EnVisioning the future: Endocrinology in cystic fibrosis

The cystic fibrosis (CF) story over the last few decades has included many successes. Advances in treatment options for people with CF have resulted in substantial increase in survival, and CF is no longer just a disease of childhood. The predicted median age of survival for a person with CF born in the UK today is 47 years [[1]Ramsden D, Carr S. Cystic fibrosis trust annual report. 28/08/2018. 2018[cited 2018 Aug 28]. p. 8–77. Available from: http://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources.Google Scholar], in the USA is 46.2 years [[2]Cystic Fibrosis Foundation patient registry 2017 annual data report Bethesda, Maryland ©2018 Cystic Fibrosis Foundation.Google Scholar] and in some countries over 50 years [[3]Canadian cystic fibrosis foundation patient registry 2017 annual data report. Available from: https://www.cysticfibrosis.ca/uploads/Registry%20Report%202017/2017%20Registry%20Annual%20Data%20Report.pdf. [Accessed 16 October 2019].Google Scholar]. Improved survival has led to an increasing proportion of adults with cystic fibrosis, and in 2017 over 60% of patients in the UK CF Registry [[1]Ramsden D, Carr S. Cystic fibrosis trust annual report. 28/08/2018. 2018[cited 2018 Aug 28]. p. 8–77. Available from: http://www.cysticfibrosis.org.uk/the-work-we-do/uk-cf-registry/reporting-and-resources.Google Scholar] were over the age of 16 and 53.3% in the US CF Registry [[2]Cystic Fibrosis Foundation patient registry 2017 annual data report Bethesda, Maryland ©2018 Cystic Fibrosis Foundation.Google Scholar] were 18 years of age or older. Furthermore, a significant proportion of people with CF over 40 years of age now have ‘classic’ CF, with 30% homozygous for Phe508del mutation and over 80% with pancreatic insufficiency [[4]Simmonds N. Cullinan P. Hodson M. et al.Growing old with cystic fibrosis – the characteristics of long-term survivors of cystic fibrosis.Resp Med. 2009; 103: 629-635Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Further changes to these demographics may become apparent as treatments aimed at the basic defect of CF such as CFTR modulators become more widely available. However, we must recognise the potential problems associated with an ageing CF population and increasing numbers of people living with chronic illness. Historically, the goal of CF treatment has focused on the management of progressive lung disease and nutritional insufficiency, since the majority of patients would succumb to end stage lung disease and respiratory failure and had evidence of under-nutrition. As the majority of people with CF now survive into adulthood, CF management must evolve to recognise and treat emerging comorbidities. These may be direct complications of CFTR dysfunction, CF treatment-related complications or even comorbidities related to a general ageing process. An increasing number of extra-pulmonary comorbidities in CF are recognised including CF-related diabetes mellitus (CFRD), metabolic bone disease, renal disease, hypertension, gastrointestinal cancers and other gastrointestinal complications (e.g. gastroesophageal reflux, bacterial overgrowth and dysmotility). Many of these comorbidities and their treatments have important implications for clinical status, treatment burden and quality of life. These complications also add significantly to the complexity of delivering healthcare especially in adult patients and will challenge the current health care models where the majority of care is provided by the core CF multidisciplinary team [[5]Conway, S. et al. European cystic fibrosis society standards of care: framework for the cystic fibrosis centre. J Cyst Fibros, Volume 13, S3–S22. DOI: https://doi.org/10.1016/j.jcf.2014.03.009Google Scholar]. The recognition, diagnosis and treatment of comorbidities will be key in the drive to further improve the health and quality of care of people with CF. Furthermore, younger patients born with CF today are likely to live much longer than previously anticipated due to improvements in care with the widespread introduction of treatment post newborn screening and development of key drugs including azithromycin [[6]Equi A. Balfour-Lynn I.M. Bush A. Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised,placebo-controlled crossover trial.Lancet. 2002; 360: 978-984Abstract Full Text Full Text PDF PubMed Scopus (470) Google Scholar], nebulised antibiotics [[7]Ramsey B.W. Pepe M.S. Quan J.M. Otto K.L. et al.Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic fibrosis inhaled tobramycin study group.N Engl J Med. 1999; 340: 23-30Crossref PubMed Scopus (1102) Google Scholar,[8]McCoy K.S. Quittner A.L. Oermann C.M. Gibson R.L. Retsch-Bogart G.Z. A.B. MontgomeryInhaled aztreonam lysine for chronic airway pseudomonas aeruginosa in cystic fibrosis.Am J Respir Crit Care Med. 2008; 178: 921-928Crossref PubMed Scopus (288) Google Scholar] and most recently treatments aimed at the basic defect of CF [9Accurso F.J. Rowe S.M. Clancy J.P. et al.Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.N Engl J Med. 2010; 363: 1991-2003Crossref PubMed Scopus (584) Google Scholar, 10Ramsey B.W. Davies J. McElvaney N.G. Tullis E. et al.A cftr potentiator in patients with cystic fibrosis and the G551D mutation.N Engl J Med. 2011; 365: 1663-1672https://doi.org/10.1056/NEJMoa1105185Crossref PubMed Scopus (1389) Google Scholar, 11Taylor-Cousar J.L. Mall M.A. Ramsey B.W. McKone E.F. et al.Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles.ERJ Open Res. 2019; 5 (pii: 00082-2019)https://doi.org/10.1183/23120541.00082-2019Crossref PubMed Scopus (33) Google Scholar]. Consideration of preventative strategies will be required to reduce the development of complications later in life and this may require us to challenge long-held beliefs over CF treatments such as nutritional therapy [[12]Nutritional management of cystic fibrosis Cystic Fibrosis Trust, London2016https://www.cysticfibrosis.org.uk/∼/media/documents/the-work-we-do/care/consensus-documents-with-old-address/nutritional-management-of-cystic-fibrosis-sep-16.ashx?la=enGoogle Scholar,[13]Stallings V.A. Stark L.J. Robinson K.A. Feranchak A.P. Quinton H. Clinical Practice Guidelines on Growth and Nutrition SubcommitteeAd Hoc Working GroupEvidence-based practice recommendations for nutrition-related management of children and adults with cystic fibrosis and pancreatic insufficiency: results of a systematic review.J Am Diet Assoc. 2008; 108 (PMID:18442507): 832-839Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar] since improved medical therapies and improved nutrition may contribute to the emergence of over-nutrition in patients with CF [[14]Litvin M. Energy balance and obesity in individuals with cystic fibrosis.J Cyst Fibros. 2019; 18S2: S38-S47Abstract Full Text Full Text PDF Scopus (9) Google Scholar]. Currently, the majority of physicians providing speciality CF care are pulmonologists. Training for physicians and other members of the CF multidisciplinary teams has often been uncoordinated [[15]Elborn J.S. Bell S.C. Madge S.L. Burgel P.R. et al.Report of the European respiratory society/European cystic fibrosis society task force on the care of adults with cystic fibrosis.Eur Respir J. 2016; 47: 420-428https://doi.org/10.1183/13993003.00592-2015Crossref PubMed Scopus (79) Google Scholar]. Training programs exist in several countries which provide specialist training in CF medicine [[12]Nutritional management of cystic fibrosis Cystic Fibrosis Trust, London2016https://www.cysticfibrosis.org.uk/∼/media/documents/the-work-we-do/care/consensus-documents-with-old-address/nutritional-management-of-cystic-fibrosis-sep-16.ashx?la=enGoogle Scholar]; the UK CF Trust's Clinical Training Fellowship Programme has sponsored 21 fellows since 2005. However, as the complexity of the disease increases, there is a need for wider specialities to be involved both in the delivery of care and research. Whilst individual CF centres will undoubtedly develop close working relationships with key specialities locally, the CF Foundation (USA) adopted a national strategic approach. It has so far developed formalised programs to train caregivers in family medicine and internal medicine/paediatrics, as well as specialists in two disciplines, gastroenterology and endocrinology. In 2014 the U.S. Cystic Fibrosis Foundation funded the first DIGEST training program (Developing Innovative Gastrointestinal Specialty Training). Now in the third cycle, it is a three-year program which has enrolled 52 paediatric and adult gastroenterologists across the U.S. The program consists of monthly didactic/case-based web seminars, a required clinic at least monthly within a CF clinic, and lastly a scholarly project. Many in the first cohort contributed to the “Best Practices in the Management of the Gastrointestinal Aspects of Cystic Fibrosis” supplement which was published in November 2017 containing 10 articles which were available for 12 months as open access through the Journal of Cystic Fibrosis [16Maqbool A. Pauwels A. Cystic fibrosis and gastroesophageal reflux disease.J Cyst Fibros. 2017; 16: S2-S13https://doi.org/10.1016/j.jcf.2017.07.007Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 17Dorsey J. Gonska T. Bacterial overgrowth, dysbiosis, inflammation, and dysmotility in the cystic fibrosis intestine.J Cyst Fibros. 2017; 16: S14-23https://doi.org/10.1016/j.jcf.2017.07.014Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 18Lusman S.S. Grand R. Approach to chronic abdominal pain in cystic fibrosis.J Cyst Fibros. 2017; 16: S24-31https://doi.org/10.1016/j.jcf.2017.06.009Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar, 19Sathe M. Houwen R. Meconium ileus in cystic fibrosis.J Cyst Fibros. 2017; 16: S32-9https://doi.org/10.1016/j.jcf.2017.06.007Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 20Abraham J.M. Taylor C.J. Cystic fibrosis & disorders of the large intestine: DIOS, constipation, and colorectal cancer.J Cyst Fibros. 2017; 16: S40-9https://doi.org/10.1016/j.jcf.2017.06.013Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 21Leung D.H. Narkewicz M.R. Cystic fibrosis-related cirrhosis.J Cyst Fibros. 2017; 16: S50-61https://doi.org/10.1016/j.jcf.2017.07.002Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 22Assis D.N. Debray D. Gallbladder and bile duct disease in cystic fibrosis.J Cyst Fibros. 2017; 16: S62-9https://doi.org/10.1016/j.jcf.2017.07.006Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 23Singh V.K. Schwarzenberg S.J. Pancreatic insufficiency in cystic fibrosis.J Cyst Fibros. 2017; 16: S70-8https://doi.org/10.1016/j.jcf.2017.06.011Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 24Freeman A.J. Ooi C.Y. Pancreatitis and pancreatic cystosis in cystic fibrosis.J Cyst Fibros. 2017; 16: S79-86https://doi.org/10.1016/j.jcf.2017.07.004Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 25Sullivan J.S. Mascarenhas M.R. Nutrition: prevention and management of nutritional failure in cystic fibrosis.J Cyst Fibros. 2017; 16: S87-93https://doi.org/10.1016/j.jcf.2017.07.010Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. They emphasise the excessively high frequency of GI issues in CF, and highlight the need for clinical trials focused on new diagnostic modalities and treatments to improve the gastrointestinal outcomes which was a previously neglected area of CF care. Articles from this supplement have been downloaded 15,538 times, which demonstrates the appetite across the CF community to focus on improving the management of emerging co-morbidities. The EnVision program is a similarly-designed program which has trained 16 paediatric and adult endocrinologists in CF care with a secondary goal of growing the academic CF endocrinology community. Participants in the first cohort of this three-year program were mentored by one of five endocrinologists who are experts in CF, and attended meetings at the CF Foundation and at annual North American CF Conferences. They participated in monthly webinars, presenting their own research or topic reviews. They created or expanded their CF endocrinology clinics at their own institutions. Many of the EnVision mentees conducted research or teaching in CF-related topics, obtained independent funding for CF-related endocrine projects, and continue to collaborate with their mentors and each other on such projects. We are delighted the U.S. CF Foundation is supporting a second cohort of EnVision mentees starting October 2019, and that some of the EnVision I mentees are co-mentoring the EnVision II cohort. This is clearly a challenge for other health jurisdictions globally to ensure this important aspect of CF is not neglected to optimise support for our patients. Nurturing the growth of the CF endocrine community brings new experiences and perspectives to the CF community which will be greatly needed in the coming years if endocrine complications become more common in an aging CF population. Ideally, every CF centre worldwide will eventually have an endocrinologist(s) as members of the team. The degree of integration will likely vary by institution, including CFRD clinics integrated into the CF pulmonary or transplant clinics, and clinics at separate sites with regular remote collaboration, and pulmonary-endocrine collaborations in research or QI projects. Bringing the EnVision group into the CF research network also fosters collaboration between the endocrinologists in the program. These multicentre research networks are exactly what is needed to advance the state of the art in CF endocrinology, not only for the individuals with CF whose needs may change because of new medications, but also those individuals ineligible for new medications but who continue to have needs that can be met by endocrine specialists. Having endocrinologists in the CF academic community also fosters multidisciplinary collaborations and generates clinical and research connections that directly and indirectly improve dissemination of information and improve the clinical care of individuals with CF. The EnVision I cohort has now co-authored a supplement to the Journal of Cystic Fibrosis, “State of the Art: Endocrinology in Cystic Fibrosis”, consisting of 15 articles which cover a variety of CF endocrine topics including CF-related diabetes, bone disease and vitamin D, growth, nutrition, obesity, adrenal insufficiency, female and male reproductive health and post-transplant endocrine care [[14]Litvin M. Energy balance and obesity in individuals with cystic fibrosis.J Cyst Fibros. 2019; 18S2: S38-S47Abstract Full Text Full Text PDF Scopus (9) Google Scholar,26Grandos A. Pathophysiology, screening and diagnosis of cystic fibrosis related diabetes.JCF. 2019; 18S2: S3-S9https://doi.org/10.1016/j.jcf.2019.08.016Abstract Full Text Full Text PDF Scopus (22) Google Scholar, 27Larson Ode K. CFRD: medical management.JCF. 2019; 18S2: S10-S18Google Scholar, 28Chan C. CFRD continuous glucose monitoring.JCF. 2019; 18S2: S25-S31Google Scholar, 29Moheet A. CFRD: hypoglycaemia.JCF. 2019; 18S2: S19-S24Google Scholar, 30Kaminski B. CFRD nutritional management.JCF. 2019; 18S2: S32-S37Google Scholar, 31Anabtawi A. CF bone disease: pathophysiology and prognostic implications.JCF. 2019; 18S2: S48-S55Google Scholar, 32Putman M. CF bone disease: treatment.JCF. 2019; 18S2: S56-S65Google Scholar, 33Daley T. Vitamin d deficiency and its treatment.JCF. 2019; 18S2: S66-S73Google Scholar, 34Le T. Growth failure and treatment with anabolic agents.JCF. 2019; 18S2: S82-S87Google Scholar, 35Goldsweig B. Abnormal puberty: when do you worry, work-up and treatment.JCF. 2019; 18S2: S88-S94Google Scholar, 36Hughan K. Female reproductive health: birth control.JCF. 2019; 18S2: S95-S104Google Scholar, 37Sidhaye A. Endocrine issues in organ transplantation in cf.JCF. 2019; 18S2: S111-S119Google Scholar, 38Yoon J. Male reproductive health. Hypogonadism, diagnosis and treatment.JCF. 2019; 18S2: S105-S110Google Scholar, 39Rayas M. Iatrogenic adrenal insufficiency.JCF. 2019; 18S2: S74-S81Google Scholar]. Each review represents a collaborative effort between an EnVision mentee and a senior co-author in the field from around the globe. We are delighted to have been able to engage the global CF endocrine community in this important endeavour. Of note, while some articles have a strong research base, others have little published evidence, highlighting areas for future research. Also, not all areas we felt were important were able to be included in the supplement, and we encourage further research in particular into psychological topics including adherence in CFRD. We believe that the endocrine complications of CF will become more important in an ageing CF population. It is encouraging that CFTR modulator treatment, begun at a young age, could possibly improve some endocrine and nutritional complications of CF, but as yet there are no data indicating whether rates of CFRD or bone disease are improved. Also, we are encouraged by the continuing work to develop new treatments for those who are ineligible for current CFTR modulators. The growing CF endocrine community, thanks to the EnVision program and those like it, will continue to focus on improving the lives of all individuals with CF. No potential conflicts of interest relevant to this article were reported. The EnVision program and the Endocrine Supplement, “State of the Art: Endocrinology in Cystic Fibrosis” were supported by the U.S. Cystic Fibrosis Foundation. Dr. Antoinette Moran conceived the program, and she and the other four mentors (Dr. Scott Blackman, Dr. Andrea Kelly, Dr. Rémi Rabasa-Lhoret, and Dr. Vin Tangpricha) developed and implemented the program.

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