Serum periostin is associated with type 2 immunity in severe asthma (2016)

Periostin is an extracellular matrix protein that is upregulated by type 2 cytokines IL-4 and IL-13 in bronchial epithelial cells and lung fibroblasts, is deposited widely in the airway of subjects with asthma, and is one of the most differentially expressed bronchial epithelial genes between patients with asthma and healthy control subjects.1Woodruff P.G. Boushey H.A. Dolganov G.M. Barker C.S. Yang Y.H. Donnelly S. et al.Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids.Proc Natl Acad Sci U S A. 2007; 104: 15858-15863Crossref PubMed Scopus (652) Google Scholar Periostin is particularly highly expressed in patients identified as TH2-high or type 2-high subjects.2Jia G. Erickson R.W. Choy D.F. Mosesova S. Wu L.C. Solberg O.D. et al.Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.J Allergy Clin Immunol. 2012; 130: 647-654.e10Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar High levels of serum periostin are associated with high numbers of sputum and tissue eosinophils in asthma,2Jia G. Erickson R.W. Choy D.F. Mosesova S. Wu L.C. Solberg O.D. et al.Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.J Allergy Clin Immunol. 2012; 130: 647-654.e10Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar with increased clinical benefit from anti–IL-13 treatment3Corren J. Lemanske R.F. Hanania N.A. Korenblat P.E. Parsey M.V. Arron J.R. et al.Lebrikizumab treatment in adults with asthma.N Engl J Med. 2011; 365: 1088-1098Crossref PubMed Scopus (1337) Google Scholar and with decline in lung function and exacerbations in patients with elevated fraction of exhaled nitric oxide (Feno).4Nagasaki T. Matsumoto H. Kanemitsu Y. Izuhara K. Tohda Y. Horiguchi T. et al.Using exhaled nitric oxide and serum periostin as a composite marker to identify severe/steroid-insensitive asthma.Am J Respir Crit Care Med. 2014; 190: 1449-1452Crossref PubMed Scopus (48) Google Scholar Plasma periostin does not change after allergen challenge, indicating that periostin is a marker of chronic (and not acute) airway inflammation.5James A. Gomes A. Daham K. Ono J. Ohta S. Dahlen B. et al.Effect of allergen challenge on two novel biomarkers of airway inflammation, periostin and YKL-40, in atopic asthmatic patients.Am J Respir Crit Care Med. 2014; (American Thoracic Society meeting abstract): A4244Google Scholar Mice lacking periostin have been reported to respond to lung challenge with significantly decreased numbers of eosinophils in the lung and increased numbers in blood.6Blanchard C. Mingler M.K. McBride M. Putnam P.E. Collins M.H. Chang G. et al.Periostin facilitates eosinophil tissue infiltration in allergic lung and esophageal responses.Mucosal Immunol. 2008; 1: 289-296Crossref PubMed Scopus (215) Google Scholar In vitro, periostin supports adhesion and migration of IL-5–stimulated human eosinophils.7Johansson M.W. Annis D.S. Mosher D.F. Alpha(M)beta(2) integrin-mediated adhesion and motility of IL-5-stimulated eosinophils on periostin.Am J Respir Cell Mol Biol. 2013; 48: 503-510Crossref PubMed Scopus (97) Google Scholar Together, these studies indicate that periostin is a type 2 immunity high–related protein that promotes eosinophil recruitment to the airway in asthma. Although the relationship between periostin and type 2 inflammation is reasonably well established, its association with asthma severity has not been demonstrated. To address this question, we analyzed serum periostin in 153 subjects who were recruited at the University of Wisconsin to participate in the National Heart, Lung, and Blood Institute's Severe Asthma Research Program (SARP).8Jarjour N.N. Erzurum S.C. Bleecker E.R. Calhoun W.J. Castro M. Comhair S.A. et al.Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.Am J Respir Crit Care Med. 2012; 185: 356-362Crossref PubMed Scopus (212) Google Scholar Participants included patients with American Thoracic Society–defined severe asthma (n = 51)9Sorkness R.L. Bleecker E.R. Busse W.W. Calhoun W.J. Castro M. Chung K.F. et al.Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation.J Appl Physiol. 2008; 104: 394-403Crossref PubMed Scopus (155) Google Scholar or nonsevere asthma (n = 75), and normal subjects (n = 27). Our study subjects (see Table E1 in this article's Online Repository at www.jacionline.org) are a well-characterized population.8Jarjour N.N. Erzurum S.C. Bleecker E.R. Calhoun W.J. Castro M. Comhair S.A. et al.Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program.Am J Respir Crit Care Med. 2012; 185: 356-362Crossref PubMed Scopus (212) Google Scholar Subjects were screened and enrolled at the University of Wisconsin as before,9Sorkness R.L. Bleecker E.R. Busse W.W. Calhoun W.J. Castro M. Chung K.F. et al.Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation.J Appl Physiol. 2008; 104: 394-403Crossref PubMed Scopus (155) Google Scholar according to a protocol approved by the University of Wisconsin-Madison Health Sciences Institutional Review Board. Informed written consent was obtained from each subject. Serum periostin was analyzed using the clinical trial version of the Elecsys Periostin assay (Roche Diagnostics, Penzberg, Germany) intended for use on the Cobas e 601. The Elecsys Periostin assay is an automated electrochemiluminescence immunoassay, based on the sandwich principle. Sample analysis was performed in a blind fashion; that is, the status of the subject was not known to the laboratory staff at the time of sample analysis. Other assessments were performed as before (see Table E1). We found that serum periostin was not significantly different among the groups with severe, nonsevere, and no asthma (Table I; Fig 1, A). Furthermore, periostin was not significantly different between patients with severe asthma on or off oral corticosteroids (OCS; median [25th, 75th percentiles] on OCS = 54 ng/mL [38, 61], off OCS = 54 ng/mL [48, 68]; P = .29) or between patients with nonsevere asthma on or off inhaled corticosteroids (ICS; on ICS = 53 ng/mL [44, 59], off ICS = 58 ng/mL [46, 66]; P = .14). Blood eosinophil percentage and counts per volume, sputum eosinophil percentage, Feno, and serum IgE levels were higher in patients with asthma than in healthy controls, but were not significantly different between patients with severe and nonsevere asthma (Table I). Because all these parameters are features of type 2 immunity,2Jia G. Erickson R.W. Choy D.F. Mosesova S. Wu L.C. Solberg O.D. et al.Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients.J Allergy Clin Immunol. 2012; 130: 647-654.e10Abstract Full Text Full Text PDF PubMed Scopus (488) Google Scholar we determined a type 2 immunity composite score for the patients with asthma consisting of the 4 parameters blood eosinophil percentage, sputum eosinophil percentage, Feno, and IgE levels, as described in this article's Online Repository. The type 2 immunity composite score was not significantly different between severe and nonsevere asthma (Table I).Table ISerum periostin level, IgE level, eosinophil and neutrophil numbers, Feno, and type 2 immunity composite score in subjects with severe, nonsevere, or no asthmaVariableGroupSevere asthmaNonsevere asthmaNo asthman517527Periostin (ng/mL)54 (46, 62)53 (44, 62)49 (46, 65)IgE (IU/mL)160 (80, 350)∗P ≤ .001 versus no asthma.170 (80, 310)∗P ≤ .001 versus no asthma.10 (6, 18)Blood eosinophils (%)3.0 (1.7, 4.7)†P ≤ .05 versus no asthma.3.1 (2.0, 5.0)∗P ≤ .001 versus no asthma.2.0 (1.0, 3.0)Blood eosinophils (cells/μL)170 (100, 300)†P ≤ .05 versus no asthma.190 (120, 300)∗P ≤ .001 versus no asthma.110 (70, 150)Blood neutrophils (%)58 (53, 68)58 (51, 63)58 (55, 62)Blood neutrophils (cells/μL)3800 (2600, 5000)3400 (2700, 4200)3300 (2600, 4300)Sputum eosinophils (%), n = 49 + 73 + 26‡A total of 36% of patients with severe asthma and 33% of patients with nonsevere asthma had >2% sputum eosinophils; 23% of patients with severe asthma and 22% of patients with nonsevere asthma had >3% sputum eosinophils.0.7 (0.0, 3.0)∗P ≤ .001 versus no asthma.1.0 (0.0, 2.9)∗P ≤ .001 versus no asthma.0.0 (0.0, 0.5)Sputum neutrophils (%), n = 49 + 73 + 2644 (32, 63)†P ≤ .05 versus no asthma.§P ≤ .05 versus nonsevere asthma.31 (16, 49)28 (19, 50)Feno (ppb), n = 46 + 63 + 2619 (13, 31)∗P ≤ .001 versus no asthma.26 (16, 39)∗P ≤ .001 versus no asthma.13 (9, 15)Type 2 immunity composite score−0.2 (−1.0, 0.7)0.1 (−0.8, 0.9)—Data are presented as median (25th, 75th percentiles). In the case of missing data, the number of subjects with available data is indicated. IgE level, cell counts, and Feno were assessed as mentioned in Table E1 legend. Type 2 immunity composite score for patients with asthma was determined as described in this article's Online Repository at www.jacionline.org.IU, International unit; ppb, parts per billion.∗ P ≤ .001 versus no asthma.† P ≤ .05 versus no asthma.‡ A total of 36% of patients with severe asthma and 33% of patients with nonsevere asthma had >2% sputum eosinophils; 23% of patients with severe asthma and 22% of patients with nonsevere asthma had >3% sputum eosinophils.§ P ≤ .05 versus nonsevere asthma. Open table in a new tab Data are presented as median (25th, 75th percentiles). In the case of missing data, the number of subjects with available data is indicated. IgE level, cell counts, and Feno were assessed as mentioned in Table E1 legend. Type 2 immunity composite score for patients with asthma was determined as described in this article's Online Repository at www.jacionline.org. IU, International unit; ppb, parts per billion. We next asked whether serum periostin correlated with any of the 4 parameters or the type 2 immunity composite score, analyzing all patients with asthma together or just patients with severe or nonsevere asthma. We found that higher serum periostin levels were associated with increased blood eosinophils, Feno, and type 2 immunity composite score in all those with asthma and severe asthma, whereas these correlations did not reach significance for those with nonsevere asthma (Fig 1, B-D). When the correlations were adjusted for age, race/ethnicity, and sex, similar P values were obtained compared with before adjustment (with blood eosinophil percentage: P = .04 in all asthma, P = .03 in severe asthma, P = .44 in nonsevere asthma; with Feno: P = .05 in all asthma, P = .02 in severe asthma, P = .90 in nonsevere asthma; with type 2 immunity composite score: P = .06 in all asthma, P = .03 in severe asthma, P = .65 in nonsevere asthma). Our significant correlation between serum periostin and Feno in all or severe, but not nonsevere, asthma (Fig 1, C) is similar to the finding by Nagasaki et al4Nagasaki T. Matsumoto H. Kanemitsu Y. Izuhara K. Tohda Y. Horiguchi T. et al.Using exhaled nitric oxide and serum periostin as a composite marker to identify severe/steroid-insensitive asthma.Am J Respir Crit Care Med. 2014; 190: 1449-1452Crossref PubMed Scopus (48) Google Scholar that serum periostin correlated with Feno and did so most strongly in patients undergoing treatment step 5 as described by the Global Initiative for Asthma.4Nagasaki T. Matsumoto H. Kanemitsu Y. Izuhara K. Tohda Y. Horiguchi T. et al.Using exhaled nitric oxide and serum periostin as a composite marker to identify severe/steroid-insensitive asthma.Am J Respir Crit Care Med. 2014; 190: 1449-1452Crossref PubMed Scopus (48) Google Scholar Associations between periostin and sputum eosinophils or IgE levels did not reach significance in our study (with sputum eosinophils: rs = 0.07, P = .46 in all asthma; rs = 0.17, P = .24 in severe asthma; rs = −0.02, P = .89 in nonsevere asthma; with IgE levels: rs = 0.01, P = .89 in all asthma, rs = 0.07, P = .62 in severe asthma, rs = −0.08, P = .48 in nonsevere asthma). Feno or blood eosinophils correlated with sputum eosinophils in all, severe, and nonsevere asthma (Feno: rs = 0.39, P < .0001 in all asthma; rs = 0.33, P < .03 in severe asthma; rs = 0.35, P < .005 in nonsevere asthma; blood eosinophil percentage: rs = 0.39, P < .0001 in all asthma; rs = 0.51, P = .0002 in severe asthma; rs = 0.33, P = .004 in nonsevere asthma; blood eosinophil concentration; rs = 0.39, P < .0001 in all asthma, rs = 0.46, P = .0008 in severe asthma; rs = 0.34, P = .003 in nonsevere asthma). In summary, we first found that serum periostin level was not significantly different among the 3 groups of severe, nonsevere, and no asthma in a SARP subject population. Furthermore, periostin correlated with blood eosinophils, Feno, or a type 2 immunity composite score in all and severe asthma. Thus, our results from a well-characterized subject population, including patients with very severe disease, demonstrate that serum periostin level is not associated with asthma severity, but corroborates the hypothesis that periostin is associated with type 2 immunity in patients who are symptomatic despite their use of corticosteroids and offer support for the use of serum periostin as a marker of systemic type 2 immunity–driven mechanisms, suggesting greater responsiveness to type 2 immunity–based therapies, for example, anti–IL-13 treatment, in asthma.3Corren J. Lemanske R.F. Hanania N.A. Korenblat P.E. Parsey M.V. Arron J.R. et al.Lebrikizumab treatment in adults with asthma.N Engl J Med. 2011; 365: 1088-1098Crossref PubMed Scopus (1337) Google Scholar, 10Scheerens H. Arron J.R. Zheng Y. Putnam W.S. Erickson R.W. Choy D.F. et al.The effects of lebrikizumab in patients with mild asthma following whole lung allergen challenge.Clin Exp Allergy. 2014; 44: 38-46Crossref PubMed Scopus (99) Google Scholar We thank Daniel Kolk, Erin Billmeyer, and Holly Eversoll for patient recruitment, screening, and assessments; Katie Popp, Helen Werner, and Jami Hauer for preparing serum samples; Meghana Handigol for coordinating serum periostin measurements; Ronald Sorkness for providing assessment data; Elizabeth Kelly and Monica Gavala for summarizing data and information and for discussions; Deane Mosher for suggestions and discussions; and William Busse for leadership of SARP and input into the manuscript. Type 2 immunity composite score for patients with asthma was determined as follows: Type 2 score = 0.512 × Zblood eos + 0.558 × Zsputum eos + 0.529 × ZFeno + 0.382 × ZIgE, where Zmeasurement is the Z score (mean = 0, SD = 1) of the log-transformed measurement. The coefficients (0.512, etc) were determined by principal-component analysis, used here as a dimensionality-reduction method to represent 4 positively correlated measurements by a single score (first principal component), which is positively correlated with all 4 measurements but is expected to be more informative (higher signal-to-noise ratio) than an individual measurement. Missing Feno and sputum eosinophil values were addressed using principal-component analysis–based imputation .E1Josse J. Husson F. Handling missing values in exploratory multivariate data analysis methods.J de la SFdS. 2013; 153: 79-99Google ScholarTable E1Subjects' characteristicsVariableGroupSevere asthmaNonsevere asthmaNo asthman517527Sex (F, M)25, 2632, 43∗P ≤ .01 versus no asthma.19, 8Age (y)43 (34, 51)†P ≤ .001 versus nonsevere asthma.‡P ≤ .001 versus no asthma.23 (20, 36)§P ≤ .05 versus no asthma.21 (20, 22)Race/ethnicity (white non-Hispanic, black, Asian American, Native American, Hispanic)38, 12, 1, 0, 0∗P ≤ .01 versus no asthma.61, 8, 3, 1, 223, 0, 1, 0, 3FEV1 (% predicted)66 (56, 82)†P ≤ .001 versus nonsevere asthma.‡P ≤ .001 versus no asthma.89 (79, 100)‡P ≤ .001 versus no asthma.101 (94, 108)FEV1/FVC (% predicted), n = 51 + 75 + 2583 (70, 92)‡P ≤ .001 versus no asthma.P ≤ .01 versus nonsevere asthma.90 (81, 96)‡P ≤ .001 versus no asthma.100 (93, 104)FVC (% predicted), n = 51 + 75 + 2680 (72, 94)†P ≤ .001 versus nonsevere asthma.‡P ≤ .001 versus no asthma.101 (90, 107)102 (96, 111)PC20 (mg/mL), n = 37 + 73 + 272.4 (0.9, 5.7)‡P ≤ .001 versus no asthma.2.0 (0.8, 7.4)‡P ≤ .001 versus no asthma.50 (50, 50)AQLQ score, n = 47 + 664.6 (3.6, 5.3)†P ≤ .001 versus nonsevere asthma.5.6 (5.0, 5.9)—Years of asthma, n = 44 + 7520 (14, 29)¶P ≤ .05 versus nonsevere asthma.15 (10, 24)—Age of onset (y), n = 48 + 7513 (5, 30)¶P ≤ .05 versus nonsevere asthma.9 (4, 14)—n on ICS51†P ≤ .001 versus nonsevere asthma.‡P ≤ .001 versus no asthma.50‡P ≤ .001 versus no asthma.0n on OCS#OCS for subjects with severe asthma: n on 1-10 mg/d = 3, 11-20 mg/d = 3, 21-30 mg/d = 0, 31-40 mg/d = 1, 21-30 mg twice daily = 1, unrecorded dose daily = 4, once per month = 4; for subjects with nonsevere asthma: n on 11-20 mg/d = 2. Assessments were performed as before.E2-E416†P ≤ .001 versus nonsevere asthma.‡P ≤ .001 versus no asthma.20ICS dose (μg/d)1000 (1000, 1000)†P ≤ .001 versus nonsevere asthma.‡P ≤ .001 versus no asthma.250 (0, 500)‡P ≤ .001 versus no asthma.0 (0, 0)Data are presented as median (25th, 75th percentiles). In the case of missing data, the number of subjects with available data is indicated.AQLQ, Asthma quality of life questionnaire; F, female; FVC, forced vital capacity; ICS, inhaled corticosteroid; M, male; OCS, oral corticosteroid; PC20, provocative concentration of methacholine producing a 20% fall in FEV1.∗ P ≤ .01 versus no asthma.† P ≤ .001 versus nonsevere asthma.‡ P ≤ .001 versus no asthma.§ P ≤ .05 versus no asthma.|| P ≤ .01 versus nonsevere asthma.¶ P ≤ .05 versus nonsevere asthma.# OCS for subjects with severe asthma: n on 1-10 mg/d = 3, 11-20 mg/d = 3, 21-30 mg/d = 0, 31-40 mg/d = 1, 21-30 mg twice daily = 1, unrecorded dose daily = 4, once per month = 4; for subjects with nonsevere asthma: n on 11-20 mg/d = 2. Assessments were performed as before.E2Sorkness R.L. Bleecker E.R. Busse W.W. Calhoun W.J. Castro M. Chung K.F. et al.Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation.J Appl Physiol. 2008; 104: 394-403Crossref PubMed Scopus (252) Google Scholar, E3Johansson M.W. Han S.-T. Gunderson K.A. Busse W.W. Jarjour N.N. Mosher D.F. Platelet activation, P-selectin, and eosinophil β1-integrin activation in asthma.Am J Respir Crit Care Med. 2012; 185: 498-507Crossref PubMed Scopus (77) Google Scholar, E4Johansson M.W. Kruger S.J. Schiebler M.L. Evans M.D. Sorkness R.L. Denlinger L.C. et al.Markers of vascular perturbation correlate with airway structural change in asthma.Am J Respir Crit Care Med. 2013; 188: 167-178Crossref PubMed Scopus (19) Google Scholar Open table in a new tab Data are presented as median (25th, 75th percentiles). In the case of missing data, the number of subjects with available data is indicated. AQLQ, Asthma quality of life questionnaire; F, female; FVC, forced vital capacity; ICS, inhaled corticosteroid; M, male; OCS, oral corticosteroid; PC20, provocative concentration of methacholine producing a 20% fall in FEV1.