Beyond the Lungs—Emerging Challenges in Adult Cystic Fibrosis Care

Abstract

Cystic fibrosis (CF) is a multisystem disease. This article provides an up-to-date review of many of the nonrespiratory complications of CF, including mental health issues, nutritional and gastrointestinal problems, fertility issues, diabetes mellitus, bone health and musculoskeletal problems, liver disease, renal problems, and risk of malignancy. It highlights the recent impact of new therapies, including CF transmembrane conductance regulator modulators, on the nonrespiratory complications of CF and provides insights into the potential challenges faced by an aging population of adults with CF and their caregivers, including the potential future risk for cardiovascular disease.

Keywords

cystic fibrosis - CFTR modulators - aging - malignancy - cardiovascular disease - bone health

Publikationsverlauf

Artikel online veröffentlicht:
19. Dezember 2022

• References

• 1 George PM, Banya W, Pareek N. et al. Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007. BMJ 2011; 342 (7797): d1008
• 2 Stephenson AL, Tom M, Berthiaume Y. et al. A contemporary survival analysis of individuals with cystic fibrosis: a cohort study. Eur Respir J 2015; 45 (03) 670-679
• 3 Middleton PG, Mall MA, Dřevínek P. et al; VX17-445-102 Study Group. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381 (19) 1809-1819
• 4 Mitchell RM, Jones AM, Stocking K, Foden P, Barry PJ. Longitudinal effects of ivacaftor and medicine possession ratio in people with the Gly551Asp mutation: a 5-year study. Thorax 2021; 76 (09) 874-879
• 5 Petersen MC, Begnel L, Wallendorf M, Litvin M. Effect of elexacaftor-tezacaftor-ivacaftor on body weight and metabolic parameters in adults with cystic fibrosis. J Cyst Fibros 2022; 21 (02) 265-271
• 6 Bonhoure A, Boudreau V, Litvin M. et al. Overweight, obesity and significant weight gain in adult patients with cystic fibrosis association with lung function and cardiometabolic risk factors. Clin Nutr 2020; 39 (09) 2910-2916
• 7 Gelfond D, Heltshe S, Ma C. et al. Impact of CFTR modulation on intestinal pH, motility, and clinical outcomes in patients with cystic fibrosis and the G551D mutation. Clin Transl Gastroenterol 2017; 8 (03) e81
• 8 Ooi CY, Syed SA, Rossi L. et al. Impact of CFTR modulation with ivacaftor on gut microbiota and intestinal inflammation. Sci Rep 2018; 8 (01) 17834
• 9 Carrion A, Borowitz DS, Freedman SD. et al. Reduction of recurrence risk of pancreatitis in cystic fibrosis with ivacaftor: case series. J Pediatr Gastroenterol Nutr 2018; 66 (03) 451-454
• 10 Garg M, Ooi CY. The enigmatic gut in cystic fibrosis: linking inflammation, dysbiosis, and the increased risk of malignancy. Curr Gastroenterol Rep 2017; 19 (02) 6
• 11 Fink AK, Yanik EL, Marshall BC. et al. Cancer risk among lung transplant recipients with cystic fibrosis. J Cyst Fibros 2017; 16 (01) 91-97
• 12 Hadjiliadis D, Khoruts A, Zauber AG, Hempstead SE, Maisonneuve P, Lowenfels AB. Cystic Fibrosis Colorectal Cancer Screening Task Force. Cystic fibrosis colorectal cancer screening consensus recommendations. Gastroenterology 2018; 154 (03) 736-745.e14
• 13 Than BLN, Linnekamp JF, Starr TK. et al. CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 2016; 35 (32) 4179-4187
• 14 Niccum DE, Billings JL, Dunitz JM, Khoruts A. Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis. J Cyst Fibros 2016; 15 (04) 548-553
• 15 Matson AG, Bunting JP, Kaul A. et al. A non-randomised single centre cohort study, comparing standard and modified bowel preparations, in adults with cystic fibrosis requiring colonoscopy. BMC Gastroenterol 2019; 19 (01) 89
• 16 Annual Data Report 2021. Cystic Fibrosis Foundation Patient Registry. Accessed November 17, 2022 at: https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf
• 17 Granados A, Chan CL, Ode KL, Moheet A, Moran A, Holl R. Cystic fibrosis related diabetes: pathophysiology, screening and diagnosis. J Cyst Fibros 2019; 18 (Suppl. 02) S3-S9
• 18 Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 2000; 162 (3 pt. 1): 891-895
• 19 Ode KL, Chan CL, Granados A, Moheet A, Moran A, Brennan AL. Cystic fibrosis related diabetes: medical management. J Cyst Fibros 2019; 18 (Suppl. 02) S10-S18
• 20 Chan CL, Ode KL, Granados A, Moheet A, Moran A, Hameed S. Continuous glucose monitoring in cystic fibrosis—a practical guide. J Cyst Fibros 2019; 18 (Suppl. 02) S25-S31
• 21 Hardin DS, Rice J, Rice M, Rosenblatt R. Use of the insulin pump in treat cystic fibrosis related diabetes. J Cyst Fibros 2009; 8 (03) 174-178
• 22 Scully KJ, Palani G, Zheng H, Moheet A, Putman MS. The effect of control IQ hybrid closed loop technology on glycemic control in adolescents and adults with cystic fibrosis-related diabetes. Diabetes Technol Ther 2022; 24 (06) 446-452
• 23 Sherwood JS, Jafri RZ, Balliro CA. et al. Automated glycemic control with the bionic pancreas in cystic fibrosis-related diabetes: a pilot study. J Cyst Fibros 2020; 19 (01) 159-161
• 24 Bessonova L, Volkova N, Higgins M. et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax 2018; 73 (08) 731-740
• 25 Scully KJ, Marchetti P, Sawicki GS. et al. The effect of elexacaftor/tezacaftor/ivacaftor (ETI) on glycemia in adults with cystic fibrosis. J Cyst Fibros 2022; 21 (02) 258-263
• 26 Sellers ZM, Kovacs A, Weinheimer CJ, Best PM. Left ventricular and aortic dysfunction in cystic fibrosis mice. J Cyst Fibros 2013; 12 (05) 517-524
• 27 Cross CE, Reverri EJ, Morrissey BM. Joining the crowd: cystic fibrosis and cardiovascular disease risk factors. Chest 2013; 143 (04) 882-884
• 28 Hull JH, Garrod R, Ho TB. et al. Increased augmentation index in patients with cystic fibrosis. Eur Respir J 2009; 34 (06) 1322-1328
• 29 Poore S, Berry B, Eidson D, McKie KT, Harris RA. Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis. Chest 2013; 143 (04) 939-945
• 30 Reverri EJ, Morrissey BM, Cross CE, Steinberg FM. Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis. Free Radic Biol Med 2014; 76: 261-277
• 31 Rhodes B, Nash EF, Tullis E. et al. Prevalence of dyslipidemia in adults with cystic fibrosis. J Cyst Fibros 2010; 9 (01) 24-28
• 32 Singh H, Coffey MJ, Ooi CY. Cystic fibrosis-related liver disease is associated with increased disease burden and endocrine comorbidities. J Pediatr Gastroenterol Nutr 2020; 70 (06) 796-800
• 33 Earnest A, Salimi F, Wainwright CE. et al. Lung function over the life course of paediatric and adult patients with cystic fibrosis from a large multi-centre registry. Sci Rep 2020; 10 (01) 17421
• 34 Cipolli M, Fethney J, Waters D. et al. Occurrence, outcomes and predictors of portal hypertension in cystic fibrosis: a longitudinal prospective birth cohort study. J Cyst Fibros 2020; 19 (03) 455-459
• 35 Colombo C, Battezzati PM, Crosignani A. et al. Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome. Hepatology 2002; 36 (06) 1374-1382
• 36 Boëlle PY, Debray D, Guillot L, Clement A, Corvol H. French CF Modifier Gene Study Investigators. Cystic fibrosis liver disease: outcomes and risk factors in a large cohort of French patients. Hepatology 2019; 69 (04) 1648-1656
• 37 Debray D, Kelly D, Houwen R, Strandvik B, Colombo C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J Cyst Fibros 2011; 10 (2, suppl 2): S29-S36
• 38 Fiorotto R, Strazzabosco M. Pathophysiology of cystic fibrosis liver disease: a channelopathy leading to alterations in innate immunity and in microbiota. Cell Mol Gastroenterol Hepatol 2019; 8 (02) 197-207
• 39 Wu H, Vu M, Dhingra S. et al. Obliterative portal venopathy without cirrhosis is prevalent in pediatric cystic fibrosis liver disease with portal hypertension. Clin Gastroenterol Hepatol 2019; 17 (10) 2134-2136
• 40 Fiorotto R, Scirpo R, Trauner M. et al. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice. Gastroenterology 2011; 141 (04) 1498-1508 , 1508.e1–1508.e5
• 41 Salehi M, Iqbal M, Dube A, AlJoudeh A, Edenborough F. Delayed hepatic necrosis in a cystic fibrosis patient taking elexacaftor/tezacaftor/ivacaftor (Kaftrio). Respir Med Case Rep 2021; 34: 101553
• 42 Drummond D, Dana J, Berteloot L. et al. Lumacaftor-ivacaftor effects on cystic fibrosis-related liver involvement in adolescents with homozygous F508 del-CFTR. J Cyst Fibros 2022; 21 (02) 212-219
• 43 Kanavaki A, Kanavaki I, Zoumpoulis PS, Moustaki M, Douros K, Loukou I. Changes in share wave elastography after lumacaftor/ivacaftor treatment in children with cystic fibrosis. Curr Drug Saf 2023; 18 (01) 93-96
• 44 Quon BS, Mayer-Hamblett N, Aitken ML, Smyth AR, Goss CH. Risk factors for chronic kidney disease in adults with cystic fibrosis. Am J Respir Crit Care Med 2011; 184 (10) 1147-1152
• 45 Nazareth D, Walshaw M. A review of renal disease in cystic fibrosis. J Cyst Fibros 2013; 12 (04) 309-317
• 46 Aris RM, Ontjes DA, Buell HE. et al. Abnormal bone turnover in cystic fibrosis adults. Osteoporos Int 2002; 13 (02) 151-157
• 47 Marquette M, Haworth CS. Bone health and disease in cystic fibrosis. Paediatr Respir Rev 2016; 20 (suppl): 2-5
• 48 Shead EF, Haworth CS, Condliffe AM, McKeon DJ, Scott MA, Compston JE. Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human bone. Thorax 2007; 62 (07) 650-651
• 49 Shead EF, Haworth CS, Barker H, Bilton D, Compston JE. Osteoclast function, bone turnover and inflammatory cytokines during infective exacerbations of cystic fibrosis. J Cyst Fibros 2010; 9 (02) 93-98
• 50 Rossini M, Del Marco A, Dal Santo F. et al. Prevalence and correlates of vertebral fractures in adults with cystic fibrosis. Bone 2004; 35 (03) 771-776
• 51 Stephenson A, Jamal S, Dowdell T, Pearce D, Corey M, Tullis E. Prevalence of vertebral fractures in adults with cystic fibrosis and their relationship to bone mineral density. Chest 2006; 130 (02) 539-544
• 52 Aris RM, Renner JB, Winders AD. et al. Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 1998; 128 (03) 186-193
• 53 Putman MS, Anabtawi A, Le T, Tangpricha V, Sermet-Gaudelus I. Cystic fibrosis bone disease treatment: current knowledge and future directions. J Cyst Fibros 2019; 18 (Suppl. 02) S56-S65
• 54 Sermet-Gaudelus I, Delion M, Durieu I, Jacquot J, Hubert D. Bone demineralization is improved by ivacaftor in patients with cystic fibrosis carrying the p.Gly551Asp mutation. J Cyst Fibros 2016; 15 (06) e67-e69
• 55 Putman MS, Greenblatt LB, Bruce M. et al. The effects of ivacaftor on bone density and microarchitecture in children and adults with cystic fibrosis. J Clin Endocrinol Metab 2021; 106 (03) e1248-e1261
• 56 Clarke EA, Watson P, Freeston JE, Peckham DG, Jones AM, Horsley A. Assessing arthritis in the context of cystic fibrosis. Pediatr Pulmonol 2019; 54 (06) 770-777
• 57 Annual Data Report 2020. Cystic Fibrosis Foundation Patient Registry. Accessed November 17, 2022 at: https://www.cff.org/sites/default/files/2021-10/2019-Patient-Registry-Annual-Data-Report.pdf
• 58 van der Ven K, Messer L, van der Ven H, Jeyendran RS, Ober C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum Reprod 1996; 11 (03) 513-517
• 59 Shteinberg M, Lulu AB, Downey DG. et al. Failure to conceive in women with CF is associated with pancreatic insufficiency and advancing age. J Cyst Fibros 2019; 18 (04) 525-529
• 60 Yefimova M, Bourmeyster N, Becq F. et al. Update on the cellular and molecular aspects of cystic fibrosis transmembrane conductance regulator (CFTR) and male fertility. Morphologie 2019; 103 (341) 4-10
• 61 O'Connor KE, Goodwin DL, NeSmith A. et al. Elexacafator/tezacaftor/ivacaftor resolves subfertility in females with CF: a two center case series. J Cyst Fibros 2021; 20 (03) 399-401
• 62 Godfrey EM, Mody S, Schwartz MR. et al. Contraceptive use among women with cystic fibrosis: a pilot study linking reproductive health questions to the Cystic Fibrosis Foundation National Patient Registry. Contraception 2020; 101 (06) 420-426
• 63 Chamayou S, Sicali M, Lombardo D. et al. Universal strategy for preimplantation genetic testing for cystic fibrosis based on next generation sequencing. J Assist Reprod Genet 2020; 37 (01) 213-222
• 64 Schechter MS, Quittner AL, Konstan MW, Millar SJ, Pasta DJ, McMullen A. Scientific Advisory Group, Investigators and Coordinators of Epidemiologic Study of Cystic Fibrosis. Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis. Ann Am Thorac Soc 2013; 10 (03) 213-219
• 65 Ashcroft A, Chapman SJ, Mackillop L. The outcome of pregnancy in women with cystic fibrosis: a UK population-based descriptive study. BJOG 2020; 127 (13) 1696-1703
• 66 Cohen-Cymberknoh M, Gindi Reiss B, Reiter J. et al. Baseline cystic fibrosis disease severity has an adverse impact on pregnancy and infant outcomes, but does not impact disease progression. J Cyst Fibros 2021; 20 (03) 388-394
• 67 Reynaud Q, Rousset Jablonski C, Poupon-Bourdy S. et al; Participating Centers of the French Cystic Fibrosis Registry. Pregnancy outcome in women with cystic fibrosis and poor pulmonary function. J Cyst Fibros 2020; 19 (01) 80-83
• 68 Middleton PG, Gade EJ, Aguilera C. et al. ERS/TSANZ Task Force Statement on the management of reproduction and pregnancy in women with airways diseases. Eur Respir J 2020; 55 (02) 1901208
• 69 Kroon MAGM, Akkerman-Nijland AM, Rottier BL, Koppelman GH, Akkerman OW, Touw DJ. Drugs during pregnancy and breast feeding in women diagnosed with cystic fibrosis—an update. J Cyst Fibros 2018; 17 (01) 17-25
• 70 Taylor-Cousar JL, Jain R. Maternal and fetal outcomes following elexacaftor-tezacaftor-ivacaftor use during pregnancy and lactation. J Cyst Fibros 2021; 20 (03) 402-406
• 71 Nash EF, Middleton PG, Taylor-Cousar JL. Outcomes of pregnancy in women with cystic fibrosis (CF) taking CFTR modulators—an international survey. J Cyst Fibros 2020; 19 (04) 521-526
• 72 Edenborough FP, Borgo G, Knoop C. et al; European Cystic Fibrosis Society. Guidelines for the management of pregnancy in women with cystic fibrosis. J Cyst Fibros 2008; 7 (1, Suppl 1): S2-S32
• 73 Quittner AL, Goldbeck L, Abbott J. et al. Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries. Thorax 2014; 69 (12) 1090-1097
• 74 Snell C, Fernandes S, Bujoreanu IS, Garcia G. Depression, illness severity, and healthcare utilization in cystic fibrosis. Pediatr Pulmonol 2014; 49 (12) 1177-1181
• 75 Hilliard ME, Eakin MN, Borrelli B, Green A, Riekert KA. Medication beliefs mediate between depressive symptoms and medication adherence in cystic fibrosis. Health Psychol 2015; 34 (05) 496-504
• 76 Riekert KA, Bartlett SJ, Boyle MP, Krishnan JA, Rand CS. The association between depression, lung function, and health-related quality of life among adults with cystic fibrosis. Chest 2007; 132 (01) 231-237
• 77 Joffres M, Jaramillo A, Dickinson J. et al; Canadian Task Force on Preventive Health Care. Recommendations on screening for depression in adults. CMAJ 2013; 185 (09) 775-782
• 78 Quittner AL, Abbott J, Georgiopoulos AM. et al; International Committee on Mental Health, EPOS Trial Study Group. International Committee on Mental Health in Cystic Fibrosis: Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus statements for screening and treating depression and anxiety. Thorax 2016; 71 (01) 26-34
• 79 Heo S, Young DC, Safirstein J. et al. Mental status changes during elexacaftor/tezacaftor/ivacaftor therapy. J Cyst Fibros 2022; 21 (02) 339-343
• 80 Spoletti G, Gillgrass L, Pollard K. et al. Dose adjustments of elexacaftor/tezacaftor/ivacaftor in response to mental health side effects in adults with cystic fibrosis. J Cyst Fibros 2022; 21 (06) 1061-1065