The Clinical Approach to Lung Disease in Patients with Cystic Fibrosis

ABSTRACT

There is strong evidence that early, aggressive therapy of lung disease leads to improved quality and quantity of life for patients with cystic fibrosis (CF). The treatment of pulmonary disease associated with CF is multifactorial, encompassing prophylaxis, aggressive treatment of infection, use of antiinflammatory agents, and treatment of severe complications. Chest physiotherapy on a regular basis, perhaps using new modalities that allow patient autonomy, is also crucial. This review covers the pathogenesis of CF lung disease and current approaches to therapy, highlighting guidelines recently published by the Cystic Fibrosis Foundation. Clinicians caring for patients with CF should maximize current therapies with the goal of preserving lung function until the time a more definitive curative or controller medication is developed. Empowering patients in the process of providing their own care is a key to achieving this goal.

KEYWORDS

Cystic fibrosis - inflammation - antibiotic therapy - treatment - prophylaxis - pathogenesis

REFERENCES

• 1 O'Sullivan B P, Freedman S D. Cystic fibrosis.  Lancet. 2009;  373 1891-1904
• 2 Carlson D, McKeen E, Mitchell M et al.. Oropharyngeal flora in healthy infants: observations and implications for cystic fibrosis care.  Pediatr Pulmonol. 2009;  44 497-502
• 3 Sagel S D, Gibson R L, Emerson J et al.. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis.  J Pediatr. 2009;  154 183-188
• 4 Fuchs H J, Borowitz D S, Christiansen D H The Pulmozyme Study Group et al. 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;  331 637-642
• 5 Hartl D, Latzin P, Hordijk P et al.. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease.  Nat Med. 2007;  13 1423-1430
• 6 Farrell P M, Li Z, Kosorok M R et al.. Longitudinal evaluation of bronchopulmonary disease in children with cystic fibrosis.  Pediatr Pulmonol. 2003;  36 230-240
• 7 Armstrong D S, Grimwood K, Carzino R, Carlin J B, Olinsky A, Phelan P D. Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis.  BMJ. 1995;  310 1571-1572
• 8 Linnane B M, Hall G L, Nolan G AREST-CF et al. Lung function in infants with cystic fibrosis diagnosed by newborn screening.  Am J Respir Crit Care Med. 2008;  178 1238-1244
• 9 Khan T Z, Wagener J S, Bost T, Martinez J, Accurso F J, Riches D W. Early pulmonary inflammation in infants with cystic fibrosis.  Am J Respir Crit Care Med. 1995;  151 1075-1082
• 10 Konstan M W, Butler S M, Wohl M EB Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis et al. Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis.  J Pediatr. 2003;  142 624-630
• 11 Padman R, McColley S A, Miller D P Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis et al. Infant care patterns at epidemiologic study of cystic fibrosis sites that achieve superior childhood lung function.  Pediatrics. 2007;  119 e531-e537
• 12 Campbell III P W, Parker R A, Roberts B T, Krishnamani M RS, Phillips III J A. Association of poor clinical status and heavy exposure to tobacco smoke in patients with cystic fibrosis who are homozygous for the F508 deletion.  J Pediatr. 1992;  120(2 Pt 1) 261-264
• 13 Johnson C, Butler S M, Konstan M W, Morgan W, Wohl M EB. Factors influencing outcomes in cystic fibrosis: a center-based analysis.  Chest. 2003;  123 20-27
• 14 Flume P A, Robinson K A, O'Sullivan B P Clinical Practice Guidelines for Pulmonary Therapies Committee et al. Cystic fibrosis pulmonary guidelines: airway clearance therapies.  Respir Care. 2009;  54 522-537
• 15 Lester M K, Flume P A. Airway clearance therapy guidelines and implementation.  Respir Care. 2009;  54 733-750
• 16 Button B M, Heine R G, Catto-Smith A G et al.. Chest physiotherapy in infants with cystic fibrosis: to tip or not? A five-year study.  Pediatr Pulmonol. 2003;  35 208-213
• 17 Donaldson S H, Bennett W D, Zeman K L, Knowles M R, Tarran R, Boucher R C. Mucus clearance and lung function in cystic fibrosis with hypertonic saline.  N Engl J Med. 2006;  354 241-250
• 18 Ratjen F. Restoring airway surface liquid in cystic fibrosis.  N Engl J Med. 2006;  354 291-293
• 19 Robinson M, Hemming A L, Regnis J A et al.. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis.  Thorax. 1997;  52 900-903
• 20 Elkins M R, Robinson M, Rose B R National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis.  N Engl J Med. 2006;  354 229-240
• 21 Flume P A, O'Sullivan B P, Robinson K A Cystic Fibrosis Foundation, Pulmonary Therapies Committee et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health.  Am J Respir Crit Care Med. 2007;  176 957-969
• 22 Robinson M, Daviskas E, Eberl S et al.. The effect of inhaled mannitol on bronchial mucus clearance in cystic fibrosis patients: a pilot study.  Eur Respir J. 1999;  14 678-685
• 23 Jaques A, Daviskas E, Turton J A et al.. Inhaled mannitol improves lung function in cystic fibrosis.  Chest. 2008;  133 1388-1396
• 24 McCoy K, Hamilton S, Johnson C. Pulmozyme Study Group . Effects of 12-week administration of dornase alfa in patients with advanced cystic fibrosis lung disease.  Chest. 1996;  110 889-895
• 25 Grasemann H, Lax H, Treseler J W, Colin A A. Dornase alpha and exhaled NO in cystic fibrosis.  Pediatr Pulmonol. 2004;  38 379-385
• 26 Quan J M, Tiddens H A, Sy J P Pulmozyme Early Intervention Trial Study Group et al. A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities.  J Pediatr. 2001;  139 813-820
• 27 Nasr S Z, Kuhns L R, Brown R W, Hurwitz M E, Sanders G M, Strouse P J. Use of computerized tomography and chest x-rays in evaluating efficacy of aerosolized recombinant human DNase in cystic fibrosis patients younger than age 5 years: a preliminary study.  Pediatr Pulmonol. 2001;  31 377-382
• 28 Subbarao P, Balkovec S, Solomon M, Ratjen F. Pilot study of safety and tolerability of inhaled hypertonic saline in infants with cystic fibrosis.  Pediatr Pulmonol. 2007;  42 471-476
• 29 Anon .2006 Annual Data Report to the Center Directors. Bethesda, MD; CF Foundation 2007
• 30 Sawicki G S, Rasouliyan L, Pasta D J Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis et al. The impact of incident methicillin resistant Staphylococcus aureus detection on pulmonary function in cystic fibrosis.  Pediatr Pulmonol. 2008;  43 1117-1123
• 31 Dasenbrook E C, Merlo C A, Diener-West M, Lechtzin N, Boyle M P. Persistent methicillin-resistant Staphylococcus aureus and rate of FEV1 decline in cystic fibrosis.  Am J Respir Crit Care Med. 2008;  178 814-821
• 32 Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson R L. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis.  Pediatr Pulmonol. 2002;  34 91-100
• 33 Pamukcu A, Bush A, Buchdahl R. Effects of Pseudomonas aeruginosa colonization on lung function and anthropometric variables in children with cystic fibrosis.  Pediatr Pulmonol. 1995;  19 10-15
• 34 Winnie G B, Cowan R G. Respiratory tract colonization with Pseudomonas aeruginosa in cystic fibrosis: correlations between anti-Pseudomonas aeruginosa antibody levels and pulmonary function.  Pediatr Pulmonol. 1991;  10 92-100
• 35 Ballmann M, Rabsch P, von der Hardt H. Long-term follow up of changes in FEV1 and treatment intensity during Pseudomonas aeruginosa colonisation in patients with cystic fibrosis.  Thorax. 1998;  53 732-737
• 36 Nixon G M, Armstrong D S, Carzino R et al.. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis.  J Pediatr. 2001;  138 699-704
• 37 Konstan M W, Morgan W J, Butler S M Scientific Advisory Group and the Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis et al. Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis.  J Pediatr. 2007;  151 134-139, 139, e1
• 38 Beardsmore C S, Thompson J R, Williams A et al.. Pulmonary function in infants with cystic fibrosis: the effect of antibiotic treatment.  Arch Dis Child. 1994;  71 133-137
• 39 Weaver L T, Green M R, Nicholson K et al.. Prognosis in cystic fibrosis treated with continuous flucloxacillin from the neonatal period.  Arch Dis Child. 1994;  70 84-89
• 40 Stutman H R, Lieberman J M, Nussbaum E, Marks M I. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial.  J Pediatr. 2002;  140 299-305
• 41 Döring G, Conway S P, Heijerman H G et al.. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus.  Eur Respir J. 2000;  16 749-767
• 42 Heinzl B, Eber E, Oberwaldner B, Haas G, Zach M S. Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study.  Pediatr Pulmonol. 2002;  33 32-37
• 43 Ratjen E, Munck A, Campello V. Safety of inhaled tobramycin nebuliser solution for treatment of early Pseudomonas aeruginosa infection: first results from the ELITE study [abstract].  J Cyst Fibros. 2006;  5 S22
• 44 Ratjen F. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis.  Curr Opin Pulm Med. 2006;  12 428-432
• 45 Treggiari M M, Rosenfeld M, Retsch-Bogart G, Gibson R, Ramsey B. Approach to eradication of initial Pseudomonas aeruginosa infection in children with cystic fibrosis.  Pediatr Pulmonol. 2007;  42 751-756
• 46 Burns J L, Gibson R L, McNamara S et al.. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis.  J Infect Dis. 2001;  183 444-452
• 47 Ramsey B W, Dorkin H L, Eisenberg J D et al.. Efficacy of aerosolized tobramycin in patients with cystic fibrosis.  N Engl J Med. 1993;  328 1740-1746
• 48 Eigen H, Rosenstein B J, FitzSimmons S, Schidlow D V. Cystic Fibrosis Foundation Prednisone Trial Group . A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis.  J Pediatr. 1995;  126 515-523
• 49 Balfour-Lynn I M, Lees B, Hall P CF WISE (Withdrawal of Inhaled Steroids Evaluation) Investigators et al. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis.  Am J Respir Crit Care Med. 2006;  173 1356-1362
• 50 Ren C L, Pasta D J, Rasouliyan L, Wagener J S, Konstan M W, Morgan W J. 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;  153 746-751
• 51 Balfour-Lynn I M, Lees B, Hall P CF WISE (Withdrawal of Inhaled Steroids Evaluation) Investigators et al. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis.  Am J Respir Crit Care Med. 2006;  173 1356-1362
• 52 Chmiel J F, Konstan M W. Inflammation and anti-inflammatory therapies for cystic fibrosis.  Clin Chest Med. 2007;  28 331-346
• 53 Konstan M W, Byard P J, Hoppel C L, Davis P B. Effect of high-dose ibuprofen in patients with cystic fibrosis.  N Engl J Med. 1995;  332 848-854
• 54 Lands L C, Milner R, Cantin A M, Manson D, Corey M. High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial.  J Pediatr. 2007;  151 249-254
• 55 Fennell P B, Quante J, Wilson K, Boyle M, Strunk R, Ferkol T. Use of high-dose ibuprofen in a pediatric cystic fibrosis center.  J Cyst Fibros. 2007;  6 153-158
• 56 Idris S F, Chilvers E R, Haworth C, McKeon D, Condliffe A M. Azithromycin therapy for neutrophilic airways disease: myth or magic?.  Thorax. 2009;  64 186-189
• 57 Köhler T, Dumas J-L, Van Delden C. Ribosome protection prevents azithromycin-mediated quorum-sensing modulation and stationary-phase killing of Pseudomonas aeruginosa .  Antimicrob Agents Chemother. 2007;  51 4243-4248
• 58 Koyama H, Geddes D M. Erythromycin and diffuse panbronchiolitis.  Thorax. 1997;  52 915-918
• 59 Ordoñez C L, Stulbarg M, Grundland H, Liu J T, Boushey H A. Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study.  Pediatr Pulmonol. 2001;  32 29-37
• 60 Equi A, Balfour-Lynn I M, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial.  Lancet. 2002;  360 978-984
• 61 Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial.  Thorax. 2002;  57 212-216
• 62 Saiman L, Marshall B C, Mayer-Hamblett N Macrolide Study Group et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial.  JAMA. 2003;  290 1749-1756
• 63 Block J K, Vandemheen K L, Tullis E et al.. Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria.  Thorax. 2006;  61 969-974
• 64 Goss C H, Burns J L. Exacerbations in cystic fibrosis, I: Epidemiology and pathogenesis.  Thorax. 2007;  62 360-367
• 65 Bell S C, Robinson P J. Exacerbations in cystic fibrosis, II: Prevention.  Thorax. 2007;  62 723-732
• 66 Smyth A, Elborn J S. Exacerbations in cystic fibrosis, III: Management.  Thorax. 2008;  63 180-184
• 67 Anderson D H. Cystic fibrosis of the pancreas and its relation to celiac disease.  Am J Dis Child. 1938;  56 344
• 68 Szaff M, Høiby N, Flensborg E W. Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection.  Acta Paediatr Scand. 1983;  72 651-657
• 69 Regelmann W E, Elliott G R, Warwick W J, Clawson C C. 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
• 70 Wolter J M, Bowler S D, Nolan P J, McCormack J G. Home intravenous therapy in cystic fibrosis: a prospective randomized trial examining clinical, quality of life and cost aspects.  Eur Respir J. 1997;  10 896-900
• 71 Proesmans M, Heyns L, Moons P, Havermans T, De Boeck K. Real life evaluation of intravenous antibiotic treatment in a paediatric cystic fibrosis centre: outcome of home therapy is not inferior.  Respir Med. 2009;  103 244-250
• 72 Yi M S, Tsevat J, Wilmott R W, Kotagal U R, Britto M T. The impact of treatment of pulmonary exacerbations on the health-related quality of life of patients with cystic fibrosis: does hospitalization make a difference?.  J Pediatr. 2004;  144 711-718
• 73 Nazer D, Abdulhamid I, Thomas R, Pendleton S. Home versus hospital intravenous antibiotic therapy for acute pulmonary exacerbations in children with cystic fibrosis.  Pediatr Pulmonol. 2006;  41 744-749
• 74 Thornton J, Elliott R, Tully M P, Dodd M, Webb A K. Long term clinical outcome of home and hospital intravenous antibiotic treatment in adults with cystic fibrosis.  Thorax. 2004;  59 242-246
• 75 Jones A M, Dodd M E, Govan J RW et al.. Burkholderia cenocepacia and Burkholderia multivorans: influence on survival in cystic fibrosis.  Thorax. 2004;  59 948-951
• 76 Kalish L A, Waltz D A, Dovey M et al.. Impact of Burkholderia dolosa on lung function and survival in cystic fibrosis.  Am J Respir Crit Care Med. 2006;  173 421-425
• 77 Burns J LMD, Saiman L MD. Burkholderia cepacia infections in cystic fibrosis.  Pediatr Infect Dis J. 1999;  18 155-156
• 78 Aaron S D, Ferris W, Henry D A, Speert D P, Macdonald N E. 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
• 79 Stevens D A, Moss R B, Kurup V P Participants in the Cystic Fibrosis Foundation Consensus Conference et al. Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference.  Clin Infect Dis. 2003;  37(Suppl 3) S225-S264
• 80 Mastella G, Rainisio M, Harms H K et al.. Allergic bronchopulmonary aspergillosis in cystic fibrosis: a European epidemiological study. Epidemiologic Registry of Cystic Fibrosis.  Eur Respir J. 2000;  16 464-471
• 81 Skov M, Høiby N, Koch C. Itraconazole treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis.  Allergy. 2002;  57 723-728
• 82 Ibrahim W H. Massive haemoptysis: the definition should be revised.  Eur Respir J. 2008;  32 1131-1132
• 83 Wong L TK, Lillquist Y P, Culham G, DeJong B P, Davidson A GF. Treatment of recurrent hemoptysis in a child with cystic fibrosis by repeated bronchial artery embolizations and long-term tranexamic acid.  Pediatr Pulmonol. 1996;  22 275-279
• 84 Brinson G M, Noone P G, Mauro M A et al.. Bronchial artery embolization for the treatment of hemoptysis in patients with cystic fibrosis.  Am J Respir Crit Care Med. 1998;  157(6 Pt 1) 1951-1958
• 85 Furnari M L, Salerno S, Rabiolo A, Caravello V, Pardo F. Bronchial to subclavian shunt in a CF patient: a potential pitfall for embolization.  J Cyst Fibros. 2003;  2 217-219
• 86 Flume P A. Pneumothorax in cystic fibrosis.  Chest. 2003;  123 217-221
• 87 Phillips G D, Trotman-Dickenson B, Hodson M E, Geddes D M. Role of CT in the management of pneumothorax in patients with complex cystic lung disease.  Chest. 1997;  112 275-278
• 88 Davis P B, di Sant'Agnese P A. Assisted ventilation for patients with cystic fibrosis.  JAMA. 1978;  239 1851-1854
• 89 Slieker M G, van Gestel J P, Heijerman H G et al.. Outcome of assisted ventilation for acute respiratory failure in cystic fibrosis.  Intensive Care Med. 2006;  32 754-758
• 90 Sood N, Paradowski L J, Yankaskas J R. Outcomes of intensive care unit care in adults with cystic fibrosis.  Am J Respir Crit Care Med. 2001;  163 335-338
• 91 Young A C, Wilson J W, Kotsimbos T C, Naughton M T. Randomised placebo controlled trial of non-invasive ventilation for hypercapnia in cystic fibrosis.  Thorax. 2008;  63 72-77
• 92 Serra A, Polese G, Braggion C, Rossi A. Non-invasive proportional assist and pressure support ventilation in patients with cystic fibrosis and chronic respiratory failure.  Thorax. 2002;  57 50-54
• 93 Kramer J M. Balancing the benefits and risks of inhaled long-acting beta-agonists—the influence of values.  N Engl J Med. 2009;  360 1592-1595
• 94 Drazen J M, O'Byrne P M. Risks of long-acting beta-agonists in achieving asthma control.  N Engl J Med. 2009;  360 1671-1672