To the Editor
Periostin is an extracellular matrix protein that is upregulated by type 2 cytokines interleukin (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 asthmatic patients and healthy control subjects.1 Periostin is particularly highly expressed in patients identified as T helper cell type (Th) 2-high or type 2-high subjects.2 High levels of serum periostin are associated with high numbers of sputum and tissue eosinophils in asthma,2 with increased clinical benefit from anti-IL-13 treatment,3 and with decline in lung function and exacerbations in patients with elevated fraction of exhaled nitric oxide (FENO).4 Plasma periostin does not change after allergen challenge, indicating that periostin is a marker of chronic (and not acute) airway inflammation.5 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.6 In vitro, periostin supports adhesion and migration of IL-5-stimulated human eosinophils.7 Together, these studies indicate that periostin is a type 2 immunity high-related protein that promotes eosinophil recruitment to the airway in asthma.
While the relationship of periostin to 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 (NHLBI) Severe Asthma Research Program (SARP).8 Participants included patients with American Thoracic Society (ATS)-defined severe asthma (n=51)9 or non-severe asthma (n=75), and normal subjects (n=27). Our study subjects (see Table EI in this article’s Online Repository at www.jacionline.org) are a well-characterized population.8 Subjects were screened and enrolled at the University of Wisconsin as before,9 according to a protocol approved by the UW-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, i.e., 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 EI).
We found that serum periostin was not significantly different among the groups of severe, non-severe, and no asthma (Table I, Fig 1A). Further, 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 = 0.29) or between patients with non-severe asthma on or off inhaled corticosteroids (ICS; on ICS = 53 ng/ml [44, 59], off ICS = 58 ng/ml [46, 66], P = 0.14). Blood eosinophil percentage and counts per volume, sputum eosinophil percentage, FENO, and serum immunoglobulin (Ig) E levels were higher in patients with asthma than in healthy controls, but were not significantly different between patients with severe and non-severe asthma (Table I). As these parameters all are features of type 2 immunity,2 we determined a type 2 immunity composite score for the patients with asthma consisting of the four parameters blood eosinophil percentage, sputum eosinophil percentage, FENO, and IgE, as described in the Online Repository. The type 2 immunity composite score was not significantly different between severe and non-severe asthma (Table I).
TABLE I.
Serum periostin, IgE, eosinophil and neutrophil numbers, FENO, and type 2 immunity composite score in subjects with severe, non-severe, or no asthma
| Group
|
|||
|---|---|---|---|
| Variable | Severe asthma | Non-severe asthma | No asthma |
| n | 51 | 75 | 27 |
| Periostin (ng/ml) | 54 (46, 62) | 53 (44, 62) | 49 (46, 65) |
| IgE (IU/ml) | 160 (80, 350)††† | 170 (80, 310)††† | 10 (6, 18) |
| Blood eosinophils (%) | 3.0 (1.7, 4.7)† | 3.1 (2.0, 5.0)††† | 2.0 (1.0, 3.0) |
| Blood eosinophils (cells per μl) | 170 (100, 300)† | 190 (120, 300)††† | 110 (70, 150) |
| Blood neutrophils (%) | 58 (53, 68) | 58 (51, 63) | 58 (55, 62) |
| Blood neutrophils (cells per μl) | 3800 (2600, 5000) | 3400 (2700, 4200) | 3300 (2600, 4300) |
| Sputum eosinophils (%), n = 49+73+26‡ | 0.7 (0.0, 3.0)††† | 1.0 (0.0, 2.9)††† | 0.0 (0.0, 0.5) |
| Sputum neutrophils (%), n = 49+73+26 | 44 (32, 63)*† | 31 (16, 49) | 28 (19, 50) |
| FENO (ppb), n = 46+63+26 | 19 (13, 31)††† | 26 (16, 39)††† | 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.
FENO, fraction of exhaled nitric oxide; Ig, immunoglobulin; IU, international unit; n, number of subjects; ppb, part per billion.
P (probability) ≤ 0.05 versus non-severe asthma;
P ≤ 0.001,
P ≤ 0.05 versus no asthma.
36% of patients with severe asthma and 33% of patients with non-severe asthma had > 2% sputum eosinophils, 23% of patients with severe asthma and 22% of patients with non-severe asthma had > 3% sputum eosinophils.
IgE, cell counts, and FENO were assessed as mentioned in Table EI legend.
Type 2 immunity composite score for patients with asthma was determined as described in the Online Repository.
FIG 1.
Serum periostin in subjects with severe asthma, non-severe asthma, or no asthma (A) and correlations between periostin and percentage of blood eosinophils (B), fraction of exhaled nitric oxide (FENO) (C), or type 2 immunity composite score (determined as described in the text) (D) in severe, non-severe, or all asthma; P, probability; rs, Spearman rank correlation coefficient.
We next asked whether serum periostin correlated with any of the four parameters or the type 2 immunity composite score, analyzing all patients with asthma together or just patients with severe or non-severe asthma. We found that higher serum periostin levels were associated with increased blood eosinophils, FENO, and type 2 immunity composite score in all asthma and severe asthma, whereas these correlations did not reach significance for non-severe asthma (Fig. 1B–D). When the correlations were adjusted for age, race/ethnicity, and sex, similar P values were obtained compared to before adjustment (with blood eosinophil percentage: P = 0.04 in all asthma, P = 0.03 in severe asthma, P = 0.44 in non-severe asthma; with FENO: P = 0.05 in all asthma, P = 0.02 in severe asthma, P = 0.90 in non-severe asthma; with type 2 immunity composite score: P = 0.06 in all asthma, P = 0.03 in severe asthma, P = 0.65 in non-severe asthma). Our significant correlation between serum periostin and FENO in all or severe, but not non-severe, asthma (Fig. 1C) is similar to the finding by Nagasaki et al. 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 (GINA).4 Associations between periostin and sputum eosinophils or IgE did not reach significance in our study (with sputum eosinophils: rs = 0.07, P = 0.46 in all asthma; rs = 0.17, P = 0.24 in severe asthma; rs = −0.02, P = 0.89 in non-severe asthma; with IgE: rs = 0.01, P = 0.89 in all asthma, rs = 0.07, P = 0.62 in severe asthma, rs = −0.08, P = 0.48 in non-severe asthma). FENO or blood eosinophils correlated with sputum eosinophils in all, severe, and non-severe asthma (FENO: rs = 0.39, P < 0.0001 in all asthma; rs = 0.33, P < 0.03 in severe asthma; rs = 0.35, P < 0.005 in non-severe asthma; blood eosinophil percentage: rs = 0.39, P < 0.0001 in all asthma; rs = 0.51, P = 0.0002 in severe asthma; rs = 0.33, P = 0.004 in non-severe asthma; blood eosinophil concentration; rs = 0.39, P < 0.0001 in all asthma, rs = 0.46, P = 0.0008 in severe asthma; rs = 0.34, P = 0.003 in non-severe asthma).
In summary, we first found that serum periostin was not significantly different among the three groups of severe, non-severe, and no asthma in a SARP subject population. Further, 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, e.g., anti-IL-13 treatment, in asthma.3, 10
Supplementary Material
Clinical implications.
Serum periostin was not different among severe, non-severe, or no asthma groups but correlated with eosinophil numbers, FENO, and type 2 immunity score, supporting a role for periostin as marker of systemic type 2 inflammation.
Acknowledgments
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.
This study was supported in part by grants R01 HL069116, U10 HL109168, General Clinical Research Center grant M01 RR03186, and Clinical and Translational Science Award grant UL1 RR025011 from the National Institutes of Health (NIH).
Footnotes
Author contributions: Concept development NNJ, JGM; data collection NNJ, GMC; periostin analysis CTJH; statistical analysis MDE; manuscript preparation MWJ, NNJ. All authors reviewed and approved the final manuscript.
Disclosure of potential conflict of interest: NNJ has received research support from the NIH and consultancy fees from Asthmatx, Genentech, and Teva Pharmaceuticals. CTJH and JGM are employees of Roche/Genentech. The rest of the authors declare that they have no relevant potential conflicts of interest.
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