Evaluating serum periostin levels in allergic bronchopulmonary aspergillosis

TY - JOUR

T1 - Evaluating serum periostin levels in allergic bronchopulmonary aspergillosis

AU - Tanaka, Jun

AU - Hebisawa, Akira

AU - Oguma, Tsuyoshi

AU - Tomomatsu, Katsuyoshi

AU - Suzuki, Junko

AU - Shimizu, Hiroshige

AU - Kawabata, Yoshinori

AU - Ishiguro, Takashi

AU - Takayanagi, Noboru

AU - Ueda, Soichiro

AU - Fukunaga, Koichi

AU - Taniguchi, Masami

AU - Ono, Junya

AU - Ohta, Shoichiro

AU - Izuhara, Kenji

AU - Asano, Koichiro

N1 - Funding Information: This study was funded by Research Grant on Allergic Disease and Immunology from The Japan Agency for Medical Research and Development under grant number JP18ek0410026 and JP19ek0410055, and a grant-in-aid from GlaxoSmithKline, plc. JO is an employee of Shino-test, which is the manufacturer of the periostin ELISA kit. KI has received research grant from Shino-test. Other authors have no conflicts of interest pertaining to this study. To the Editor, Allergic bronchopulmonary aspergillosis/mycosis (ABPA/ABPM) is caused by hypersensitivity associated with type 2 immune responses to Aspergillus fumigatus or other fungi present in the airway. High level of total IgE in the serum is an essential biomarker for the differential diagnosis of ABPA from asthma, although a third of Japanese patients with ABPA exhibit serum IgE levels <1000?IU/mL. Therefore, additional biomarker(s) would be desirable to improve the diagnostic accuracy. Periostin, a matricellular protein, is produced in response to transforming growth factor-? in the mesenchymal cells including fibroblasts, and in the bronchial epithelial cells in response to IL-4/IL-13. Because serum periostin level is considered a biomarker of type 2 inflammation in asthmatic airways, we examined its serum levels and pulmonary expression in patients with ABPA/ABPM. Enzyme-linked immunosorbent assay (Shino-Test Corp.) was performed to measure the serum periostin concentrations in 44 patients with ABPA satisfying the diagnostic criteria of the International Society of Human and Animal Mycology. Thirty-three (75%) patients with ABPA presented with asthma and none with cystic fibrosis. Other demographic data and clinical characteristics of these patients are shown in Table S1. Patients in the previous cohort study of severe asthma requiring the Global Initiative for Asthma step 4 or 5 treatment were examined as control. They were divided into four groups: those with Aspergillus-sensitized severe asthma with fungal sensitization (Asp-SAFS, n?=?24 [19%]), those with non-Aspergillus fungi-sensitized SAFS (non-Asp-SAFS, n?=?25 [20%]), those with atopic asthma without fungal sensitization (atopic non-SAFS, n?=?32 [26%]) and those with nonatopic asthma without fungal sensitization (nonatopic non-SAFS, n?=?44 [35%]) (Table S1). Details about ethical issues and statistical analyses are described in the Appendix S1. The median serum periostin level was higher in patients with ABPA (107?ng/mL; interquartile range (IQR), 76-139?ng/mL) than in patients with severe asthma (72?ng/mL; IQR, 56-100?ng/mL) (P?<.0005, Figure A). Serum periostin levels were equivalent in ABPA patients regardless of the asthma comorbidity: 106 (76-139) ng/mL in patients with asthma (n?=?33) and 109 (74-149) ng/mL without asthma (n?=?11). There were no differences in the clinical characteristics between the ABPA patients with high (?94?ng/mL) and low (<94?ng/mL) serum periostin levels (Table S2). Among the subgroups of patients with severe asthma, the serum periostin concentrations were not significantly different regardless of atopic status or fungal sensitization (Figure A). The serum periostin levels in patients with severe asthma exhibiting positive IgE and precipitating antibody to A fumigatus but lacked radiological findings characteristic for ABPA such as central bronchiectasis or mucus plugs in the bronchi (65 [56-73] ng/mL, n?=?7) were not different from those of patients with positive IgE alone (73 [58-92] ng/mL, n?=?17, P?=.41) and significantly lower than those in patients with ABPA (P?=.005), suggesting that increased serum periostin levels in the patients with ABPA are associated with the presence of bronchopulmonary lesion. We compared the usefulness of serum periostin to differentiate ABPA from Asp-SAFS with other type 2 biomarkers using receiver operating characteristic curve analysis. The area under the curve values (AUC) for serum periostin (P?<.001), total serum IgE (P?=.01) and peripheral blood eosinophil count (P?=.92) were 0.75, 0.69 and 0.51, respectively (Figure B). The sensitivity, positive and negative predictive values, and odds ratio for serum periostin levels to differentiate ABPA from Asp-SAFS at the cut-off values with the sensitivity of 70%, 82% and 91% were equivalent or better than those for serum IgE levels or peripheral blood eosinophil counts (Table S3A, Figure S1A). Serum periostin levels, relatively consistent regardless of the treatment with systemic corticosteroids, might be a more robust diagnostic biomarker than peripheral blood eosinophil counts or serum IgE levels in patients with severe asthma under systemic corticosteroids. To examine this hypothesis, a subgroup of patients with ABPA (n?=?20) or Asp-SAFS (n?=?12) already under treatment with oral corticosteroids was analysed. The AUC values for serum periostin, total serum IgE and peripheral blood eosinophil count were 0.85, 0.71 and 0.61, respectively. In this subgroup analysis, serum periostin levels seem to differentiate ABPA from Asp-SAFS more precisely than other biomarkers (Table S2B, Figure S1B), although the number of subjects is too small to conclude this hypothesis and further study in a larger cohort should be performed. For the evaluation of periostin immunoreactivity in the lungs, we examined the surgically resected lung tissues from five patients with ABPM (one man and four women, 63???18?years) that fulfilled the pathological criteria; eosinophilic mucin with fungal hyphae and central bronchiectasis were detected in all patients, bronchocentric granulomatosis in four and organizing pneumonia in three patients. Only two patients had asthma. Immunohistochemical staining with antiperiostin serum (SS19C) was performed as previously reported. Periostin deposition in the bronchi was observed in the subepithelial basement membrane (Figure A). Periostin was also expressed in the granulation tissues adjacent to the area with bronchocentric granulomatosis or organizing pneumonia of peripheral lungs (Figure B-E). This expression pattern of periostin is consistent with that observed in the lungs of patients with idiopathic pulmonary fibrosis or cryptogenic organizing pneumonia, suggesting that nonallergic immune response may also play an important role in the elevation of serum periostin levels in patients with ABPA. However, we had to be cautious in interpreting these data using resected lung tissues as (a) the serum samples from these patients were not available, and we could not confirm whether the serum levels of periostin were elevated in these cases, and (b) data necessary for the clinical diagnosis of ABPA were not available, even though they fulfilled the pathological criteria of ABPM. In conclusion, serum periostin concentrations in ABPA/ABPM patients were elevated, reflecting its enhanced expression in the bronchi and peripheral lungs, and can be useful for the diagnosis of ABPA even in the patients pretreated with systemic corticosteroids. Funding Information: JO is an employee of Shino‐test, which is the manufacturer of the periostin ELISA kit. KI has received research grant from Shino‐test. Other authors have no conflicts of interest pertaining to this study.

PY - 2020/4/1

Y1 - 2020/4/1

UR - http://www.scopus.com/inward/record.url?scp=85076092788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85076092788&partnerID=8YFLogxK

U2 - 10.1111/all.14114

DO - 10.1111/all.14114

M3 - Letter

C2 - 31715007

AN - SCOPUS:85076092788

SN - 0105-4538

VL - 75

SP - 974

EP - 977

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

IS - 4

ER -