Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients

Philip E. Silkoff, Michel Laviolette, Dave Singh, J. Mark FitzGerald, Steven Kelsen, Vibeke Backer, Celeste M. Porsbjerg, Pierre Olivier Girodet, Patrick Berger, Joel N. Kline, Geoffrey Chupp, Vedrana S. Susulic, Elliot S. Barnathan, Frédéric Baribaud, Matthew J. Loza, I. Strambu, S. Lam, A. Eich, A. Ludwig-Sengpiel, R. Leigh & 4 others M. Dransfield, William Calhoun, A. Hussaini, P. Chanez

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (FENO) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had FENO values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of FENO values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of FENO values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

Original languageEnglish (US)
Pages (from-to)710-719
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume140
Issue number3
DOIs
StatePublished - Sep 1 2017

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Asthma
Eosinophils
Biomarkers
Inflammation
Nitric Oxide
Gene Expression
Healthy Volunteers
Serum
Interleukin-13
Patient Selection
Therapeutics
Cell Count
Cell Line
Population
Genes

Keywords

  • airway mucosal gene expression
  • Asthma
  • biomarkers
  • phenotypes
  • type 2 inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Silkoff, P. E., Laviolette, M., Singh, D., FitzGerald, J. M., Kelsen, S., Backer, V., ... Chanez, P. (2017). Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. Journal of Allergy and Clinical Immunology, 140(3), 710-719. https://doi.org/10.1016/j.jaci.2016.11.038

Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. / Silkoff, Philip E.; Laviolette, Michel; Singh, Dave; FitzGerald, J. Mark; Kelsen, Steven; Backer, Vibeke; Porsbjerg, Celeste M.; Girodet, Pierre Olivier; Berger, Patrick; Kline, Joel N.; Chupp, Geoffrey; Susulic, Vedrana S.; Barnathan, Elliot S.; Baribaud, Frédéric; Loza, Matthew J.; Strambu, I.; Lam, S.; Eich, A.; Ludwig-Sengpiel, A.; Leigh, R.; Dransfield, M.; Calhoun, William; Hussaini, A.; Chanez, P.

In: Journal of Allergy and Clinical Immunology, Vol. 140, No. 3, 01.09.2017, p. 710-719.

Research output: Contribution to journalArticle

Silkoff, PE, Laviolette, M, Singh, D, FitzGerald, JM, Kelsen, S, Backer, V, Porsbjerg, CM, Girodet, PO, Berger, P, Kline, JN, Chupp, G, Susulic, VS, Barnathan, ES, Baribaud, F, Loza, MJ, Strambu, I, Lam, S, Eich, A, Ludwig-Sengpiel, A, Leigh, R, Dransfield, M, Calhoun, W, Hussaini, A & Chanez, P 2017, 'Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients', Journal of Allergy and Clinical Immunology, vol. 140, no. 3, pp. 710-719. https://doi.org/10.1016/j.jaci.2016.11.038
Silkoff, Philip E. ; Laviolette, Michel ; Singh, Dave ; FitzGerald, J. Mark ; Kelsen, Steven ; Backer, Vibeke ; Porsbjerg, Celeste M. ; Girodet, Pierre Olivier ; Berger, Patrick ; Kline, Joel N. ; Chupp, Geoffrey ; Susulic, Vedrana S. ; Barnathan, Elliot S. ; Baribaud, Frédéric ; Loza, Matthew J. ; Strambu, I. ; Lam, S. ; Eich, A. ; Ludwig-Sengpiel, A. ; Leigh, R. ; Dransfield, M. ; Calhoun, William ; Hussaini, A. ; Chanez, P. / Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. In: Journal of Allergy and Clinical Immunology. 2017 ; Vol. 140, No. 3. pp. 710-719.
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abstract = "Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (FENO) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had FENO values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36{\%}) of subjects with low airway mucosal CCL26 expression. A combination of FENO values, bEOS counts, and serum CCL17 and CCL26 expression had 100{\%} positive predictive value and 87{\%} negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of FENO values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.",
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T1 - Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients

AU - Silkoff, Philip E.

AU - Laviolette, Michel

AU - Singh, Dave

AU - FitzGerald, J. Mark

AU - Kelsen, Steven

AU - Backer, Vibeke

AU - Porsbjerg, Celeste M.

AU - Girodet, Pierre Olivier

AU - Berger, Patrick

AU - Kline, Joel N.

AU - Chupp, Geoffrey

AU - Susulic, Vedrana S.

AU - Barnathan, Elliot S.

AU - Baribaud, Frédéric

AU - Loza, Matthew J.

AU - Strambu, I.

AU - Lam, S.

AU - Eich, A.

AU - Ludwig-Sengpiel, A.

AU - Leigh, R.

AU - Dransfield, M.

AU - Calhoun, William

AU - Hussaini, A.

AU - Chanez, P.

PY - 2017/9/1

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N2 - Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (FENO) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had FENO values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of FENO values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of FENO values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

AB - Background The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects. Objective We explored this data set to define type 2 inflammation based on airway mucosal IL-13–driven gene expression and how this related to clinically accessible biomarkers. Methods IL-13–driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (FENO) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression. Results Expression of airway mucosal CCL26, periostin, and IL-13–IVS all facilitated segregation of subjects into type 2–high and type 2–low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had FENO values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm3) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of FENO values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26–high status. Clinical variables did not differ between subjects with type 2–high and type 2–low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression. Conclusion A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13–IVS gene expression. Use of FENO values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

KW - airway mucosal gene expression

KW - Asthma

KW - biomarkers

KW - phenotypes

KW - type 2 inflammation

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