.
      • Corris P.
      • Egan J.J.
      • et al.
      International guidelines for the selection of lung transplant candidates: 2006 update–a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation.
      ,
      • Kerem E.
      • Reisman J.
      • Corey M.
      • Canny G.J.
      • Levison H.
      Prediction of mortality in patients with cystic fibrosis.
      ,
      • Snell G.I.
      • Bennetts K.
      • Bartolo J.
      • Levvey B.
      • Griffiths A.
      • Williams T.
      • et al.
      Body mass index as a predictor of survival in adults with cystic fibrosis referred for lung transplantation.
      ] should be given to CF patients with:
      • a.
        Oxygen-dependent respiratory failure.
      • b.
        Chronic hypercapnia.
      • c.
        Pulmonary hypertension [
        • Venuta F.
        • Tonelli A.R.
        • Anile M.
        • Diso D.
        • De Giacomo T.
        • Ruberto F.
        • et al.
        Pulmonary hypertension is associated with higher mortality in cystic fibrosis patients awaiting lung transplantation.
        ,
        • Hayes Jr., D.
        • Higgins R.S.
        • Kirkby S.
        • McCoy K.S.
        • Wehr A.M.
        • Lehman A.M.
        • et al.
        Impact of pulmonary hypertension on survival in patients with cystic fibrosis undergoing lung transplantation: an analysis of the UNOS registry.
        ].
      • d.
        Under-nutrition - 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 [
      • Thabut G.
      • Christie J.D.
      • Mal H.
      • Fournier M.
      • Brugiere O.
      • Leseche G.
      • et al.
      Survival benefit of lung transplant for cystic fibrosis since lung allocation score implementation.
      ,
      • Braun A.T.
      • Dasenbrook E.C.
      • Shah A.S.
      • Orens J.B.
      • Merlo C.A.
      Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients.
      ]. Aggressive approaches to nutritional restoration should be considered in all under-nourished patients being considered for lung transplantation.

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

      Exclusions for lung transplantation [
      • Weill D.
      • Benden C.
      • Corris P.A.
      • Dark J.H.
      • Davis R.D.
      • Keshavjee S.
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.
      ] include:
      • a.
        Malignancy within 2 years. A disease-free period of 5 years is generally required. Consideration for cutaneous and some urogenital cancers may be given.
      • b.
        Untreatable dysfunction of another major organ (e.g. heart, liver, kidney).
      • c.
        Chronic extra-pulmonary infection (e.g. hepatitis B, hepatitis C, HIV).
      • d.
        Severe skeletal deformity.
      • e.
        Prolonged poor-adherence or irregular clinic attendance.
      • f.
        Untreatable psychological condition/s limiting ability to participate with therapies.
      • g.
        Lack of consistent social support system.
      • h.
        Substance addiction (e.g. alcohol, tobacco, within previous 6 months).
      Most transplant services do not assess patients with chronic Burkholderia cenocepacia and/or Mycobacteria abscessus (M. abscessus).
      The impact of M. abscessus infection remains unclear, with recent studies reporting higher rates of post-transplant infection requiring intensive therapy but not necessarily increased mortality [
      • Lobo L.J.
      • Chang L.C.
      • Esther Jr., C.R.
      • Gilligan P.H.
      • Tulu Z.
      • Noone P.G.
      Lung transplant outcomes in cystic fibrosis patients with pre-operative Mycobacterium abscessus respiratory infections.
      ,
      • Qvist T.
      • Pressler T.
      • Thomsen V.O.
      • Skov M.
      • Iversen M.
      • Katzenstein T.L.
      Nontuberculous mycobacterial disease is not a contraindication to lung transplantation in patients with cystic fibrosis: a retrospective analysis in a Danish patient population.
      ], M. abscessus is often associated with increased morbidity following transplantation. Careful consideration about suitability for listing includes the presence of smear positive sputum status and presence of multi-resistant M. abscessus [
      • Floto R.A.
      • Olivier K.N.
      • Saiman L.
      • Daley C.L.
      • Herrmann J.L.
      • Nick J.A.
      • et al.
      US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary.
      ].
      Other infections (e.g. multi-resistant Pseudomonas aeruginosa, Scedosporium species and Clostridium difficile) are influenced by local transplant unit policy and experience and require detailed discussion.
      Combined ‘liver/lung’ or ‘lung only’ transplantation both require careful consideration in patients with advanced lung disease and portal hypertension [
      • Miller M.R.
      • Sokol R.J.
      • Narkewicz M.R.
      • Sontag M.K.
      Pulmonary function in individuals who underwent liver transplantation: from the US cystic fibrosis foundation registry.
      ]. CF may be associated with worse outcomes following liver transplantation than for other indications [
      • Black S.M.
      • Woodley F.W.
      • Tumin D.
      • Mumtaz K.
      • Whitson B.A.
      • Tobias J.D.
      • et al.
      Cystic fibrosis associated with worse survival after liver transplantation.
      ,
      • Nash E.F.
      • Volling C.
      • Gutierrez C.A.
      • Tullis E.
      • Coonar A.
      • McRae K.
      • et al.
      Outcomes of patients with cystic fibrosis undergoing lung transplantation with and without cystic fibrosis-associated liver cirrhosis.
      ,
      • Desai C.S.
      • Gruessner A.
      • Habib S.
      • Gruessner R.
      • Khan K.M.
      Survival of cystic fibrosis patients undergoing liver and liver-lung transplantations.
      ].
      Re-transplantation may be considered in specific circumstances in some transplant recipients [
      • Benden C.
      • Goldfarb S.B.
      • Edwards L.B.
      • Kucheryavaya A.Y.
      • Christie J.D.
      • Dipchand A.I.
      • et al.
      The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric lung and heart-lung transplantation report–2014; focus theme: re-transplantation.