Unmet needs in cystic fibrosis: the next steps in improving outcomes

References

• Cystic Fibrosis Foundation. Cystic fibrosis foundation patient registry, 2016 annual data report. In: Bethesda, Maryland. 2017.
   Google Scholar
• Sanders DB, Hoffman LR, Emerson J, et al. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol. 2010;45:127–134.
   PubMed Web of Science ®Google Scholar
• Liou TG, Adler FR, Fitzsimmons SC, et al. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol. 2001;153:345–352.
   PubMed Web of Science ®Google Scholar
• Mayer-Hamblett N, Rosenfeld M, Emerson J, et al. Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir Crit Care Med. 2002;166:1550–1555.
   PubMed Web of Science ®Google Scholar
• Emerson J, Rosenfeld M, McNamara S, et al. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol. 2002;34:91–100.
   PubMed Web of Science ®Google Scholar
• Ellaffi M, Vinsonneau C, Coste J, et al. One-year outcome after severe pulmonary exacerbation in adults with cystic fibrosis. Am J Respir Crit Care Med. 2005;171:158–164.
   PubMed Web of Science ®Google Scholar
• De Boer K, Vandemheen KL, Tullis E, et al. Exacerbation frequency and clinical outcomes in adult patients with cystic fibrosis. Thorax. 2011;66:680–685.
   PubMed Web of Science ®Google Scholar
• Konstan MW, Wagener JS, VanDevanter DR, et al. Risk factors for rate of decline in FEV1 in adults with cystic fibrosis. Journal of Cystic Fibrosis. 2012;11:405–411.
   PubMed Web of Science ®Google Scholar
• Britto MT, Kotagal UR, Hornung RW, et al. Impact of Recent Pulmonary Exacerbations on Quality of Life in Patients With Cystic Fibrosis. Chest. 2002;121:64–72.
   PubMed Web of Science ®Google Scholar
• Wagener JS, Rasouliyan L, VanDevanter DR, et al. Oral, inhaled, and intravenous antibiotic choice for treating pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2013;48:666–673.
   PubMed Web of Science ®Google Scholar
• Sanders DB, Solomon GM, Beckett VV, et al. Standardized Treatment of Pulmonary Exacerbations (STOP) study: observations at the initiation of intravenous antibiotics for cystic fibrosis pulmonary exacerbations. J Cyst Fibros. 2017;16:592–599.
   PubMed Web of Science ®Google Scholar
• West NE, Beckett VV, Jain R, et al. Standardized Treatment of Pulmonary Exacerbations (STOP) study: physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary exacerbations. J Cyst Fibros. 2017;16:600–606.
   PubMed Web of Science ®Google Scholar
• Sanders DB, Zhao Q, Li Z, et al. Poor recovery from cystic fibrosis pulmonary exacerbations is associated with poor long-term outcomes. Pediatr Pulmonol. 2017;52:1268–1275.
   PubMed Web of Science ®Google Scholar
• Elborn JS. Cystic fibrosis. The Lancet. 2016;388:2519–2531.
   PubMed Web of Science ®Google Scholar
• Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med. 2006;173:475–482.
   PubMed Web of Science ®Google Scholar
• Boyle MP, De Boeck K. A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med. 2013;1:158–163.
   PubMed Web of Science ®Google Scholar
• Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N.Engl.J.Med.. 1994;331:637–642.
   PubMed Web of Science ®Google Scholar
• Ramsey BW, Pepe MS, Quan JM, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N.Engl.J.Med.. 1999;340:23–30.
   PubMed Web of Science ®Google Scholar
• Retsch-Bogart GZ, Quittner AL, Gibson RL, et al. Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis. Chest. 2009;135:1223–1232.
   PubMed Web of Science ®Google Scholar
• Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–1672.
   PubMed Web of Science ®Google Scholar
• Ivacaftor. [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2017.
   Google Scholar
• Flume PA, Liou TG, Borowitz DS, et al. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012;142:718–724.
   PubMed Web of Science ®Google Scholar
• Mijnders M, Kleizen B, Correcting BI. CFTR folding defects by small-molecule correctors to cure cystic fibrosis. Curr Opin Pharmacol. 2017;34:83–90.
   PubMed Web of Science ®Google Scholar
• Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220–231.
   PubMed Web of Science ®Google Scholar
• Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377:2013–2023.
   PubMed Web of Science ®Google Scholar
• Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377:2024–2035.
   PubMed Web of Science ®Google Scholar
• Vertex selects two next-generation correctors, vx-659 and vx-445, to advance into phase 3 development as part of two different triple combination regimens for people with cystic fibrosis [Press Release]. [Internet]. Vertex Pharmaceuticals Incorporated; 2018. [cited 2018 May 15]. Available from: http://investors.vrtx.com/releasedetail.cfm?ReleaseID=1055958
   Google Scholar
• Miller JP, Drew L, Green O, et al. CFTR amplifiers: a new class of cftr modulator that complements the substrate limitations of other cf therapeutic modalities. C60. ALL ABOUT CYSTIC FIBROSIS [Internet]. American Thoracic Society. 2016:A5574–A5574. [cited 2018 Mar 6]. Available from: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts.A5574
   Google Scholar
• Miller J, Drew L, Green O, et al. Amplifiers are a new class of CFTR modulators that increase the abundance of CFTR protein and combined with potentiators and correctors enhance CFTR chloride transport activity. Pediatr Pulmonol. 2015;50(S41):265.
   Google Scholar
• ProQR Therapeutics N.V. ProQR announces positive top-line results from a phase 1b study of qr-010 in subjects with cystic fibrosis [Press Release]. 2017 Sep 25 [cited 2018 Mar 6]; Available from: http://ir.proqr.com/news-releases/news-release-details/proqr-announces-positive-top-line-results-phase-1b-study-qr-010
   Google Scholar
• Schwank G, Koo B-K, Sasselli V, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13:653–658.
   PubMed Web of Science ®Google Scholar
• Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354:229–240.
   PubMed Web of Science ®Google Scholar
• Konstan MW, Flume PA, Kappler M, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J Cyst Fibros. 2011;10:54–61.
   PubMed Web of Science ®Google Scholar
• Konstan MW, Geller DE, Minić P, et al. Tobramycin inhalation powder for P. Aeruginosa Infection Cystic Fibrosis: EVOLVE Trial Pediatr Pulmonol. 2011;46:230–238.
   Google Scholar
• McCoy KS, Quittner AL, Oermann CM, et al. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178:921–928.
   PubMed Web of Science ®Google Scholar
• Flume PA, Robinson KA, O’Sullivan BP, et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies. Respir Care. 2009;54:522–537.
   PubMed Web of Science ®Google Scholar
• Quittner AL, Zhang J, Marynchenko M, et al. Pulmonary medication adherence and health-care use in cystic fibrosis. Chest. 2014;146:142–151.
   PubMed Web of Science ®Google Scholar
• Mayer-Hamblett N, Kloster M, Rosenfeld M, et al. Impact of sustained eradication of new pseudomonas aeruginosa infection on long-term outcomes in cystic fibrosis. Clin Infect Dis. 2015;61:707–715.
   PubMed Web of Science ®Google Scholar
• Huang YJ, LiPuma JJ. The microbiome in cystic fibrosis. Clin Chest Med. 2016;37:59–67.
   PubMed Web of Science ®Google Scholar
• Lechtzin N, John M, Irizarry R, et al. Outcomes of adults with cystic fibrosis infected with antibiotic-resistant Pseudomonas aeruginosa. Respiration. 2006;73:27–33.
   PubMed Web of Science ®Google Scholar
• Döring G, Flume P, Heijerman H, et al. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J Cyst Fibros. 2012;11:461–479.
   PubMed Web of Science ®Google Scholar
• Dasenbrook EC, Merlo CA, Diener-West M, et al. Persistent methicillin-resistant staphylococcus aureus and rate of FEV1 decline in cystic fibrosis. Am J Respir Crit Care Med. 2008;178:814–821.
   PubMed Web of Science ®Google Scholar
• Dasenbrook EC, Checkley W, Merlo CA, et al. Association between respiratory tract methicillin-resistant staphylococcus aureus and survival in cystic fibrosis. JAMA. 2010;303:2386–2392.
   PubMed Web of Science ®Google Scholar
• Muhlebach MS, Beckett V, Popowitch E, et al. Microbiological efficacy of early MRSA treatment in cystic fibrosis in a randomised controlled trial. Thorax. 2017;72:318–326.
   PubMed Web of Science ®Google Scholar
• Flume PA, VanDevanter DR, Morgan EE, et al. A phase 3, multi-center, multinational, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of levofloxacin inhalation solution (APT-1026) in stable cystic fibrosis patients. Journal of Cystic Fibrosis. 2016;15:495–502.
   PubMed Web of Science ®Google Scholar
• Elborn JS, Flume PA, Cohen F, et al. Safety and efficacy of prolonged levofloxacin inhalation solution (APT-1026) treatment for cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. J Cyst Fibros. 2016;15:634–640.
   PubMed Web of Science ®Google Scholar
• Goss CH, Singh PK. Gallium, a novel approach to treating chronic Pseudomonal lung infections in CF. In: Pediatr Pulmonol. 2012;47(S35):174-175.
   Google Scholar
• Tyrrell J, Callaghan M. Iron acquisition in the cystic fibrosis lung and potential for novel therapeutic strategies. Microbiology (Reading, Engl.). 2016;162:191–205.
   PubMed Web of Science ®Google Scholar
• Moreau-Marquis S, O’Toole GA, Stanton BA. Tobramycin and FDA-approved iron chelators eliminate pseudomonas aeruginosa biofilms on cystic fibrosis cells. Am J Respir Cell Mol Biol. 2009;41:305–313.
   PubMed Web of Science ®Google Scholar
• Ghaffari A, Miller CC, McMullin B, et al. Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide. 2006;14:21–29.
   PubMed Web of Science ®Google Scholar
• Miller C, Miller M, McMullin B, et al. A phase I clinical study of inhaled nitric oxide in healthy adults. J Cyst Fibros. 2012;11:324–331.
   PubMed Web of Science ®Google Scholar
• Papp-Wallace KM, Becka SA, Zeiser ET, et al. Overcoming an Extremely Drug Resistant (XDR) Pathogen: avibactam restores susceptibility to ceftazidime for Burkholderia cepacia complex isolates from cystic fibrosis patients. ACS Infect Dis. 2017;3:502–511.
   PubMed Web of Science ®Google Scholar
• Rhodes KA, Schweizer HP. Antibiotic resistance in Burkholderia species. Drug Resist Updat. 2016;28:82–90.
   PubMed Web of Science ®Google Scholar
• Chmiel JF, Aksamit TR, Chotirmall SH, et al. Antibiotic management of lung infections in cystic fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus Aureus, Gram-Negative Bacteria, and Multiple Infections. Ann Am Thorac Soc.. 2014;11:1120–1129.
   Google Scholar
• Griffith DE, Aksamit T, Brown-Elliott BA, et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367–416.
   PubMed Web of Science ®Google Scholar
• Griffith DE. Emergence of nontuberculous mycobacteria as pathogens in cystic fibrosis. Am J Respir Crit Care Med. 2003;167:810–812.
   PubMed Web of Science ®Google Scholar
• Floto RA, Olivier KN, Saiman L, 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. Thorax. 2016;71:i1–i22.
   PubMed Web of Science ®Google Scholar
• Furukawa B, Flume PA. Nontuberculous mycobacteria in cystic fibrosis. Semin Respir Med. In press.
   Google Scholar
• Hong G, Psoter KJ, Jennings MT, et al. Risk factors for persistent Aspergillus respiratory isolation in cystic fibrosis. J Cyst Fibros. 2018. doi: 10.1016/j.jcf.2018.01.008
   PubMedGoogle Scholar
• Hong G, White M, Lechtzin N, et al. Fatal disseminated Rasamsonia infection in cystic fibrosis post-lung transplantation. J Cyst Fibros. 2017;16:e3–e7.
   PubMedGoogle Scholar
• Mogayzel PJ, Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic Medications Maintenance Lung Health Am J Respir Crit Care Med. 2013;187:680–689.
   PubMed Web of Science ®Google Scholar
• Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848–854.
   PubMed Web of Science ®Google Scholar
• Konstan MW. Association of high-dose ibuprofen use. lung function decline, and long-term survival in children with cystic fibrosis. ANN AM THORAC SOC; 2018. Available from: https://doi.org/10.1513/AnnalsATS.201706-486OC
   Google Scholar
• Fennell PB, Quante J, Wilson K, et al. Use of high-dose ibuprofen in a pediatric cystic fibrosis center. J Cyst Fibros. 2007;6:153–158.
   PubMedGoogle Scholar
• Gifford AH, Willger SD, Dolben EL, et al. Use of a multiplex transcript method for analysis of pseudomonas aeruginosa gene expression profiles in the cystic fibrosis lung. Infect Immun. 2016;84:2995–3006.
   PubMed Web of Science ®Google Scholar
• Flume PA. Macrolides. Commentaries on Chronic Airways Infection. 2007;1:13–19.
   Google Scholar
• Mw K, Döring G, Sl H, et al. A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis. J Cyst Fibros. 2014;13:148–155.
   PubMed Web of Science ®Google Scholar
• Chmiel JF, Konstan MW. Inflammation and anti-inflammatory therapies for cystic fibrosis. Clin Chest Med. 2007;28:331–346.
   PubMed Web of Science ®Google Scholar
• Muhlebach MS, Clancy JP, Heltshe SL, et al. Biomarkers for cystic fibrosis drug development. J Cyst Fibros. 2016;15:714–723.
   PubMed Web of Science ®Google Scholar
• Sanders DB, Bittner RC, Rosenfeld M, et al. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010;182:627–632.
   PubMed Web of Science ®Google Scholar
• Sanders DB, Bittner RC, Rosenfeld M, et al. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol. 2011;46:393–400.
   PubMed Web of Science ®Google Scholar
• Flume PA, Wainwright CE, Elizabeth Tullis D, et al. Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor. J Cyst Fibros. 2018;17:83–88.
   PubMed Web of Science ®Google Scholar
• Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry. Bethesda, Maryland: ©2015 Cystic Fibrosis Foundation; 2014. Annual Data Report.
   Google Scholar
• Heltshe SL, Goss CH, Thompson V, et al. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax. 2016;71:223–229.
   PubMed Web of Science ®Google Scholar
• Kraynack NC, Gothard MD, Falletta LM, et al. Approach to treating cystic fibrosis pulmonary exacerbations varies widely across US CF care centers. Pediatr Pulmonol. 2011;46:870–881.
   PubMed Web of Science ®Google Scholar
• Schechter MS, Regelmann WE, Sawicki GS, et al. Antibiotic treatment of signs and symptoms of pulmonary exacerbations: A comparison by care site. Pediatr Pulmonol. 2015;50:431–440.
   PubMed Web of Science ®Google Scholar
• Collaco JM, Green DM, Cutting GR, et al. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med. 2010;182:1137–1143.
   PubMed Web of Science ®Google Scholar
• Flume PA, Mogayzel PJ, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180:802–808.
   PubMed Web of Science ®Google Scholar
• VanDevanter DR, Heltshe SL, Spahr J, et al. Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis. J Cyst Fibros. 2017;16:607–615.
   PubMed Web of Science ®Google Scholar
• VanDevanter DR, Mayer-Hamblett N. Innovating cystic fibrosis clinical trial designs in an era of successful standard of care therapies. Curr Opin Pulm Med. 2017;23:530–535.
   PubMed Web of Science ®Google Scholar
• Ramos KJ, Quon BS, Heltshe SL, et al. Heterogeneity in survival in adult patients with cystic fibrosis with FEV1 < 30% of predicted in the United States. Chest. 2017;151:1320–1328.
   PubMed Web of Science ®Google Scholar
• Stephenson AL, Sykes J, Stanojevic S, et al. Survival comparison of patients with cystic fibrosis in canada and the United States: A population-based cohort study. Ann Intern Med. 2017;166:537–546.
   PubMed Web of Science ®Google Scholar
• Ramos KJ, Quon BS, Psoter KJ, et al. Predictors of non-referral of patients with cystic fibrosis for lung transplant evaluation in the United States. J Cyst Fibros. 2016;15:196–203.
   PubMed Web of Science ®Google Scholar
• Braun AT, Dasenbrook EC, Shah AS, et al. Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients. J Heart Lung Transplant. 2015;34:1436–1441.
   PubMedGoogle Scholar
• Merlo CA, Clark SC, Arnaoutakis GJ, et al. National healthcare delivery systems influence lung transplant outcomes for cystic fibrosis. Am J Transplant. 2015;15:1948–1957.
   PubMed Web of Science ®Google Scholar
• Gelfond D, Ma C, Semler J, et al. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci. 2013;58:2275–2281.
   PubMed Web of Science ®Google Scholar
• Pennings J, Wansink B, Meulenberg M. A note on modeling consumer reactions ns a crisis: the case of the mad cow disease. Internat J Res Market. 2002;19:91–100.
   Web of Science ®Google Scholar
• Borowitz D, Stevens C, Brettman LR, et al. International phase III trial of liprotamase efficacy and safety in pancreatic-insufficient cystic fibrosis patients. J Cyst Fibros. 2011;10:443–452.
   PubMed Web of Science ®Google Scholar
• Abraham JM, Taylor CJ. Cystic Fibrosis. & disorders of the large intestine: DIOS, constipation, and colorectal cancer. J Cyst Fibros. 2017;16(Suppl 2):S40–S49.
   PubMedGoogle Scholar
• Leung DH, Narkewicz MR. Cystic Fibrosis-related cirrhosis. Journal of Cystic Fibrosis. 2017;16:S50–S61.
   PubMedGoogle Scholar