Early pulmonary inflammation and lung damage in children with cystic fibrosis

Respirology

Volumn 20, Issue 4, 2015, Pages 569-578

  Schultz, André ^a,b,c   Stick, Stephen ^a,c  

^a PRINCESS MARGARET HOSPITAL FOR CHILDREN   (Australia)

^b UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^c UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

biochemistry; cell biology; cystic fibrosis; infection and inflammation; paediatric lung disease

Indexed keywords

AMINOGLYCOSIDE ANTIBIOTIC AGENT; ATALUREN; AZITHROMYCIN; BICARBONATE; CATHEPSIN S; CHLORIDE CHANNEL; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; DORNASE ALFA; GENTAMICIN; GLUCOCORTICOID; IBUPROFEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MACROLIDE; MANNITOL; METALLOPROTEINASE; MUCIN; MUCIN 1; MUCIN 16; MUCIN 4; MUCIN 5AC; MUCIN 5B; NONSTEROID ANTIINFLAMMATORY AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PROTEINASE; SERINE PROTEINASE; TOBRAMYCIN; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG;

AUTOPHAGOSOME; CYSTIC FIBROSIS; ENDOPLASMIC RETICULUM STRESS; GASTROINTESTINAL HEMORRHAGE; GENE MUTATION; HUMAN; INFLAMMATION; LUNG INFECTION; LUNG INJURY; MUCOSAL IMMUNITY; PH; PNEUMONIA; PRIORITY JOURNAL; PSEUDOMONAS INFECTION; REVIEW; VIRUS INFECTION; BODY FLUID; CHEMISTRY; CHILD; GENETICS; IMMUNOLOGY; LUNG; METABOLISM;

BODY FLUIDS; CHILD; CYSTIC FIBROSIS; CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR; HUMANS; HYDROGEN-ION CONCENTRATION; INFLAMMATION; LUNG; LUNG INJURY; MUCINS; PNEUMONIA;

EID: 84927710902     PISSN: 13237799     EISSN: 14401843     Source Type: Journal    
DOI: 10.1111/resp.12521     Document Type: Review

References (88)

1. Armstrong DS, Grimwood K, Carzino R, Carlin JB, Olinsky A, Phelan PD,. Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis. BMJ 1995; 310: 1571-1572.
2. Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ, Riches DW,. Early pulmonary inflammation in infants with cystic fibrosis. Am. J. Respir. Crit. Care Med. 1995; 151: 1075-1082.
3. Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson PJ, Robertson CF, Ranganathan SC, Sly PD, Stick SM,. Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 2012; 67: 509-516.
4. Pillarisetti N, Williamson E, Linnane B, Skoric B, Robertson CF, Robinson P, Massie J, Hall GL, Sly P, Stick S, et al. Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2011; 184: 75-81.
5. Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP, Stick SM,. Risk factors for bronchiectasis in children with cystic fibrosis. N. Engl. J. Med. 2013; 368: 1963-1970.
6. Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B, Ranganathan S, et al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J. Pediatr. 2009; 155: 623-681.
7. Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, Stick SM, Robinson PJ, Robertson CF, Ranganathan SC,. Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am. J. Respir. Crit. Care Med. 2009; 180: 146-152.
8. Helbich TH, Heinz-Peer G, Eichler I, Wunderbaldinger P, Gotz M, Wojnarowski C, Brasch RC, Herold CJ,. Cystic fibrosis: CT assessment of lung involvement in children and adults. Radiology 1999; 213: 537-544.
9. de Jong PA, Nakano Y, Hop WC, Long FR, Coxson HO, Pare PD, Tiddens HA,. Changes in airway dimensions on computed tomography scans of children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2005; 172: 218-224.
10. Wainwright CE, Vidmar S, Armstrong DS, Byrnes CA, Carlin JB, Cheney J, Cooper PJ, Grimwood K, Moodie M, Robertson CF, et al. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA 2011; 306: 163-171.
11. Calder AD, Bush A, Brody AS, Owens CM,. Scoring of chest CT in children with cystic fibrosis: state of the art. Pediatr. Radiol. 2014; 44: 1496-1506.
12. Kunzelmann K, Mehta A,. CFTR: a hub for kinases and crosstalk of cAMP and Ca2. FEBS J. 2013; 280: 4417-4429.
13. Bell SC, De Boeck K, Amaral MD,. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol. Ther. 2015; 145: 19-34.
14. Wei L, Vankeerberghen A, Cuppens H, Eggermont J, Cassiman JJ, Droogmans G, Nilius B,. Interaction between calcium-activated chloride channels and the cystic fibrosis transmembrane conductance regulator. Pflugers Arch. 1999; 438: 635-641.
15. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE,. Regulation of the epithelial sodium channel by serine proteases in human airways. J. Biol. Chem. 2002; 277: 8338-8345.
16. Donaldson SH, Boucher RC,. Sodium channels and cystic fibrosis. Chest 2007; 132: 1631-1636.
17. Gaillard EA, Kota P, Gentzsch M, Dokholyan NV, Stutts MJ, Tarran R,. Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases. Pflugers Arch. 2010; 460: 1-17.
18. Garland AL, Walton WG, Coakley RD, Tan CD, Gilmore RC, Hobbs CA, Tripathy A, Clunes LA, Bencharit S, Stutts MJ, et al. Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 15973-15978.
19. Pezzulo AA, Tang XX, Hoegger MJ, Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenane CL, Haagsman HP, van Eijk M, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 2012; 487: 109-113.
20. Lukinskiene L, Liu Y, Reynolds SD, Steele C, Stripp BR, Leikauf GD, Kolls JK, Di YP,. Antimicrobial activity of PLUNC protects against Pseudomonas aeruginosa infection. J. Immunol. 2011; 187: 382-390.
21. Liu Y, Bartlett JA, Di ME, Bomberger JM, Chan YR, Gakhar L, Mallampalli RK, McCray PB Jr, Di YP,. SPLUNC1/BPIFA1 contributes to pulmonary host defense against Klebsiella pneumoniae respiratory infection. Am. J. Pathol. 2013; 182: 1519-1531.
22. Henderson AG, Ehre C, Button B, Abdullah LH, Cai LH, Leigh MW, DeMaria GC, Matsui H, Donaldson SH, Davis CW, et al. Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J. Clin. Invest. 2014; 124: 3047-3060.
23. Button B, Cai LH, Ehre C, Kesimer M, Hill DB, Sheehan JK, Boucher RC, Rubinstein M,. A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 2012; 337: 937-941.
24. Pelaseyed T, Zach M, Petersson AC, Svensson F, Johansson DG, Hansson GC,. Unfolding dynamics of the mucin SEA domain probed by force spectroscopy suggest that it acts as a cell-protective device. FEBS J. 2013; 280: 1491-1501.
25. Livraghi-Butrico A, Kelly EJ, Klem ER, Dang H, Wolfgang MC, Boucher RC, Randell SH, O'Neal WK,. Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation. Mucosal Immunol. 2012; 5: 397-408.
26. Ambort D, Johansson ME, Gustafsson JK, Nilsson HE, Ermund A, Johansson BR, Koeck PJ, Hebert H, Hansson GC,. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 5645-5650.
27. Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, Thorell K, Hebert H, Sjovall H, Hansson GC,. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J. Exp. Med. 2012; 209: 1263-1272.
28. Griese M, Kappler M, Gaggar A, Hartl D,. Inhibition of airway proteases in cystic fibrosis lung disease. Eur. Respir. J. 2008; 32: 783-795.
29. Griese M, Essl R, Schmidt R, Rietschel E, Ratjen F, Ballmann M, Paul K,. Pulmonary surfactant, lung function, and endobronchial inflammation in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2004; 170: 1000-1005.
30. Weldon S, McNally P, McAuley DF, Oglesby IK, Wohlford-Lenane CL, Bartlett JA, Scott CJ, McElvaney NG, Greene CM, McCray PB Jr, et al. miR-31 dysregulation in cystic fibrosis airways contributes to increased pulmonary cathepsin S production. Am. J. Respir. Crit. Care Med. 2014; 190: 165-174.
31. Gaggar A, Li Y, Weathington N, Winkler M, Kong M, Jackson P, Blalock JE, Clancy JP,. Matrix metalloprotease-9 dysregulation in lower airway secretions of cystic fibrosis patients. Am. J. Physiol. Lung Cell. Mol. Physiol. 2007; 293: L96-104.
32. Chen GY, Nunez G,. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 2010; 10: 826-837.
33. Frickmann H, Jungblut S, Hirche TO, Gross U, Kuhns M, Zautner AE,. Spectrum of viral infections in patients with cystic fibrosis. Eur. J. Microb. Immunol. 2012; 2: 161-175.
34. Kieninger E, Singer F, Tapparel C, Alves MP, Latzin P, Tan HL, Bossley C, Casaulta C, Bush A, Davies JC, et al. High rhinovirus burden in lower airways of children with cystic fibrosis. Chest 2013; 143: 782-790.
35. Mills PR, Davies RJ, Devalia JL,. Airway epithelial cells, cytokines, and pollutants. Am. J. Respir. Crit. Care Med. 1999; 160: S38-43.
36. Vareille M, Kieninger E, Edwards MR, Regamey N,. The airway epithelium: soldier in the fight against respiratory viruses. Clin. Microbiol. Rev. 2011; 24: 210-229.
37. Sutanto EN, Kicic A, Foo CJ, Stevens PT, Mullane D, Knight DA, Stick SM,. Innate inflammatory responses of pediatric cystic fibrosis airway epithelial cells: effects of nonviral and viral stimulation. Am. J. Respir. Cell Mol. Biol. 2011; 44: 761-767.
38. Armstrong DS, Hook SM, Jamsen KM, Nixon GM, Carzino R, Carlin JB, Robertson CF, Grimwood K,. Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr. Pulmonol. 2005; 40: 500-510.
39. Gangell C, Gard S, Douglas T, Park J, de Klerk N, Keil T, Brennan S, Ranganathan S, Robins-Browne R, Sly PD,. Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin. Infect. Dis. 2011; 53: 425-432.
40. Sagel SD, Gibson RL, Emerson J, McNamara S, Burns JL, Wagener JS, Ramsey BW,. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J. Pediatr. 2009; 154: 183-188.
41. Akira S, Takeda K,. Toll-like receptor signalling. Nat. Rev. Immunol. 2004; 4: 499-511.
42. Vij N, Mazur S, Zeitlin PL,. CFTR is a negative regulator of NFkappaB mediated innate immune response. PLoS ONE 2009; 4: e4664.
43. Blohmke CJ, Victor RE, Hirschfeld AF, Elias IM, Hancock DG, Lane CR, Davidson AG, Wilcox PG, Smith KD, Overhage J, et al. Innate immunity mediated by TLR5 as a novel antiinflammatory target for cystic fibrosis lung disease. J. Immunol. 2008; 180: 7764-7773.
44. Fu L, Sztul E,. ER-associated complexes (ERACs) containing aggregated cystic fibrosis transmembrane conductance regulator (CFTR) are degraded by autophagy. Eur. J. Cell Biol. 2009; 88: 215-226.
45. Knorre A, Wagner M, Schaefer HE, Colledge WH, Pahl HL,. DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs. Biol. Chem. 2002; 383: 271-282.
46. Blohmke CJ, Mayer ML, Tang AC, Hirschfeld AF, Fjell CD, Sze MA, Falsafi R, Wang S, Hsu K, Chilvers MA, et al. Atypical activation of the unfolded protein response in cystic fibrosis airway cells contributes to p38 MAPK-mediated innate immune responses. J. Immunol. 2012; 189: 5467-5475.
47. Mayer ML, Blohmke CJ, Falsafi R, Fjell CD, Madera L, Turvey SE, Hancock RE,. Rescue of dysfunctional autophagy attenuates hyperinflammatory responses from cystic fibrosis cells. J. Immunol. 2013; 190: 1227-1238.
48. Ringholz FC, Buchanan PJ, Clarke DT, Millar RG, McDermott M, Linnane B, Harvey BJ, McNally P, Urbach V,. Reduced 15-lipoxygenase 2 and lipoxin A4/leukotriene B4 ratio in children with cystic fibrosis. Eur. Respir. J. 2014; 44: 394-404.
49. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 18825-18830.
50. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 2011; 365: 1663-1672.
51. Van Goor F, Hadida S, Grootenhuis PD, Burton B, Stack JH, Straley KS, Decker CJ, Miller M, McCartney J, Olson ER, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 18843-18848.
52. Ong T, Ramsey BW,. Modifying disease in cystic fibrosis: current and future therapies on the horizon. Curr. Opin. Pulm. Med. 2013; 19: 645-651.
53. Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, et al. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N. Engl. J. Med. 2003; 349: 1433-1441.
54. Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008; 372: 719-727.
55. Cheng K, Ashby D, Smyth RL,. Oral steroids for long-term use in cystic fibrosis. Cochrane Database Syst. Rev. 1999; (6): CD000407.
56. De Boeck K, Vermeulen F, Wanyama S, Thomas M,. Inhaled corticosteroids and lower lung function decline in young children with cystic fibrosis. Eur. Respir. J. 2011; 37: 1091-1095.
57. Balfour-Lynn IM, Lees B, Hall P, Phillips G, Khan M, Flather M, Elborn JS,. Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2006; 173: 1356-1362.
58. Lands LC, Stanojevic S,. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database Syst. Rev. 2013; (6): CD001505.
59. Konstan MW,. Ibuprofen therapy for cystic fibrosis lung disease: revisited. Curr. Opin. Pulm. Med. 2008; 14: 567-573.
60. Kanoh S, Rubin BK,. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin. Microbiol. Rev. 2010; 23: 590-615.
61. Saiman L, Anstead M, Mayer-Hamblett N, Lands LC, Kloster M, Hocevar-Trnka J, Goss CH, Rose LM, Burns JL, Marshall BC, et al. Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2010; 303: 1707-1715.
62. Nick JA, Moskowitz SM, Chmiel JF, Forssen AV, Kim SH, Saavedra MT, Saiman L, Taylor-Cousar JL, Nichols DP,. Azithromycin may antagonize inhaled tobramycin when targeting Pseudomonas aeruginosa in cystic fibrosis. Ann. Am. Thorac. Soc. 2014; 11: 342-350.
63. Tarran R, Sabater JR, Clarke TC, Tan CD, Davies CM, Liu J, Yeung A, Garland AL, Stutts MJ, Abraham WM, et al. Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion. Am. J. Physiol. Lung Cell. Mol. Physiol. 2013; 304: L746-756.
64. Ollero M, Junaidi O, Zaman MM, Tzameli I, Ferrando AA, Andersson C, Blanco PG, Bialecki E, Freedman SD,. Decreased expression of peroxisome proliferator activated receptor gamma in cftr-/- mice. J. Cell. Physiol. 2004; 200: 235-244.
65. Perez A, van Heeckeren AM, Nichols D, Gupta S, Eastman JF, Davis PB,. Peroxisome proliferator-activated receptor-gamma in cystic fibrosis lung epithelium. Am. J. Physiol. Lung Cell. Mol. Physiol. 2008; 295: L303-313.
66. Konstan MW, Krenicky J, Hilliard K, Hilliard JB,. A pilot study evaluating the effect of poiglitazone, simvastatin, and ibuprofen on neutrophil migration in vivo in healthy subjects. Pediatr. Pulmonol. 2009; 44: 289-290.
67. Griese M, Latzin P, Kappler M, Weckerle K, Heinzlmaier T, Bernhardt T, Hartl D,. alpha1-Antitrypsin inhalation reduces airway inflammation in cystic fibrosis patients. Eur. Respir. J. 2007; 29: 240-250.
68. Grimbert D, Vecellio L, Delepine P, Attucci S, Boissinot E, Poncin A, Gauthier F, Valat C, Saudubray F, Antonioz P, et al. Characteristics of EPI-hNE4 aerosol: a new elastase inhibitor for treatment of cystic fibrosis. J. Aerosol Med. 2003; 16: 121-129.
69. Weaver LT, Green MR, Nicholson K, Mills J, Heeley ME, Kuzemko JA, Austin S, Gregory GA, Dux AE, Davis JA,. Prognosis in cystic fibrosis treated with continuous flucloxacillin from the neonatal period. Arch. Dis. Child. 1994; 70: 84-89.
70. Ranganathan SC, Parsons F, Gangell C, Brennan S, Stick SM, Sly PD,. Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis. Thorax 2011; 66: 408-413.
71. Stutman HR, Lieberman JM, Nussbaum E, Marks MI,. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial. J. Pediatr. 2002; 140: 299-305.
72. Pier GB, Boyer D, Preston M, Coleman FT, Llosa N, Mueschenborn-Koglin S, Theilacker C, Goldenberg H, Uchin J, Priebe GP, et al. Human monoclonal antibodies to Pseudomonas aeruginosa alginate that protect against infection by both mucoid and nonmucoid strains. J. Immunol. 2004; 173: 5671-5678.
73. Rowe SM, Heltshe SL, Gonska T, Donaldson SH, Borowitz D, Gelfond D, Sagel SD, Khan U, Mayer-Hamblett N, Van Dalfsen JM, et al. Network GIotCFFTD. Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am. J. Respir. Crit. Care Med. 2014; 190: 175-184.
74. Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King M, Edwards LJ, Helms RW, Boucher RC,. A pilot study of aerosolized amiloride for the treatment of lung disease in cystic fibrosis. N. Engl. J. Med. 1990; 322: 1189-1194.
75. Graham A, Hasani A, Alton EW, Martin GP, Marriott C, Hodson ME, Clarke SW, Geddes DM,. No added benefit from nebulized amiloride in patients with cystic fibrosis. Eur. Respir. J. 1993; 6: 1243-1248.
76. Pons G, Marchand MC, d'Athis P, Sauvage E, Foucard C, Chaumet-Riffaud P, Sautegeau A, Navarro J, Lenoir G,. French multicenter randomized double-blind placebo-controlled trial on nebulized amiloride in cystic fibrosis patients. The Amiloride-AFLM Collaborative Study Group. Pediatr. Pulmonol. 2000; 30: 25-31.
77. Mall MA,. Role of the amiloride-sensitive epithelial Na+ channel in the pathogenesis and as a therapeutic target for cystic fibrosis lung disease. Exp. Physiol. 2009; 94: 171-174.
78. Hirsh AJ, Zhang J, Zamurs A, Fleegle J, Thelin WR, Caldwell RA, Sabater JR, Abraham WM, Donowitz M, Cha B, et al. Pharmacological properties of N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N-4-[4-(2,3-dihydroxypropoxy)phenyl] butyl-guanidine methanesulfonate (552-02), a novel epithelial sodium channel blocker with potential clinical efficacy for cystic fibrosis lung disease. J. Pharmacol. Exp. Ther. 2008; 325: 77-88.
79. Deterding RR, Lavange LM, Engels JM, Mathews DW, Coquillette SJ, Brody AS, Millard SP, Ramsey BW,. Phase 2 randomized safety and efficacy trial of nebulized denufosol tetrasodium in cystic fibrosis. Am. J. Respir. Crit. Care Med. 2007; 176: 362-369.
80. Donaldson SH, Galietta L,. New pulmonary therapies directed at targets other than CFTR. Cold Spring Harb. Perspect. Med. 2013; 3: pii: a009787.
81. Daviskas E, Anderson SD, Jaques A, Charlton B,. Inhaled mannitol improves the hydration and surface properties of sputum in patients with cystic fibrosis. Chest 2010; 137: 861-868.
82. Rosenfeld M, Ratjen F, Brumback L, Daniel S, Rowbotham R, McNamara S, Johnson R, Kronmal R, Davis SD,. Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 2012; 307: 2269-2277.
83. Subbarao P, Stanojevic S, Brown M, Jensen R, McDonald N, Gent K, Davis SD, Rosenfeld M, Gustafsson P, Ratjen F,. Effects of hypertonic saline on lung clearance index in infants and preschool children with CF: a pilot study. Am. J. Respir. Crit. Care Med. 2013; 188: 456-460.
84. Paul K, Rietschel E, Ballmann M, Griese M, Worlitzsch D, Shute J, Chen C, Schink T, Doring G, van Koningsbruggen S, et al., Bronchoalveolar Lavage for the Evaluation of Antiinflammatory Treatment Study Group. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2004; 169: 719-725.
85. Jones AP, Wallis C,. Dornase alfa for cystic fibrosis. Cochrane Database Syst. Rev. 2010; (3): CD001127.
86. Nasr SZ, Kuhns LR, Brown RW, Hurwitz ME, Sanders GM, Strouse PJ,. 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.
87. Ramsey KA, Rosenow T, Skoric B, Adams A, Gallagher CM, Banton GL, Murray C, Ranganathan S, Stick SM, Hall GL,. The ability of the lung clearance index to detect bronchiectasis on chest computed tomography in infants and children with cystic fibrosis. Pediatr. Pulmonol. 2014; S49: 359.
88. Stick S, Tiddens H, Aurora P, Gustafsson P, Ranganathan S, Robinson P, Rosenfeld M, Sly P, Ratjen F,. Early intervention studies in infants and preschool children with cystic fibrosis: are we ready? Eur. Respir. J. 2013; 42: 527-538.