Download PDF
Semin Respir Crit Care Med 2019; 40(06): 792-803
DOI: 10.1055/s-0039-1697975
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Acute Pulmonary Exacerbations in Cystic Fibrosis

Christopher H. Goss
1   CFF Therapeutics Development Network Coordinating Center, Department of Pediatrics, Seattle Children's Research Institute, Seattle, Washington
2   Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine and Pediatrics, University of Washington School of Medicine, Seattle, Washington
› Author Affiliations Funding C.H.G.'s research time is supported by the Cystic Fibrosis Foundation Therapeutics (GOSS13A0) and NIH (P30 DK089507, UL1TR000423). There was no role of funding sources in writing of this manuscript, or the decision to submit for publication.
Further Information

Publication History

Publication Date:
28 October 2019 (online)

    Permissions and Reprints

Abstract

With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator therapy, the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the disease course, prognosis, and complications. This work has now led to a number of large scale clinical trials with the goal of improving the treatment paradigm for CF pulmonary exacerbation. The primary goal of this review is to provide a summary of the pathophysiology, the clinical epidemiology, microbial epidemiology, outcome and the treatment of CF pulmonary exacerbation.

Keywords

FEV1 - respiratory symptoms - pulmonary exacerbation - cystic fibrosis - treatment duration
 

  • References

  • 1 Knapp EA, Fink AK, Goss CH. , et al. The cystic fibrosis foundation patient registry. Design and methods of a National Observational Disease Registry. Ann Am Thorac Soc 2016; 13 (07) 1173-1179
    CrossrefPubMedSearch in Google Scholar
  • 2 Jain M, Goss CH. Update in cystic fibrosis 2013. Am J Respir Crit Care Med 2014; 189 (10) 1181-1186
    CrossrefPubMedSearch in Google Scholar
  • 3 MacKenzie T, Gifford AH, Sabadosa KA. , et al. Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the Cystic Fibrosis Foundation Patient Registry. Ann Intern Med 2014; 161 (04) 233-241
    CrossrefPubMedSearch in Google Scholar
  • 4 Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001; 153 (04) 345-352
    CrossrefPubMedSearch in Google Scholar
  • 5 Liou TG, Adler FR, Huang D. Use of lung transplantation survival models to refine patient selection in cystic fibrosis. Am J Respir Crit Care Med 2005; 171 (09) 1053-1059
    CrossrefPubMedSearch in Google Scholar
  • 6 Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002; 34 (02) 91-100
    CrossrefPubMedSearch in Google Scholar
  • 7 Britto MT, Kotagal UR, Hornung RW, Atherton HD, Tsevat J, Wilmott RW. Impact of recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Chest 2002; 121 (01) 64-72
    CrossrefPubMedSearch in Google Scholar
  • 8 Dobbin CJ, Bartlett D, Melehan K, Grunstein RR, Bye PT. The effect of infective exacerbations on sleep and neurobehavioral function in cystic fibrosis. Am J Respir Crit Care Med 2005; 172 (01) 99-104
    CrossrefPubMedSearch in Google Scholar
  • 9 Wagener JS, Rasouliyan L, VanDevanter DR. , et al; Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Oral, inhaled, and intravenous antibiotic choice for treating pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol 2013; 48 (07) 666-673
    CrossrefPubMedSearch in Google Scholar
  • 10 Hiatt PW, Grace SC, Kozinetz CA. , et al. Effects of viral lower respiratory tract infection on lung function in infants with cystic fibrosis. Pediatrics 1999; 103 (03) 619-626
    CrossrefPubMedSearch in Google Scholar
  • 11 Piedra PA, Grace S, Jewell A. , et al. Purified fusion protein vaccine protects against lower respiratory tract illness during respiratory syncytial virus season in children with cystic fibrosis. Pediatr Infect Dis J 1996; 15 (01) 23-31
    CrossrefPubMedSearch in Google Scholar
  • 12 Piedra PA, Cron SG, Jewell A. , et al; Purified Fusion Protein Vaccine Study Group. Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: a multi-center trial in children with cystic fibrosis. Vaccine 2003; 21 (19-20): 2448-2460
    CrossrefPubMedSearch in Google Scholar
  • 13 Ortiz JR, Neuzil KM, Victor JC, Wald A, Aitken ML, Goss CH. Influenza-associated cystic fibrosis pulmonary exacerbations. Chest 2010; 137 (04) 852-860
    CrossrefPubMedSearch in Google Scholar
  • 14 Somayaji R, Goss CH, Khan U, Neradilek M, Neuzil KM, Ortiz JR. Cystic fibrosis pulmonary exacerbations attributable to respiratory syncytial virus and influenza: a population-based study. Clin Infect Dis 2017; 64 (12) 1760-1767
    CrossrefPubMedSearch in Google Scholar
  • 15 Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do bronchodilators and chest physiotherapy alone. Am Rev Respir Dis 1990; 141 (4 Pt 1): 914-921
    CrossrefPubMedSearch in Google Scholar
  • 16 Smith AL, Redding G, Doershuk C. , et al. Sputum changes associated with therapy for endobronchial exacerbation in cystic fibrosis. J Pediatr 1988; 112 (04) 547-554
    CrossrefPubMedSearch in Google Scholar
  • 17 Ramsey BW, Pepe MS, Quan JM. , et al; Cystic Fibrosis Inhaled Tobramycin Study Group. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med 1999; 340 (01) 23-30
    CrossrefPubMedSearch in Google Scholar
  • 18 Aaron SD, Ramotar K, Ferris W. , et al. Adult cystic fibrosis exacerbations and new strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2004; 169 (07) 811-815
    CrossrefPubMedSearch in Google Scholar
  • 19 Mayer-Hamblett N, Aitken ML, Accurso FJ. , et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med 2007; 175 (08) 822-828
    CrossrefPubMedSearch in Google Scholar
  • 20 Sagel SD, Thompson V, Chmiel JF. , et al. Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation. Ann Am Thorac Soc 2015; 12 (05) 708-717
    CrossrefPubMedSearch in Google Scholar
  • 21 Heltshe SL, Goss CH, Thompson V. , et al. Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis. Thorax 2016; 71 (03) 223-229
    CrossrefPubMedSearch in Google Scholar
  • 22 Ordoñez CL, Henig NR, Mayer-Hamblett N. , et al. Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis. Am J Respir Crit Care Med 2003; 168 (12) 1471-1475
    CrossrefPubMedSearch in Google Scholar
  • 23 Colombo C, Costantini D, Rocchi A. , et al. Cytokine levels in sputum of cystic fibrosis patients before and after antibiotic therapy. Pediatr Pulmonol 2005; 40 (01) 15-21
    CrossrefPubMedSearch in Google Scholar
  • 24 Waters VJ, Stanojevic S, Sonneveld N. , et al. Factors associated with response to treatment of pulmonary exacerbations in cystic fibrosis patients. J Cyst Fibros 2015; 14 (06) 755-762
    CrossrefPubMedSearch in Google Scholar
  • 25 Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995; 332 (13) 848-854
    CrossrefPubMedSearch in Google Scholar
  • 26 Lands LC, Milner R, Cantin AM, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial. J Pediatr 2007; 151 (03) 249-254
    CrossrefPubMedSearch in Google Scholar
  • 27 Conrad C, Lymp J, Thompson V. , et al. Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. J Cyst Fibros 2015; 14 (02) 219-227
    CrossrefPubMedSearch in Google Scholar
  • 28 Ren CL, Pasta DJ, Rasouliyan L, Wagener JS, Konstan MW, Morgan WJ. ; Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Relationship between inhaled corticosteroid therapy and rate of lung function decline in children with cystic fibrosis. J Pediatr 2008; 153 (06) 746-751
    CrossrefPubMedSearch in Google Scholar
  • 29 Chmiel JF, Konstan MW, Accurso FJ. , et al; Assessment of Induced Sputum in Cystic Fibrosis Study Group. Use of ibuprofen to assess inflammatory biomarkers in induced sputum: Implications for clinical trials in cystic fibrosis. J Cyst Fibros 2015; 14 (06) 720-726
    CrossrefPubMedSearch in Google Scholar
  • 30 Konstan MW, VanDevanter DR, Sawicki GS. , et al. Association of high-dose ibuprofen use, lung function decline, and long-term survival in children with cystic fibrosis. Ann Am Thorac Soc 2018; 15 (04) 485-493
    CrossrefPubMedSearch in Google Scholar
  • 31 Ramsey BW, Boat TF. Outcome measures for clinical trials in cystic fibrosis. Summary of a Cystic Fibrosis Foundation Consensus Conference. J Pediatr 1994; 124 (02) 177-192
    CrossrefPubMedSearch in Google Scholar
  • 32 Goss CH, Burns JL. Exacerbations in cystic fibrosis. 1: epidemiology and pathogenesis. Thorax 2007; 62 (04) 360-367
    CrossrefPubMedSearch in Google Scholar
  • 33 Fuchs HJ, Borowitz DS, Christiansen DH. , et al; The Pulmozyme Study Group. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994; 331 (10) 637-642
    CrossrefPubMedSearch in Google Scholar
  • 34 Konstan MW, Döring G, Heltshe SL. , et al; Investigators and Coordinators of BI Trial 543.45. 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 (02) 148-155
    CrossrefPubMedSearch in Google Scholar
  • 35 Dakin C, Henry RL, Field P, Morton J. Defining an exacerbation of pulmonary disease in cystic fibrosis. Pediatr Pulmonol 2001; 31 (06) 436-442
    CrossrefPubMedSearch in Google Scholar
  • 36 Rosenfeld M, Emerson J, Williams-Warren J. , et al. Defining a pulmonary exacerbation in cystic fibrosis. J Pediatr 2001; 139 (03) 359-365
    CrossrefPubMedSearch in Google Scholar
  • 37 Rabin HR, Butler SM, Wohl ME. , et al; Epidemiologic Study of Cystic Fibrosis. Pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol 2004; 37 (05) 400-406
    CrossrefPubMedSearch in Google Scholar
  • 38 Ferkol T, Rosenfeld M, Milla CE. Cystic fibrosis pulmonary exacerbations. J Pediatr 2006; 148 (02) 259-264
    CrossrefPubMedSearch in Google Scholar
  • 39 Johnson C, Butler SM, Konstan MW, Morgan W, Wohl ME. Factors influencing outcomes in cystic fibrosis: a center-based analysis. Chest 2003; 123 (01) 20-27
    CrossrefPubMedSearch in Google Scholar
  • 40 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 (02) 158-164
    CrossrefPubMedSearch in Google Scholar
  • 41 Texereau J, Jamal D, Choukroun G. , et al. Determinants of mortality for adults with cystic fibrosis admitted in Intensive Care Unit: a multicenter study. Respir Res 2006; 7: 14
    CrossrefPubMedSearch in Google Scholar
  • 42 Sood N, Paradowski LJ, Yankaskas JR. Outcomes of intensive care unit care in adults with cystic fibrosis. Am J Respir Crit Care Med 2001; 163 (02) 335-338
    CrossrefPubMedSearch in Google Scholar
  • 43 Vedam H, Moriarty C, Torzillo PJ, McWilliam D, Bye PT. Improved outcomes of patients with cystic fibrosis admitted to the intensive care unit. J Cyst Fibros 2004; 3 (01) 8-14
    CrossrefPubMedSearch in Google Scholar
  • 44 Dobbin CJ, Milross MA, Piper AJ, Sullivan C, Grunstein RR, Bye PT. Sequential use of oxygen and bi-level ventilation for respiratory failure in cystic fibrosis. J Cyst Fibros 2004; 3 (04) 237-242
    CrossrefPubMedSearch in Google Scholar
  • 45 Siuba M, Attaway A, Zein J. , et al. Mortality in adults with cystic fibrosis requiring mechanical ventilation. Cross-sectional analysis of nationwide events. Ann Am Thorac Soc 2019; 16 (08) 1017-1023
    CrossrefPubMedSearch in Google Scholar
  • 46 Liou TG, Adler FR, Cahill BC. , et al. Survival effect of lung transplantation among patients with cystic fibrosis. JAMA 2001; 286 (21) 2683-2689
    CrossrefPubMedSearch in Google Scholar
  • 47 Mayer-Hamblett N, Rosenfeld M, Emerson J, Goss CH, Aitken ML. Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir Crit Care Med 2002; 166 (12 Pt 1): 1550-1555
    CrossrefPubMedSearch in Google Scholar
  • 48 Burgel PR, Lemonnier L, Dehillotte C. , et al. Cluster and CART analyses identify large subgroups of adults with cystic fibrosis at low risk of 10-year death. Eur Respir J 2019; 53 (03) 53
    Search in Google Scholar
  • 49 Coriati A, Sykes J, Nkam L, Hocine MN, Burgel PR, Stephenson AL. Validation of the French 3-year prognostic score using the Canadian Cystic Fibrosis registry. J Cyst Fibros 2019; 18 (03) 396-398
    CrossrefPubMedSearch in Google Scholar
  • 50 Stanojevic S, Sykes J, Stephenson AL, Aaron SD, Whitmore GA. Development and external validation of 1- and 2- year mortality prediction models in cystic fibrosis. Eur Respir J 2019; 54 (03) 1900224 . doi: 10.1183/13993003.00224-2019
    CrossrefPubMedSearch in Google Scholar
  • 51 Lehr CJ, Skeans M, Dasenbrook EC. , et al. Effect of including important clinical variables on accuracy of the lung allocation score for cystic fibrosis and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2019
    PubMedSearch in Google Scholar
  • 52 Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005; 146 (05) 681-687
    CrossrefPubMedSearch in Google Scholar
  • 53 Goss CH, Otto K, Aitken ML, Rubenfeld GD. Detecting Stenotrophomonas maltophilia does not reduce survival of patients with cystic fibrosis. Am J Respir Crit Care Med 2002; 166 (03) 356-361
    CrossrefPubMedSearch in Google Scholar
  • 54 Goss CH, Rubenfeld GD, Otto K, Aitken ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest 2003; 124 (04) 1460-1468
    CrossrefPubMedSearch in Google Scholar
  • 55 VanDevanter DR, Flume PA, Morris N, Konstan MW. 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 2016; 15 (06) 783-790
    CrossrefPubMedSearch in Google Scholar
  • 56 Schechter MS, Shelton BJ, Margolis PA, Fitzsimmons SC. The association of socioeconomic status with outcomes in cystic fibrosis patients in the United States. Am J Respir Crit Care Med 2001; 163 (06) 1331-1337
    CrossrefPubMedSearch in Google Scholar
  • 57 Goss CH, Newsom SA, Schildcrout JS, Sheppard L, Kaufman JD. Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis. Am J Respir Crit Care Med 2004; 169 (07) 816-821
    CrossrefPubMedSearch in Google Scholar
  • 58 Brody AS, Sucharew H, Campbell JD. , et al. Computed tomography correlates with pulmonary exacerbations in children with cystic fibrosis. Am J Respir Crit Care Med 2005; 172 (09) 1128-1132
    CrossrefPubMedSearch in Google Scholar
  • 59 Smith JA, Owen EC, Jones AM, Dodd ME, Webb AK, Woodcock A. Objective measurement of cough during pulmonary exacerbations in adults with cystic fibrosis. Thorax 2006; 61 (05) 425-429
    CrossrefPubMedSearch in Google Scholar
  • 60 Ramsey BW, Davies J, McElvaney NG. , et al; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 2011; 365 (18) 1663-1672
    CrossrefPubMedSearch in Google Scholar
  • 61 Wainwright CE, Elborn JS, Ramsey BW. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 2015; 373 (18) 1783-1784
    CrossrefPubMedSearch in Google Scholar
  • 62 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 (21) 2013-2023
    CrossrefPubMedSearch in Google Scholar
  • 63 Mayer-Hamblett N, Rosenfeld M, Treggiari MM. , et al; EPIC; ESCF Investigators. Standard care versus protocol based therapy for new onset Pseudomonas aeruginosa in cystic fibrosis. Pediatr Pulmonol 2013; 48 (10) 943-953
    CrossrefPubMedSearch in Google Scholar
  • 64 Vandevanter DR, Yegin A, Morgan WJ, Millar SJ, Pasta DJ, Konstan MW. Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint. J Cyst Fibros 2011; 10 (06) 453-459
    CrossrefPubMedSearch in Google Scholar
  • 65 Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010; 182 (05) 627-632
    CrossrefPubMedSearch in Google Scholar
  • 66 Parkins MD, Rendall JC, Elborn JS. Incidence and risk factors for pulmonary exacerbation treatment failures in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. Chest 2012; 141 (02) 485-493
    CrossrefPubMedSearch in Google Scholar
  • 67 Schechter MS, Leonard A, Nash J. , et al. Benchmarking: signature themes. Pediatr Pulmonol 2006; 41: 122-123
    CrossrefPubMedSearch in Google Scholar
  • 68 Konstan MW, Morgan WJ, Butler SM. , et al; Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr 2007; 151 (02) 134-139 , 139.e1
    CrossrefPubMedSearch in Google Scholar
  • 69 Byrnes CA, Vidmar S, Cheney JL. , et al; ACFBAL Study Investigators. Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age. Thorax 2013; 68 (07) 643-651
    CrossrefPubMedSearch in Google Scholar
  • 70 Kusel MM, de Klerk N, Holt PG, Landau LI, Sly PD. Occurrence and management of acute respiratory illnesses in early childhood. J Paediatr Child Health 2007; 43 (03) 139-146
    CrossrefPubMedSearch in Google Scholar
  • 71 van Ewijk BE, van der Zalm MM, Wolfs TF. , et al. Prevalence and impact of respiratory viral infections in young children with cystic fibrosis: prospective cohort study. Pediatrics 2008; 122 (06) 1171-1176
    CrossrefPubMedSearch in Google Scholar
  • 72 Chattoraj SS, Ganesan S, Jones AM. , et al. Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells. Thorax 2011; 66 (04) 333-339
    CrossrefPubMedSearch in Google Scholar
  • 73 Van Ewijk BE, Wolfs TF, Aerts PC. , et al. RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells. Pediatr Res 2007; 61 (04) 398-403
    CrossrefPubMedSearch in Google Scholar
  • 74 Rosenfeld M, Ratjen F, Brumback L. , et al; ISIS Study Group. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307 (21) 2269-2277
    PubMedSearch in Google Scholar
  • 75 Mayer-Hamblett N, Retsch-Bogart G, Kloster M. , et al; OPTIMIZE Study Group. Azithromycin for early pseudomonas infection in cystic fibrosis. The OPTIMIZE randomized trial. Am J Respir Crit Care Med 2018; 198 (09) 1177-1187
    CrossrefPubMedSearch in Google Scholar
  • 76 Mott LS, Park J, Murray CP. , et al; AREST CF. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67 (06) 509-516
    CrossrefPubMedSearch in Google Scholar
  • 77 Stick SM, Brennan S, Murray C. , et al; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF). Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr 2009; 155 (05) 623-628.e1
    CrossrefPubMedSearch in Google Scholar
  • 78 Belessis Y, Dixon B, Hawkins G. , et al. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Respir Crit Care Med 2012; 185 (08) 862-873
    CrossrefPubMedSearch in Google Scholar
  • 79 Aurora P, Stanojevic S, Wade A. , et al; London Cystic Fibrosis Collaboration. Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care Med 2011; 183 (06) 752-758
    CrossrefPubMedSearch in Google Scholar
  • 80 Kiska DL, Kerr A, Jones MC. , et al. Accuracy of four commercial systems for identification of Burkholderia cepacia and other gram-negative nonfermenting bacilli recovered from patients with cystic fibrosis. J Clin Microbiol 1996; 34 (04) 886-891
    CrossrefPubMedSearch in Google Scholar
  • 81 Shelly DB, Spilker T, Gracely EJ, Coenye T, Vandamme P, LiPuma JJ. Utility of commercial systems for identification of Burkholderia cepacia complex from cystic fibrosis sputum culture. J Clin Microbiol 2000; 38 (08) 3112-3115
    CrossrefPubMedSearch in Google Scholar
  • 82 Saiman L, Burns JL, Larone D, Chen Y, Garber E, Whittier S. Evaluation of MicroScan Autoscan for identification of Pseudomonas aeruginosa isolates from cystic fibrosis patients. J Clin Microbiol 2003; 41 (01) 492-494
    CrossrefPubMedSearch in Google Scholar
  • 83 Wong K, Roberts MC, Owens L, Fife M, Smith AL. Selective media for the quantitation of bacteria in cystic fibrosis sputum. J Med Microbiol 1984; 17 (02) 113-119
    CrossrefPubMedSearch in Google Scholar
  • 84 Carson LA, Tablan OC, Cusick LB, Jarvis WR, Favero MS, Bland LA. Comparative evaluation of selective media for isolation of Pseudomonas cepacia from cystic fibrosis patients and environmental sources. J Clin Microbiol 1988; 26 (10) 2096-2100
    CrossrefPubMedSearch in Google Scholar
  • 85 Henry DA, Campbell ME, LiPuma JJ, Speert DP. Identification of Burkholderia cepacia isolates from patients with cystic fibrosis and use of a simple new selective medium. J Clin Microbiol 1997; 35 (03) 614-619
    CrossrefPubMedSearch in Google Scholar
  • 86 Burns JL, Emerson J, Stapp JR. , et al. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin Infect Dis 1998; 27 (01) 158-163
    CrossrefPubMedSearch in Google Scholar
  • 87 Davies JC, Moskowitz SM, Brown C. , et al; VX16-659-101 Study Group. VX-659-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379 (17) 1599-1611
    CrossrefPubMedSearch in Google Scholar
  • 88 Armstrong DS, Grimwood K, Carlin JB, Carzino R, Olinsky A, Phelan PD. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21 (05) 267-275
    CrossrefPubMedSearch in Google Scholar
  • 89 Rosenfeld M, Emerson J, Accurso F. , et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999; 28 (05) 321-328
    CrossrefPubMedSearch in Google Scholar
  • 90 Kabra SK, Alok A, Kapil A. , et al. Can throat swab after physiotherapy replace sputum for identification of microbial pathogens in children with cystic fibrosis?. Indian J Pediatr 2004; 71 (01) 21-23
    CrossrefPubMedSearch in Google Scholar
  • 91 De Boeck K, Alifier M, Vandeputte S. Sputum induction in young cystic fibrosis patients. Eur Respir J 2000; 16 (01) 91-94
    CrossrefPubMedSearch in Google Scholar
  • 92 Henig NR, Tonelli MR, Pier MV, Burns JL, Aitken ML. Sputum induction as a research tool for sampling the airways of subjects with cystic fibrosis. Thorax 2001; 56 (04) 306-311
    CrossrefPubMedSearch in Google Scholar
  • 93 Suri R, Marshall LJ, Wallis C, Metcalfe C, Shute JK, Bush A. Safety and use of sputum induction in children with cystic fibrosis. Pediatr Pulmonol 2003; 35 (04) 309-313
    CrossrefPubMedSearch in Google Scholar
  • 94 Ho SA, Ball R, Morrison LJ, Brownlee KG, Conway SP. Clinical value of obtaining sputum and cough swab samples following inhaled hypertonic saline in children with cystic fibrosis. Pediatr Pulmonol 2004; 38 (01) 82-87
    CrossrefPubMedSearch in Google Scholar
  • 95 Burns JL, Saiman L, Whittier S. , et al. Comparison of two commercial systems (Vitek and MicroScan-WalkAway) for antimicrobial susceptibility testing of Pseudomonas aeruginosa isolates from cystic fibrosis patients. Diagn Microbiol Infect Dis 2001; 39 (04) 257-260
    CrossrefPubMedSearch in Google Scholar
  • 96 Burns JL, Saiman L, Whittier S. , et al. Comparison of agar diffusion methodologies for antimicrobial susceptibility testing of Pseudomonas aeruginosa isolates from cystic fibrosis patients. J Clin Microbiol 2000; 38 (05) 1818-1822
    CrossrefPubMedSearch in Google Scholar
  • 97 Ciofu O, Giwercman B, Pedersen SS, Høiby N. Development of antibiotic resistance in Pseudomonas aeruginosa during two decades of antipseudomonal treatment at the Danish CF Center. APMIS 1994; 102 (09) 674-680
    CrossrefPubMedSearch in Google Scholar
  • 98 Taccetti G, Campana S, Marianelli L. Multiresistant non-fermentative gram-negative bacteria in cystic fibrosis patients: the results of an Italian multicenter study. Italian Group for Cystic Fibrosis Microbiology. Eur J Epidemiol 1999; 15 (01) 85-88
    CrossrefPubMedSearch in Google Scholar
  • 99 Aaron SD, Vandemheen KL, Ferris W. , et al. Combination antibiotic susceptibility testing to treat exacerbations of cystic fibrosis associated with multiresistant bacteria: a randomised, double-blind, controlled clinical trial. Lancet 2005; 366 (9484): 463-471
    CrossrefPubMedSearch in Google Scholar
  • 100 Aaron SD, Ferris W, Ramotar K, Vandemheen K, Chan F, Saginur R. Single and combination antibiotic susceptibilities of planktonic, adherent, and biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with cystic fibrosis. J Clin Microbiol 2002; 40 (11) 4172-4179
    CrossrefPubMedSearch in Google Scholar
  • 101 Smith AL, Fiel SB, Mayer-Hamblett N, Ramsey B, Burns JL. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 2003; 123 (05) 1495-1502
    CrossrefPubMedSearch in Google Scholar
  • 102 Moskowitz SM, Foster JM, Emerson JC, Gibson RL, Burns JL. Use of Pseudomonas biofilm susceptibilities to assign simulated antibiotic regimens for cystic fibrosis airway infection. J Antimicrob Chemother 2005; 56 (05) 879-886
    CrossrefPubMedSearch in Google Scholar
  • 103 Yau YC, Ratjen F, Tullis E. , et al. Randomized controlled trial of biofilm antimicrobial susceptibility testing in cystic fibrosis patients. J Cyst Fibros 2015; 14 (02) 262-266
    CrossrefPubMedSearch in Google Scholar
  • 104 Somayaji R, Parkins MD, Shah A. , et al; Antimicrobial Resistance in Cystic Fibrosis InternationalWorking Group. Antimicrobial susceptibility testing (AST) and associated clinical outcomes in individuals with cystic fibrosis: a systematic review. J Cyst Fibros 2019; 18 (02) 236-243
    CrossrefPubMedSearch in Google Scholar
  • 105 Moore RA, Hancock RE. Involvement of outer membrane of Pseudomonas cepacia in aminoglycoside and polymyxin resistance. Antimicrob Agents Chemother 1986; 30 (06) 923-926
    CrossrefPubMedSearch in Google Scholar
  • 106 Lewin C, Doherty C, Govan J. In vitro activities of meropenem, PD 127391, PD 131628, ceftazidime, chloramphenicol, co-trimoxazole, and ciprofloxacin against Pseudomonas cepacia. Antimicrob Agents Chemother 1993; 37 (01) 123-125
    CrossrefPubMedSearch in Google Scholar
  • 107 Aaron SD, Ferris W, Henry DA, Speert DP, Macdonald NE. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with Burkholderia cepacia. Am J Respir Crit Care Med 2000; 161 (4 Pt 1): 1206-1212
    CrossrefPubMedSearch in Google Scholar
  • 108 Burns JL, Saiman L. Burkholderia cepacia infections in cystic fibrosis. Pediatr Infect Dis J 1999; 18 (02) 155-156
    CrossrefPubMedSearch in Google Scholar
  • 109 Lang BJ, Aaron SD, Ferris W, Hebert PC, MacDonald NE. Multiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med 2000; 162 (06) 2241-2245
    CrossrefPubMedSearch in Google Scholar
  • 110 Krueger TS, Clark EA, Nix DE. In vitro susceptibility of Stenotrophomonas maltophilia to various antimicrobial combinations. Diagn Microbiol Infect Dis 2001; 41 (1-2): 71-78
    CrossrefPubMedSearch in Google Scholar
  • 111 Saiman L, Chen Y, Tabibi S. , et al. Identification and antimicrobial susceptibility of Alcaligenes xylosoxidans isolated from patients with cystic fibrosis. J Clin Microbiol 2001; 39 (11) 3942-3945
    CrossrefPubMedSearch in Google Scholar
  • 112 Flume PA, Mogayzel Jr PJ, Robinson KA. , et al; Clinical Practice Guidelines for Pulmonary Therapies Committee. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180 (09) 802-808
    CrossrefPubMedSearch in Google Scholar
  • 113 VanDevanter DR, O'Riordan MA, Blumer JL, Konstan MW. Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. Respir Res 2010; 11: 137
    CrossrefPubMedSearch in Google Scholar
  • 114 Horsley A, Jones AM, Lord R. Antibiotic treatment for Burkholderia cepacia complex in people with cystic fibrosis experiencing a pulmonary exacerbation. Cochrane Database Syst Rev 2016; (01) CD009529
    PubMedSearch in Google Scholar
  • 115 West NE, Beckett VV, Jain R. , et al; STOP investigators. 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 (05) 600-606
    CrossrefPubMedSearch in Google Scholar
  • 116 Dovey M, Aitken ML, Emerson J, McNamara S, Waltz DA, Gibson RL. Oral corticosteroid therapy in cystic fibrosis patients hospitalized for pulmonary exacerbation: a pilot study. Chest 2007; 132 (04) 1212-1218
    CrossrefPubMedSearch in Google Scholar
  • 117 Smyth A, Tan KH, Hyman-Taylor P. , et al; TOPIC Study Group. Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial. Lancet 2005; 365 (9459): 573-578
    CrossrefPubMedSearch in Google Scholar
  • 118 Smyth A, Lewis S, Bertenshaw C, Choonara I, McGaw J, Watson A. Case-control study of acute renal failure in patients with cystic fibrosis in the UK. Thorax 2008; 63 (06) 532-535
    CrossrefPubMedSearch in Google Scholar
  • 119 Öbrink-Hansen K, Jensen-Fangel S, Brock B. , et al. Piperacillin/tazobactam continuous infusion at 12G/1.5G per day in CF patients results in target plasma-concentrations. J Cyst Fibros 2016; 15 (02) e13-e14
    CrossrefPubMedSearch in Google Scholar
  • 120 Riethmueller J, Junge S, Schroeter TW. , et al. Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis. Infection 2009; 37 (05) 418-423
    CrossrefPubMedSearch in Google Scholar
  • 121 Hubert D, Le Roux E, Lavrut T. , et al. Continuous versus intermittent infusions of ceftazidime for treating exacerbation of cystic fibrosis. Antimicrob Agents Chemother 2009; 53 (09) 3650-3656
    CrossrefPubMedSearch in Google Scholar
  • 122 VanDevanter DR, Heltshe SL, Spahr J. , et al; STOP Study Group. Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis. J Cyst Fibros 2017; 16 (05) 607-615
    CrossrefPubMedSearch in Google Scholar
  • 123 Sanders DB, Solomon GM, Beckett VV. , et al; STOP Study Group. Standardized Treatment of Pulmonary Exacerbations (STOP) study: observations at the initiation of intravenous antibiotics for cystic fibrosis pulmonary exacerbations. J Cyst Fibros 2017; 16 (05) 592-599
    CrossrefPubMedSearch in Google Scholar
  • 124 Heltshe SL, West NE, VanDevanter DR. , et al. Study design considerations for the Standardized Treatment of Pulmonary Exacerbations 2 (STOP2): a trial to compare intravenous antibiotic treatment durations in CF. Contemp Clin Trials 2018; 64: 35-40
    CrossrefPubMedSearch in Google Scholar
  • 125 Bennett AV, Patrick DL, Lymp JF, Edwards TC, Goss CH. Comparison of 7-day and repeated 24-hour recall of symptoms of cystic fibrosis. J Cyst Fibros 2010; 9 (06) 419-424
    CrossrefPubMedSearch in Google Scholar
  • 126 Goss CH, Edwards TC, Ramsey BW, Aitken ML, Patrick DL. Patient-reported respiratory symptoms in cystic fibrosis. J Cyst Fibros 2009; 8 (04) 245-252
    CrossrefPubMedSearch in Google Scholar
  • 127 Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-—revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest 2009; 135 (06) 1610-1618
    CrossrefPubMedSearch in Google Scholar
  • 128 VanDevanter DR, Pasta DJ, Konstan MW. Treatment and demographic factors affecting time to next pulmonary exacerbation in cystic fibrosis. J Cyst Fibros 2015; 14 (06) 763-769
    CrossrefPubMedSearch in Google Scholar
  • 129 Collaco JM, Green DM, Cutting GR, Naughton KM, Mogayzel Jr PJ. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med 2010; 182 (09) 1137-1143
    CrossrefPubMedSearch in Google Scholar
  • 130 Waters V, Stanojevic S, Klingel M. , et al. Prolongation of antibiotic treatment for cystic fibrosis pulmonary exacerbations. J Cyst Fibros 2015; 14 (06) 770-776
    CrossrefPubMedSearch in Google Scholar
  • 131 Cystic Fibrosis Foundation Patient Registry 2011 Annual Data Report to the Center Directors, Cystic Fibrosis Foundation, Bethesda Maryland; 2012
    PubMed
  • 132 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 (01) 83-88
    CrossrefPubMedSearch in Google Scholar
  • 133 Wolter JM, Bowler SD, Nolan PJ, McCormack JG. Home intravenous therapy in cystic fibrosis: a prospective randomized trial examining clinical, quality of life and cost aspects. Eur Respir J 1997; 10 (04) 896-900
    PubMedSearch in Google Scholar
  • 134 Schechter MS, VanDevanter DR, Pasta DJ. , et al. Treatment setting and outcomes of cystic fibrosis pulmonary exacerbations. Ann Am Thorac Soc 2018; 15 (02) 225-233
    CrossrefPubMedSearch in Google Scholar
  • 135 CF Foundation. Cystic Fibrosis Foundation Patient Registry 2015 Annual Data Report, Cystic Fibrosis Foundation, Bethesda Maryland; 2016
    PubMed
  • 136 Roehrer E, Cummings E, Beggs S. , et al. Pilot evaluation of web enabled symptom monitoring in cystic fibrosis. Inform Health Soc Care 2013; 38 (04) 354-365
    CrossrefPubMedSearch in Google Scholar
  • 137 Roehrer E, Cummings E, Turner P. , et al. Supporting cystic fibrosis with ICT. Stud Health Technol Inform 2013; 183: 137-141
    PubMedSearch in Google Scholar
  • 138 Cummings E, Hauser J, Cameron-Tucker H. , et al. Enhancing self-efficacy for self-management in people with cystic fibrosis. Stud Health Technol Inform 2011; 169: 33-37
    PubMedSearch in Google Scholar
  • 139 Aitken ML, Caldwell E, Wilhelm E, Goss CH. Early intervention in pulmonary exacerbation. Pediatr Pulmonol 2011; 46: A331
    PubMedSearch in Google Scholar
  • 140 Keating D, Marigowda G, Burr L. , et al; VX16-445-001 Study Group. VX-445-Tezacaftor-Ivacaftor in patients with cystic fibrosis and one or two Phe508del alleles. N Engl J Med 2018; 379 (17) 1612-1620
    CrossrefPubMedSearch in Google Scholar
  • 141 Kirwan L, Fletcher G, Harrington M. , et al. Longitudinal trends in real-world outcomes after initiation of ivacaftor. A cohort study from the Cystic Fibrosis Registry of Ireland. Ann Am Thorac Soc 2019; 16 (02) 209-216
    CrossrefPubMedSearch in Google Scholar
  • 142 Heltshe SL, Mayer-Hamblett N, Burns JL. , et al; GOAL (the G551D Observation-AL) Investigators of the Cystic Fibrosis Foundation Therapeutics Development Network. Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor. Clin Infect Dis 2015; 60 (05) 703-712
    CrossrefPubMedSearch in Google Scholar
  • 143 Frost FJ, Nazareth DS, Charman SC, Winstanley C, Walshaw MJ. Ivacaftor is associated with reduced lung infection by key cystic fibrosis pathogens: a cohort study using National Registry Data. Ann Am Thorac Soc 2019; (e-pub ahead of print)
    CrossrefPubMedSearch in Google Scholar