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Am. J. Respir. Crit. Care Med., Volume 160, Number 3, September 1999, 1001-1008

Evidence That Severe Asthma Can Be Divided Pathologically into Two Inflammatory Subtypes with Distinct Physiologic and Clinical Characteristics

SALLY E. WENZEL, LAWRENCE B. SCHWARTZ, ESTHER L. LANGMACK, JANET L. HALLIDAY, JOHN B. TRUDEAU, ROBYN L. GIBBS, and HONG WEI CHU

Departments of Medicine, Medical College of Virginia, Richmond, Virginia; and National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado

The mechanisms associated with the development of severe, corticosteroid (CS)-dependent asthma are poorly understood, but likely heterogenous. It was hypothesized that severe asthma could be divided pathologically into two inflammatory groups based on the presence or absence of eosinophils, and that the inflammatory subtype would be associated with distinct structural, physiologic, and clinical characteristics. Thirty-four severe, refractory CS-dependent asthmatics were evaluated with endobronchial biopsy, pulmonary function, allergy testing, and clinical history. Milder asthmatic and normal control subjects were also evaluated. Tissue cell types and subbasement membrane (SBM) thickness were evaluated immunohistochemically. Fourteen severe asthmatics [eosinophil (-)] had nearly absent eosinophils (< 2 SD from the normal mean). The remaining 20 severe asthmatics were categorized as eosinophil (+). Eosinophil (+) severe asthmatics had associated increases (p < 0.05) in lymphocytes (CD3+, CD4+, CD8+), mast cells, and macrophages. Neutrophils were increased in severe asthmatics and not different between the groups. The SBM was significantly thicker in eosinophil (+) severe asthmatics than eosinophil (-) severe asthmatics and correlated with eosinophil numbers (r = 0.50). Despite the absence of eosinophils and the thinner SBM, the FEV1 was marginally lower in eosinophil (-) asthmatics (p = 0.05) with no difference in bronchodilator response. The eosinophil (+) group (with a thicker SBM) had more intubations than the eosinophil (-) group (p = 0.0004). Interestingly, this group also had a decreased FVC/slow vital capacity (SVC). These results suggest that two distinct pathologic, physiologic, and clinical subtypes of severe asthma exist, with implications for further research and treatment.




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W. Busse, S. Banks-Schlegel, P. Noel, H. Ortega, V. Taggart, and J. Elias
Future Research Directions in Asthma: An NHLBI Working Group Report
Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 683 - 690.
[Abstract] [Full Text] [PDF]

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 Occup. Environ. Med.Home page
T Sjaheim, T S Halstensen, M B Lund, O Bjortuft, P A Drablos, D Malterud, and J Kongerud
Airway inflammation in aluminium potroom asthma
Occup. Environ. Med., September 1, 2004; 61(9): 779 - 785.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
N. S. Undevia, D. R. Dorscheid, B. A. Marroquin, W. L. Gugliotta, R. Tse, and S. R. White
Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-{beta}1 in human airway epithelial cells
Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L515 - L524.
[Abstract] [Full Text] [PDF]

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 Clin Med ResHome page
G. L. Colice
Categorizing Asthma Severity: An Overview of National Guidelines
Clin. Med. Res., August 1, 2004; 2(3): 155 - 163.
[Abstract] [Full Text] [PDF]

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 ChestHome page
J. Elias
The Relationship Between Asthma and COPD: Lessons From Transgenic Mice
Chest, August 1, 2004; 126(2_suppl_1): 111S - 116S.
[Abstract] [Full Text] [PDF]

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 ChestHome page
F. C. Sciurba
Physiologic Similarities and Differences Between COPD and Asthma
Chest, August 1, 2004; 126(2_suppl_1): 117S - 124S.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
M. Gaga
Fixed obstruction in severe asthma: not just a matter of time
Eur. Respir. J., July 1, 2004; 24(1): 8 - 10.
[Full Text] [PDF]

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 Eur Respir JHome page
D. Bumbacea, D. Campbell, L. Nguyen, D. Carr, P.J. Barnes, D. Robinson, and K.F. Chung
Parameters associated with persistent airflow obstruction in chronic severe asthma
Eur. Respir. J., July 1, 2004; 24(1): 122 - 128.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
C. Taube, J. A. Nick, B. Siegmund, C. Duez, K. Takeda, Y.-H. Rha, J.-W. Park, A. Joetham, K. Poch, A. Dakhama, et al.
Inhibition of Early Airway Neutrophilia Does Not Affect Development of Airway Hyperresponsiveness
Am. J. Respir. Cell Mol. Biol., June 1, 2004; 30(6): 837 - 843.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
S. Hazarika, M. R. Van Scott, and R. M. Lust
Myocardial ischemia-reperfusion injury is enhanced in a model of systemic allergy and asthma
Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1720 - H1725.
[Abstract] [Full Text] [PDF]

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 Proc Am Thorac SocHome page
D. C. Grootendorst and K. F. Rabe
Mechanisms of Bronchial Hyperreactivity in Asthma and Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, April 1, 2004; 1(2): 77 - 87.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
A. Pastva, K. Estell, T. R. Schoeb, T. P. Atkinson, and L. M. Schwiebert
Aerobic Exercise Attenuates Airway Inflammatory Responses in a Mouse Model of Atopic Asthma
J. Immunol., April 1, 2004; 172(7): 4520 - 4526.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
R. Gagliardo, P. Chanez, M. Mathieu, A. Bruno, G. Costanzo, C. Gougat, I. Vachier, J. Bousquet, G. Bonsignore, and A. M. Vignola
Persistent Activation of Nuclear Factor-{kappa}B Signaling Pathway in Severe Uncontrolled Asthma
Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1190 - 1198.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
P. Jeffery, S. Holgate, and S. Wenzel
Methods for the Assessment of Endobronchial Biopsies in Clinical Research: Application to Studies of Pathogenesis and the Effects of Treatment
Am. J. Respir. Crit. Care Med., September 15, 2003; 168(6): S1 - 17.
[Full Text] [PDF]

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 Eur Respir JHome page
S.E. Wenzel
A different disease, many diseases or mild asthma gone bad? Challenges of severe asthma
Eur. Respir. J., September 1, 2003; 22(3): 397 - 398.
[Full Text] [PDF]

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 Eur Respir JHome page
The ENFUMOSA Study Group
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma
Eur. Respir. J., September 1, 2003; 22(3): 470 - 477.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
D.S. Robinson, D.A. Campbell, S.R. Durham, J. Pfeffer, P.J. Barnes, and K.F. Chung
Systematic assessment of difficult-to-treat asthma
Eur. Respir. J., September 1, 2003; 22(3): 478 - 483.
[Abstract] [Full Text] [PDF]

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 ThoraxHome page
N J Kenyon, R W Ward, G McGrew, and J A Last
TGF-{beta}1 causes airway fibrosis and increased collagen I and III mRNA in mice
Thorax, September 1, 2003; 58(9): 772 - 777.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
A. Brown, K. Farmer, L. MacDonald, N. Kalsheker, D. Pritchard, C. Haslett, J. Lamb, and J.-M. Sallenave
House Dust Mite Der p 1 Downregulates Defenses of the Lung by Inactivating Elastase Inhibitors
Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): 381 - 389.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
A. C. Henderson, E. P. Ingenito, H. Atileh, E. Israel, B. Suki, and K. R. Lutchen
Selected Contribution: How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study
J Appl Physiol, August 1, 2003; 95(2): 873 - 882.
[Abstract] [Full Text] [PDF]

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 ChestHome page
H. A. Jenkins, C. Cool, S. J. Szefler, R. Covar, S. Brugman, E. W. Gelfand, and J. D. Spahn
Histopathology of Severe Childhood Asthma: A Case Series
Chest, July 1, 2003; 124(1): 32 - 41.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
S. Mukherjee and S. Baksi
Noneosinophilic asthma.
Eur. Respir. J., July 1, 2003; 22(1): 188 - 189.
[Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
G. S. Whitehead, J. K. L. Walker, K. G. Berman, W. M. Foster, and D. A. Schwartz
Allergen-induced airway disease is mouse strain dependent
Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L32 - L42.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
J. C. Kips, B. J. O'Connor, S. J. Langley, A. Woodcock, H. A. M. Kerstjens, D. S. Postma, M. Danzig, F. Cuss, and R. A. Pauwels
Effect of SCH55700, a Humanized Anti-Human Interleukin-5 Antibody, in Severe Persistent Asthma: A Pilot Study
Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1655 - 1659.
[Abstract] [Full Text] [PDF]

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 ThoraxHome page
C E Brightling, F A Symon, S S Birring, P Bradding, A J Wardlaw, and I D Pavord
Comparison of airway immunopathology of eosinophilic bronchitis and asthma
Thorax, June 1, 2003; 58(6): 528 - 532.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
L. Benayoun, A. Druilhe, M.-C. Dombret, M. Aubier, and M. Pretolani
Airway Structural Alterations Selectively Associated with Severe Asthma
Am. J. Respir. Crit. Care Med., May 15, 2003; 167(10): 1360 - 1368.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
S. H. Cho, Z. Yao, S.-W. Wang, R. F. Alban, R. G. Barbers, S. W. French, and C. K. Oh
Regulation of Activin A Expression in Mast Cells and Asthma: Its Effect on the Proliferation of Human Airway Smooth Muscle Cells
J. Immunol., April 15, 2003; 170(8): 4045 - 4052.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
C. Taube, A. Dakhama, Y.-H. Rha, K. Takeda, A. Joetham, J.-W. Park, A. Balhorn, T. Takai, K. R. Poch, J. A. Nick, et al.
Transient Neutrophil Infiltration After Allergen Challenge Is Dependent on Specific Antibodies and Fc{gamma}III Receptors
J. Immunol., April 15, 2003; 170(8): 4301 - 4309.
[Abstract] [Full Text] [PDF]

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 Eur Respir JHome page
H.A. Jones, P.S. Marino, B.H. Shakur, and N.W. Morrell
In vivo assessment of lung inflammatory cell activity in patients with COPD and asthma
Eur. Respir. J., April 1, 2003; 21(4): 567 - 573.
[Abstract] [Full Text] [PDF]

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 ChestHome page
S. Wenzel
Severe/Fatal Asthma
Chest, March 1, 2003; 123 (2009): 405S - 410S.
[Abstract] [Full Text] [PDF]

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 ChestHome page
A. M. Vignola, F. Mirabella, G. Costanzo, R. Di Giorgi, M. Gjomarkaj, V. Bellia, and G. Bonsignore
Airway Remodeling in Asthma
Chest, March 1, 2003; 123 (2009): 417S - 422S.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Cell Mol. Bio.Home page
M. A. Olman
Epithelial Cell Modulation of Airway Fibrosis in Asthma
Am. J. Respir. Cell Mol. Biol., February 1, 2003; 28(2): 125 - 128.
[Full Text] [PDF]


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