Constrictive Bronchiolitis in Cystic Fibrosis Adolescents with Refractory Pulmonary Decline.
Refractory lung function decline in association with recurrent pulmonary exacerbations is a common, yet poorly explained finding in cystic fibrosis (CF). To investigate the histopathologic mechanisms of pulmonary deterioration during adolescence and early adulthood, we reviewed clinically-indicated lung biopsy specimens obtained during a period of persistent decline.



To determine if peribronchiolar remodeling is prominent in lung biopsy specimens obtained in adolescents with CF refractory to conventional therapy.



Six adolescents with CF (mean age, 16.2 y; mean FEV1, 52% predicted at biopsy) with significant pulmonary deterioration over 12-24 months (mean FEV1decline of 14% predicted/year) despite aggressive intervention underwent computed tomography imaging and ultimately lung biopsy to aid clinical management. In addition to routine clinical evaluation, histopathologic investigation included staining for transforming growth factor-β (TGF-β, a genetic modifier of CF lung disease), collagen deposition (a marker of fibrosis), elastin (to evaluate for bronchiectasis), and α-smooth muscle actin (to identify myofibroblasts).



All computed tomography scans demonstrated a mix of bronchiectasis and hyperinflation that was variable across lung regions and within patients. Lung biopsy revealed significant peribronchiolar remodeling, particularly in patients with more advanced disease, with near complete obliteration of the peribronchiolar lumen (constrictive bronchiolitis). Myofibroblast differentiation (a TGF-β-dependent process) was prominent in specimens with significant airway remodeling.



Constrictive bronchiolitis is widely present in the lung tissue of adolescents with CF with advanced disease and may contribute to impaired lung function that is refractory to conventional therapy (antibiotics, antiinflammatories, and mucolytics). TGF-β-dependent myofibroblast differentiation is prominent in areas of active fibrogenesis and may foster small airway remodeling in CF lung disease.
1 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.
William T
WT
Harris
2 Department of Pathology, Dayton Children's Hospital, Dayton, Ohio.
J Todd
JT
Boyd
3 Division of Pulmonary Medicine.
Gary L
GL
McPhail
4 Department of Radiology.
Alan S
AS
Brody
3 Division of Pulmonary Medicine.|5 Division of Biostatistics and Epidemiology, and.
Rhonda D
RD
Szczesniak
6 Office for Clinical and Translational Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; and.
Leslie L
LL
Korbee
7 Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio.
Michael L
ML
Baker
3 Division of Pulmonary Medicine.
John P
JP
Clancy
D000293:Adolescent; D056151:Airway Remodeling; D001989:Bronchiolitis Obliterans / Q000175:diagnosis* / Q000473:pathology*; D016022:Case-Control Studies; D002648:Child; D003550:Cystic Fibrosis / Q000150:complications* / Q000473:pathology*; D018450:Disease Progression; D004549:Elastin / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D058628:Myofibroblasts; D013147:Spirometry; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000378:metabolism; D055815:Young Adult
D016212:Transforming Growth Factor beta; D004549:Elastin
airway remodeling; constrictive bronchiolitis; cystic fibrosis; myofibroblast; transforming growth factor-β
Am J Respir Crit Care Med. 2016 Mar 1;193(5):516-26
26551917
J Pediatr. 2007 Aug;151(2):134-9, 139.e1
17643762
Am Rev Respir Dis. 1986 Aug;134(2):290-5
3740655
Am J Respir Cell Mol Biol. 2012 Sep;47(3):340-8
22461426
Chest. 1992 Jul;102(1 Suppl):38S-43S
1623809
Cold Spring Harb Perspect Med. 2012 Sep 01;2(9):a009589
22951447
Chest. 2002 Dec;122(6 Suppl):286S-289S
12475801
Am J Respir Crit Care Med. 1999 Jan;159(1):179-87
9872837
Thorax. 2007 Feb;62(2):153-61
16928707
Am J Respir Crit Care Med. 2002 Apr 15;165(8):1172-5
11956063
Ann Intern Med. 2001 Jan 16;134(2):136-51
11177318
Ann Diagn Pathol. 2008 Jun;12(3):171-80
18486892
N Engl J Med. 2015 Apr 16;372(16):1574-5
25875271
PLoS One. 2014 Sep 30;9(9):e106842
25268501
Proc Am Thorac Soc. 2006;3(1):41-7
16493150
Ann Epidemiol. 2013 Dec;23(12):771-7
24103586
Am J Respir Crit Care Med. 2005 Nov 15;172(10 ):1246-52
16100011
J Pediatr. 2004 Feb;144(2):145-6
14760248
N Engl J Med. 2005 Oct 6;353(14):1443-53
16207846
J Pediatr. 2004 Jul;145(1):32-8
15238903
Respir Res. 2010 Oct 06;11:137
20925941
Thorax. 2011 Aug;66(8):680-5
21680566
Eur Respir J. 2004 Jan;23 (1):93-7
14738238
JAMA. 2008 Jan 30;299(4):417-24
18230779
J Clin Invest. 2008 Mar;118(3):1040-9
18292811
Am J Respir Crit Care Med. 2006 Mar 1;173(5):475-82
16126935
Pediatr Pulmonol. 2009 Nov;44(11):1057-64
19830844
Annu Rev Pathol. 2013 Jan 24;8:241-76
23092186
Am J Respir Crit Care Med. 2010 Sep 1;182(5):627-32
20463179
Am J Pathol. 2009 Jul;175(1):3-16
19497999
Am J Respir Crit Care Med. 2003 Oct 15;168(8):918-51
14555458
Arch Pediatr Adolesc Med. 2010 Oct;164(10):957-60
20921354
Chest. 2005 Oct;128(4):2327-35
16236891
F1000 Med Rep. 2010 Apr 27;2:null
20948853
Eur Respir J. 2012 Jul;40(1):61-6
22135280
Eur Respir J. 2005 Aug;26(2):319-38
16055882
Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9448-53
22566629
Am J Physiol Lung Cell Mol Physiol. 2012 Aug 1;303(3):L169-80
22659883
Proc Am Thorac Soc. 2012 Jul;9(3):137-47
22802288
Am J Physiol Lung Cell Mol Physiol. 2015 Feb 15;308(4):L344-57
25502501
Matrix Biol. 2015 Sep;47:54-65
25960420
Am J Respir Crit Care Med. 2010 Nov 1;182(9):1137-43
20581166
Am J Pathol. 2007 Jun;170(6):1807-16
17525249
Pediatr Pulmonol. 2011 Apr;46(4):393-400
20967845
Pediatr Pulmonol. 2011 Jul;46(7):688-95
21337732
J Cyst Fibros. 2014 Jul;13(4):416-23
24388063
Thorax. 2007 Jul;62(7):638-49
17600295
Radiology. 1999 Nov;213(2):537-44
10551238
Thorax. 1968 Nov;23(6):670-5
5711776
Am J Respir Crit Care Med. 2014 Oct 15;190(8):898-905
25222938
PLoS One. 2013 May 09;8(5):e63167
23671668
PLoS One. 2013 Aug 12;8(8):e70196
23950911
Pediatr Pulmonol. 2010 Feb;45(2):127-34
20054859
Proc Am Thorac Soc. 2012 Jul;9(3):148-52
22802289
Am J Respir Crit Care Med. 2012 Nov 1;186(9):866-76
22936357
Chest. 2012 Feb;141(2):485-93
21835906
J Thorac Imaging. 2006 Mar;21(1):14-21
16538150