1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Medicine
  4. Volume 70, 2019
  5. Article

Annual Review of Medicine

Volume 70, 2019

Cystic Fibrosis: Emerging Understanding and Therapies

Abstract

Cystic fibrosis (CF) is the most common life-limiting genetic disease in Caucasian patients. Continued advances have led to improved survival, and adults with CF now outnumber children. As our understanding of the disease improves, new therapies have emerged that improve the basic defect, enabling patient-specific treatment and improved outcomes. However, recurrent exacerbations continue to lead to morbidity and mortality, and new pathogens have been identified that may lead to worse outcomes. In addition, new complications, such as CF-related diabetes and increased risk of gastrointestinal cancers, are creating new challenges in management. For patients with end-stage disease, lung transplantation has remained one of the few treatment options, but challenges in identifying the most appropriate patients remain.

Keyword(s): CF exacerbations, CF-related diabetes, CFTR modification, cystic fibrosis, lung transplantation
Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-112717-094536
2019-01-27
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/med/70/1/annurev-med-112717-094536.html?itemId=/content/journals/10.1146/annurev-med-112717-094536&mimeType=html&fmt=ahah

Literature Cited

  1. 1. Cystic Fibrosis Foundation Patient Registry. 2017. 2016 Annual Data Report Bethesda, MD: Cystic Fibrosis Found
  2. 2.  Anderson MP, Berger HA, Rich DP et al. 1991. Nucleoside triphosphates are required to open the CFTR chloride channel. Cell 67:775–84
     [Google Scholar]
  3. 3.  Mihalyi C, Torocsik B, Csanady L 2016. Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization. eLife 5:e18164
     [Google Scholar]
  4. 4.  Liu F, Zhang Z, Csanady L et al. 2017. Molecular structure of the human CFTR ion channel. Cell 169:85–95.e8
     [Google Scholar]
  5. 5.  Rowe SM, Miller S, Sorscher EJ 2005. Cystic fibrosis. N. Engl. J. Med. 352:1992–2001
     [Google Scholar]
  6. 6.  Guggino WB, Stanton BA 2006. New insights into cystic fibrosis: molecular switches that regulate CFTR. Nat. Rev. Mol. Cell Biol. 7:426–36
     [Google Scholar]
  7. 7.  Agrawal PB, Wang R, Li HL et al. 2017. The epithelial sodium channel is a modifier of the long-term nonprogressive phenotype associated with F508del CFTR mutations. Am. J. Respir. Cell Mol. Biol. 57:711–20
     [Google Scholar]
  8. 8.  Luan X, Belev G, Tam JS et al. 2017. Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens. Nat. Commun. 8:786
     [Google Scholar]
  9. 9.  Abdullah LH, Coakley R, Webster MJ et al. 2018. Mucin production and hydration responses to mucopurulent materials in normal versus cystic fibrosis airway epithelia. Am. J. Respir. Crit. Care Med. 197:481–91
     [Google Scholar]
  10. 10.  Cutting GR 2010. Modifier genes in Mendelian disorders: the example of cystic fibrosis. Ann. N. Y. Acad. Sci. 1214:57–69
     [Google Scholar]
  11. 11.  Drumm ML, Konstan MW, Schluchter MD et al. 2005. Genetic modifiers of lung disease in cystic fibrosis. N. Engl. J. Med. 353:1443–53
     [Google Scholar]
  12. 12.  Magalhaes M, Rivals I, Claustres M et al. 2017. DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis. Clin. Epigenetics 9:19
     [Google Scholar]
  13. 13.  Terlizzi V, Castaldo G, Salvatore D et al. 2017. Genotype-phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles. J. Med. Genet. 54:224–35
     [Google Scholar]
  14. 14.  Van Goor F, Hadida S, Grootenhuis PD et al. 2009. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. PNAS 106:18825–30
     [Google Scholar]
  15. 15.  Ramsey BW, Davies J, McElvaney NG et al. 2011. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365:1663–72
     [Google Scholar]
  16. 16.  US Food Drug Admin 2017. FDA expands approved use of Kalydeco to treat additional mutations of cystic fibrosis Press Release, May 17. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm559212.htm
  17. 17.  Bagdany M, Veit G, Fukuda R et al. 2017. Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell. Nat. Commun 8:398
     [Google Scholar]
  18. 18.  Clancy JP, Rowe SM, Accurso FJ et al. 2012. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax 67:12–18
     [Google Scholar]
  19. 19.  Wainwright CE, Elborn JS, Ramsey BW et al. 2015. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N. Engl. J. Med. 373:220–31
     [Google Scholar]
  20. 20.  Hubert D, Chiron R, Camara B et al. 2017. Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease. J. Cyst. Fibros. 16:388–91
     [Google Scholar]
  21. 21.  Taylor-Cousar JL, Munck A, McKone EF et al. 2017. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N. Engl. J. Med. 377:2013–23
     [Google Scholar]
  22. 22.  Cystic Fibrosis Found 2018. Drug development pipeline https://www.cff.org/trials/pipeline
  23. 23.  Beumer W, Swildens J, Henig N et al. 2015. QR-010, an RNA therapy, restores CFTR function using in vitro and in vivo models of ΔF508 CFTR. J. Cyst. Fibros. 14:Suppl. 1 S1 (Abstr
    [Google Scholar]
  24. 24.  Hollywood JA, Lee CM, Scallan MF et al. 2016. Analysis of gene repair tracts from Cas9/gRNA double-stranded breaks in the human CFTR gene. Sci. Rep. 6:32230
     [Google Scholar]
  25. 25.  Harrison PT, Sanz DJ, Hollywood JA 2016. Impact of gene editing on the study of cystic fibrosis. Hum. Genet. 135:983–92
     [Google Scholar]
  26. 26.  Waters V, Stanojevic S, Atenafu EG et al. 2012. Effect of pulmonary exacerbations on long-term lung function decline in cystic fibrosis. Eur. Respir. J. 40:61–66
     [Google Scholar]
  27. 27.  Liou TG, Adler FR, Fitzsimmons SC et al. 2001. Predictive 5-year survivorship model of cystic fibrosis. Am. J. Epidemiol. 153:345–52
     [Google Scholar]
  28. 28.  Lieu TA, Ray GT, Farmer G et al. 1999. The cost of medical care for patients with cystic fibrosis in a health maintenance organization. Pediatrics 103:e72
     [Google Scholar]
  29. 29.  de Boer K, Vandemheen KL, Tullis E et al. 2011. Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. Thorax 66:680–85
     [Google Scholar]
  30. 30.  Britto MT, Kotagal UR, Hornung RW et al. 2002. Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Chest 121:64–72
     [Google Scholar]
  31. 31.  Sanders DB, Bittner RC, Rosenfeld M et al. 2010. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am. J. Respir. Crit. Care Med. 182:627–32
     [Google Scholar]
  32. 32.  Florescu MC, Lyden E, Murphy PJ et al. 2012. Long-term effect of chronic intravenous and inhaled nephrotoxic antibiotic treatment on the renal function of patients with cystic fibrosis. Hemodial Int 16:414–19
     [Google Scholar]
  33. 33.  Handelsman JA, Nasr SZ, Pitts C et al. 2017. Prevalence of hearing and vestibular loss in cystic fibrosis patients exposed to aminoglycosides. Pediatr. Pulmonol. 52:1157–62
     [Google Scholar]
  34. 34.  Chalmers JD, Singanayagam A, Hill AT 2008. C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am. J. Med. 121:219–25
     [Google Scholar]
  35. 35.  Shoki AH, Mayer-Hamblett N, Wilcox PG et al. 2013. Systematic review of blood biomarkers in cystic fibrosis pulmonary exacerbations. Chest 144:1659–70
     [Google Scholar]
  36. 36.  Sharma A, Kirkpatrick G, Chen V et al. 2017. Clinical utility of C-reactive protein to predict treatment response during cystic fibrosis pulmonary exacerbations. PLOS ONE 12:e0171229
     [Google Scholar]
  37. 37.  Sagel SD, Thompson V, Chmiel JF et al. 2015. Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation. Ann. Am. Thorac. Soc. 12:708–17
     [Google Scholar]
  38. 38.  Sequeiros IM, Jarad NA 2012. Extending the course of intravenous antibiotics in adult patients with cystic fibrosis with acute pulmonary exacerbations. Chron. Respir. Dis. 9:213–20
     [Google Scholar]
  39. 39.  Giron-Moreno RM, Justicia JL, Yamamoto S et al. 2014. Role of C-reactive protein as a biomarker for prediction of the severity of pulmonary exacerbations in patients with cystic fibrosis. BMC Pulm. Med. 14:150
     [Google Scholar]
  40. 40.  Gray RD, Imrie M, Boyd AC et al. 2010. Sputum and serum calprotectin are useful biomarkers during CF exacerbation. J. Cyst. Fibros. 9:193–98
     [Google Scholar]
  41. 41.  Ikhtaire S, Shajib MS, Reinisch W et al. 2016. Fecal calprotectin: its scope and utility in the management of inflammatory bowel disease. J. Gastroenterol. 51:434–46
     [Google Scholar]
  42. 42.  Reid PA, McAllister DA, Boyd AC et al. 2015. Measurement of serum calprotectin in stable patients predicts exacerbation and lung function decline in cystic fibrosis. Am. J. Respir. Crit. Care Med. 191:233–36
     [Google Scholar]
  43. 43.  Quon BS, Dai DL, Hollander Z et al. 2016. Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry. Thorax 71:216–22
     [Google Scholar]
  44. 44.  Nick JA, Sanders LA, Ickes B et al. 2013. Blood mRNA biomarkers for detection of treatment response in acute pulmonary exacerbations of cystic fibrosis. Thorax 68:929–37
     [Google Scholar]
  45. 45.  Johnson C, Butler SM, Konstan MW et al. 2003. Factors influencing outcomes in cystic fibrosis: a center-based analysis. Chest 123:20–27
     [Google Scholar]
  46. 46.  Boyle MP, Sabadosa KA, Quinton HB et al. 2014. Key findings of the US Cystic Fibrosis Foundation's clinical practice benchmarking project. BMJ Qual. Saf. 23:Suppl. 1i15–22
     [Google Scholar]
  47. 47.  Lechtzin N, Mayer-Hamblett N, West NE et al. 2017. Home monitoring of patients with cystic fibrosis to identify and treat acute pulmonary exacerbations. eICE study results. Am. J. Respir. Crit. Care Med. 196:1144–51
     [Google Scholar]
  48. 48.  West NE, Beckett VV, Jain R et al. 2017. Standardized Treatment of Pulmonary Exacerbations (STOP) study: physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary exacerbations. J. Cyst. Fibros. 16:600–6
     [Google Scholar]
  49. 49.  Kraynack NC, Gothard MD, Falletta LM et al. 2011. Approach to treating cystic fibrosis pulmonary exacerbations varies widely across US CF care centers. Pediatr. Pulmonol. 46:870–81
     [Google Scholar]
  50. 50.  Collaco JM, Green DM, Cutting GR et al. 2010. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am. J. Respir. Crit. Care Med. 182:1137–43
     [Google Scholar]
  51. 51.  VanDevanter DR, Flume PA, Morris N et al. 2016. Probability of IV antibiotic retreatment within thirty days is associated with duration and location of IV antibiotic treatment for pulmonary exacerbation in cystic fibrosis. J. Cyst. Fibros. 15:783–90
     [Google Scholar]
  52. 52.  Waters V, Stanojevic S, Klingel M et al. 2015. Prolongation of antibiotic treatment for cystic fibrosis pulmonary exacerbations. J. Cyst. Fibros. 14:770–76
     [Google Scholar]
  53. 53.  Thornton J, Elliott RA, Tully MP et al. 2005. Clinical and economic choices in the treatment of respiratory infections in cystic fibrosis: comparing hospital and home care. J. Cyst. Fibros. 4:239–47
     [Google Scholar]
  54. 54.  Wolter JM, Bowler SD, Nolan PJ et al. 1997. Home intravenous therapy in cystic fibrosis: a prospective randomized trial examining clinical, quality of life and cost aspects. Eur. Respir. J. 10:896–900
     [Google Scholar]
  55. 55.  Schechter MS, VanDevanter DR, Pasta DJ et al. 2018. Treatment setting and outcomes of cystic fibrosis pulmonary exacerbations. Ann. Am. Thorac. Soc. 15:225–33
     [Google Scholar]
  56. 56.  Ramsay KA, Sandhu H, Geake JB et al. 2017. The changing prevalence of pulmonary infection in adults with cystic fibrosis: a longitudinal analysis. J. Cyst. Fibros. 16:70–77
     [Google Scholar]
  57. 57.  Chen SCA, Patel S, Meyer W et al. 2018. Pseudomonasaeruginosa inhibits the growth of Scedosporium and Lomentospora in vitro. Mycopathologia 183:251–61
     [Google Scholar]
  58. 58.  Nagano Y, Millar BC, Johnson E et al. 2007. Fungal infections in patients with cystic fibrosis. Rev. Med. Microbiol. 18:11–16
     [Google Scholar]
  59. 59.  Hong G, Miller HB, Allgood S et al. 2017. Use of selective fungal culture media increases rates of detection of fungi in the respiratory tract of cystic fibrosis patients. J. Clin. Microbiol. 55:1122–30
     [Google Scholar]
  60. 60.  Ziesing S, Suerbaum S, Sedlacek L 2016. Fungal epidemiology and diversity in cystic fibrosis patients over a 5-year period in a national reference center. Med. Mycol. 54:781–86
     [Google Scholar]
  61. 61.  Esther CR Jr, Plongla R, Kerr A et al. 2016. Clinical outcomes in cystic fibrosis patients with Trichosporon respiratory infection. J. Cyst Fibros. 15:e45–49
     [Google Scholar]
  62. 62.  Amin R, Dupuis A, Aaron SD et al. 2010. The effect of chronic infection with Aspergillusfumigatus on lung function and hospitalization in patients with cystic fibrosis. Chest 137:171–76
     [Google Scholar]
  63. 63.  Cimon B, Carrere J, Vinatier JF et al. 2000. Clinical significance of Scedosporiumapiospermum in patients with cystic fibrosis. Eur. J. Clin. Microbiol. Infect. Dis. 19:53–56
     [Google Scholar]
  64. 64.  Hong G, White M, Lechtzin N et al. 2017. Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation. J. Cyst. Fibros. 16:e3–e7
     [Google Scholar]
  65. 65.  Adjemian J, Olivier KN, Prevots DR 2014. Nontuberculous mycobacteria among patients with cystic fibrosis in the United States: screening practices and environmental risk. Am. J. Respir. Crit. Care Med. 190:581–86
     [Google Scholar]
  66. 66.  Bryant JM, Grogono DM, Greaves D et al. 2013. Whole-genome sequencing to identify transmission of Mycobacteriumabscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet 381:1551–60
     [Google Scholar]
  67. 67.  Skolnik K, Kirkpatrick G, Quon BS 2016. Nontuberculous mycobacteria in cystic fibrosis. Curr. Treat. Options Infect. Dis. 8:259–74
     [Google Scholar]
  68. 68.  Hayes D Jr, Patel AV, Black SM et al. 2015. Influence of diabetes on survival in patients with cystic fibrosis before and after lung transplantation. J. Thorac. Cardiovasc. Surg. 150:707–13.e2
     [Google Scholar]
  69. 69.  Koch C, Rainisio M, Madessani U et al. 2001. Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis. Pediatr. Pulmonol. 32:343–50
     [Google Scholar]
  70. 70.  Lavie M, Fisher D, Vilozni D et al. 2015. Glucose intolerance in cystic fibrosis as a determinant of pulmonary function and clinical status. Diabetes Res. Clin. Pract. 110:276–84
     [Google Scholar]
  71. 71.  Lehoux Dubois C, Boudreau V, Tremblay F et al. 2017. Association between glucose intolerance and bacterial colonisation in an adult population with cystic fibrosis, emergence of Stenotrophomonasmaltophilia. J. Cyst. . Fibros 16:418–24
     [Google Scholar]
  72. 72.  Limoli DH, Yang J, Khansaheb MK et al. 2016. Staphylococcusaureus and Pseudomonasaeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes. Eur. J. Clin. Microbiol. Infect. Dis. 35:947–53
     [Google Scholar]
  73. 73.  Brennan AL, Gyi KM, Wood DM et al. 2007. Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis. J. Cyst. Fibros. 6:101–9
     [Google Scholar]
  74. 74.  Bilodeau C, Bardou O, Maille E et al. 2016. Deleterious impact of hyperglycemia on cystic fibrosis airway ion transport and epithelial repair. J. Cyst. Fibros. 15:43–51
     [Google Scholar]
  75. 75.  Ntimbane T, Comte B, Mailhot G et al. 2009. Cystic fibrosis-related diabetes: from CFTR dysfunction to oxidative stress. Clin. Biochem. Rev. 30:153–77
     [Google Scholar]
  76. 76.  Moheet A, Moran A 2017. CF-related diabetes: containing the metabolic miscreant of cystic fibrosis. Pediatr. Pulmonol. 52:S37–43
     [Google Scholar]
  77. 77.  Moran A, Brunzell C, Cohen RC et al. 2010. 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. Diabetes Care 33:2697–708
     [Google Scholar]
  78. 78.  Coriati A, Ziai S, Lavoie A et al. 2016. The 1-h oral glucose tolerance test glucose and insulin values are associated with markers of clinical deterioration in cystic fibrosis. Acta Diabetol 53:359–66
     [Google Scholar]
  79. 79.  Brodsky J, Dougherty S, Makani R et al. 2011. Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis. Diabetes Care 34:292–95
     [Google Scholar]
  80. 80.  Burgess JC, Bridges N, Banya W et al. 2016. HbA1c as a screening tool for cystic fibrosis related diabetes. J. Cyst. Fibros. 15:251–57
     [Google Scholar]
  81. 81.  Uc A, Olivier AK, Griffin MA et al. 2015. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin. Sci. 128:131–42
     [Google Scholar]
  82. 82.  Yi Y, Norris AW, Wang K et al. 2016. Abnormal glucose tolerance in infants and young children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 194:974–80
     [Google Scholar]
  83. 83.  Edlund A, Pedersen MG, Lindqvist A et al. 2017. CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells. Sci. Rep. 7:90
     [Google Scholar]
  84. 84.  Stalvey MS, Muller C, Schatz DA et al. 2006. Cystic fibrosis transmembrane conductance regulator deficiency exacerbates islet cell dysfunction after beta-cell injury. Diabetes 55:1939–45
     [Google Scholar]
  85. 85.  Koivula FNM, McClenaghan NH, Harper AGS et al. 2016. Islet-intrinsic effects of CFTR mutation. Diabetologia 59:1350–55
     [Google Scholar]
  86. 86.  Hayes D Jr, McCoy KS, Sheikh SI 2014. Resolution of cystic fibrosis-related diabetes with ivacaftor therapy. Am. J. Respir. Crit. Care Med. 190:590–91
     [Google Scholar]
  87. 87.  Kelly A, Moran A 2013. Update on cystic fibrosis-related diabetes. J. Cyst. Fibros. 12:318–31
     [Google Scholar]
  88. 88.  Neglia JP, FitzSimmons SC, Maisonneuve P et al. 1995. The risk of cancer among patients with cystic fibrosis. N. Engl. J. Med. 332:494–99
     [Google Scholar]
  89. 89.  Maisonneuve P, Marshall BC, Knapp EA et al. 2013. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J. Natl. Cancer Inst. 105:122–29
     [Google Scholar]
  90. 90.  Niccum DE, Billings JL, Dunitz JM et al. 2016. Colonoscopic screening shows increased early incidence and progression of adenomas in cystic fibrosis. J. Cyst. Fibros. 15:548–53
     [Google Scholar]
  91. 91.  Billings JL, Dunitz JM, McAllister S et al. 2014. Early colon screening of adult patients with cystic fibrosis reveals high incidence of adenomatous colon polyps. J. Clin. Gastroenterol. 48:e85–88
     [Google Scholar]
  92. 92.  Than BL, Linnekamp JF, Starr TK et al. 2016. CFTR is a tumor suppressor gene in murine and human intestinal cancer. Oncogene 35:4179–87
     [Google Scholar]
  93. 93.  Garg M, Ooi CY 2017. The enigmatic gut in cystic fibrosis: linking inflammation, dysbiosis, and the increased risk of malignancy. Curr. Gastroenterol. Rep. 19:6
     [Google Scholar]
  94. 94.  Hadjiliadis D, Khoruts A, Zauber AG et al. 2018. Cystic fibrosis colorectal cancer screening consensus recommendations. Gastroenterology 154:736–45.e14
     [Google Scholar]
  95. 95.  Kimura N, Khan MS, Schecter M et al. 2016. Changing demographics and outcomes of lung transplantation recipients with cystic fibrosis. J. Heart Lung Transplant. 35:1237–44
     [Google Scholar]
  96. 96.  Sole A, Perez I, Vazquez I et al. 2016. Patient-reported symptoms and functioning as indicators of mortality in advanced cystic fibrosis: a new tool for referral and selection for lung transplantation. J. Heart Lung Transplant. 35:789–94
     [Google Scholar]
  97. 97.  Ramos KJ, Quon BS, Heltshe SL et al. 2017. Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States. Chest 151:1320–28
     [Google Scholar]
  98. 98.  Stephenson AL, Sykes J, Stanojevic S et al. 2017. Survival comparison of patients with cystic fibrosis in Canada and the United States: a population-based cohort study. Ann. Intern. Med. 166:537–46
     [Google Scholar]
  99. 99.  Ramos KJ, Quon BS, Psoter KJ et al. 2016. Predictors of non-referral of patients with cystic fibrosis for lung transplant evaluation in the United States. J. Cyst. Fibros. 15:196–203
     [Google Scholar]
  100. 100.  Durmowicz AG, Lim R, Rogers H et al. 2018. The U.S. Food and Drug Administration's experience with ivacaftor in cystic fibrosis. Establishing efficacy using in vitro data in lieu of a clinical trial. Ann. Am. Thorac. Soc. 15:1–2
     [Google Scholar]
/content/journals/10.1146/annurev-med-112717-094536
Loading
Cystic Fibrosis: Emerging Understanding and Therapies
Annual Review of Medicine 70, 197 (2019); https://doi.org/10.1146/annurev-med-112717-094536
/content/journals/10.1146/annurev-med-112717-094536
/content/journals/10.1146/annurev-med-112717-094536
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error