Periostin: A Biomarker Useful in Treating Patients with Progressive Fibrosing Interstitial Lung Diseases

doi:10.21203/rs.3.rs-713223/v1

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Periostin: A Biomarker Useful in Treating Patients with Progressive Fibrosing Interstitial Lung Diseases

https://doi.org/10.21203/rs.3.rs-713223/v1

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Background: The concept of progressive fibrosing interstitial lung diseases (PF-ILD) has been recently proposed to describe a progressive phenotype in fibrosing ILDs, separate from the classical differential diagnosis of ILDs. However, we still do not know enough about how we can differentiate PF-ILD patients from non–PF-ILD patients in advance or how we can predict decline of lung function in PF-ILD patients. Periostin is a matricellular protein playing a critical role in the pathogenesis of pulmonary fibrosis significantly high in idiopathic pulmonary fibrosis patients.

Methods: In this study, we applied three periostin ELISA systems—an original ELISA system recognizing total periostin, an ELISA system recognizing only the monomeric periostin, and a modified ELISA system that can measure periostin independently of the IgA complex established in this study—to serum from idiopathic interstitial pneumonia (IIP) patients to address whether periostin can differentiate PF-ILD from non–PF-ILD patients in advance, whether periostin can predict the decline of lung function in PF-ILD patients, and which ELISA system for periostin is the most suitable for these purposes.

Results: We established the modified ELISA system using SS16A recognizing the R3 domain instead of SS18A recognizing the R1 domain as the primary mAb that can measure periostin independently of the IgA complex. All periostin values found by the three systems were significantly higher in PF-ILD patients than in healthy subjects in addition to SP-D and KL-6, whereas all the periostin values, but not SP-D or KL-6, could differentiate PF-ILD patients from patients with IIP other than PF-ILD, in the order of the monomer system, the modified system, and the original system. Moreover, the periostin values by all three systems, but not SP-D or KL-6, showed significant correlations with decline of either %VC or D_{L, CO}, in order of the monomer system, the modified system, and the original system.

Conclusions: Serum periostin, but not SP-D and KL-6, differentiates PF-ILD from non–PF-ILD and predicts decline of lung function in PF-ILD patients. The monomer periostin ELISA system is the best at doing so. These results demonstrate that periostin, particularly the monomeric form, is useful in treating PF-ILD patients.

Pulmonology

progressive fibrosing interstitial lung disease

periostin

diagnosis

lung function

%VC

%DL

monomer

ELISA

Interstitial lung diseases (ILDs) are heterogeneous, encompassing more than 200 different diseases, many of which are classified as rare [1–3]. Progressive fibrosis is an important factor for treatment of ILDs patients because it is tightly linked to progressive deterioration in lung function, respiratory symptoms, quality of life, and the risk of early death. Therefore, it is reasonable to propose the concept of progressive fibrosing ILD (PF-ILD), which presents as a progressive phenotype in fibrosing ILDs, despite currently available treatment, and separate from the classical differential diagnosis of ILDs [1–5]. Even the natural course of idiopathic pulmonary fibrosis (IPF), the representative disease of ILDs that shows a devastating course with a median survival of two to three years, is variable [6]; patients die within a year after diagnosis, whereas some live much longer. Currently, two anti-fibrotic agents, nintedanib and pirfenidone, are available for treating IPF patients. The importance of the concept of PF-ILD has been highlighted by reports that these two agents showed beneficial effects in treating PF-ILD patients as well [7–9]. However, the definition of PF-ILD has not been agreed upon. Most criteria that have been proposed involve the relative decline of %FVC in combination with the relative decline of %D_{L, CO}, worsened respiratory symptoms, and increased fibrotic changes as shown by high-resolution computed tomography (HRCT) [10–15]. Moreover, it is a key question how we can predict the decline of lung function in ILD patients. In other words, we need to know how we can differentiate PF-ILD patients from non–PF-ILD patients in advance; currently, we can diagnose PF-ILD only retrospectively.

Periostin is a matricellular protein that modulates cell functions by binding to several integrins [16, 17]. It has been shown that periostin plays a critical role in the pathogenesis of pulmonary fibrosis. Either genetic disruption of periostin or administration of neutralizing anti-periostin antibodies (Abs) improved bleomycin-induced pulmonary fibrosis in mice [18, 19]. We recently found that cross-talk exists between TGF-β and periostin signals via integrins converging into Smad3. This cross-talk is necessary for the expression of TGF-β downstream effector molecules important in pulmonary fibrosis [20]. Moreover, periostin can enhance proliferation of lung fibroblasts by modulating expression of cell-cycle–related genes, contributing to the formation of pulmonary fibrosis [21]. In IPF patients, periostin is highly expressed in the fibrotic foci, the active center of pulmonary fibrosis, supporting the significance of periostin in pulmonary fibrosis in humans [19, 22].

We and others have shown that periostin in blood is significantly high in IPF patients compared to heathy subjects and is correlated with the risk of high mortality, reflecting high expression of periostin in the lungs [15, 22–25]. In particular, we found that monomeric periostin is significantly high in IPF patients and is strongly correlated with their declines of %VC and %D_{L, CO} compared to total periostin [24]. Moreover, we recently showed that retention of monomeric periostin after acute exacerbation predicts poor prognosis in IPF patients [26]. These results suggest that periostin, particularly monomeric periostin, has the potential to be a useful biomarker to predict prognosis in IPF patients. However, it remains elusive whether periostin is a useful biomarker for PF-ILD and which system for detecting serum periostin would be the most suitable.

In this study, we prepared three kinds of enzyme-linked immunosorbent assay (ELISA) systems to detect serum periostin. The first measures the total periostin in serum and has been used in many studies targeting various diseases [17, 27]. The second can measure only the monomeric type of periostin that is significantly high in IPF patients and has been shown to be better than total periostin to differentiate IPF patients from healthy subjects and to predict the decline of lung function in IPF patients [24]. The last system is what we established in this study. We recently found that periostin forms a complex with IgA in human serum via intermolecular disulfide bonds, which may affect the binding of some anti-periostin Abs to periostin [28]. We found that formation of the periostin-IgA complex affects the original periostin ELISA system, decreasing the values of serum periostin. Therefore, in order to precisely measure serum periostin. we established a novel ELISA system that is not affected by formation of the IgA complex. We applied these three ELISA systems to the serum of idiopathic interstitial pneumonia (IIP) patients to address whether periostin can differentiate PF-ILD from non–PF-ILD patients in advance, whether periostin can predict their decline of lung function, and which ELISA system for periostin is the most suitable for these purposes.

Periostin protein and anti-periostin monoclonal Abs (mAbs)

We prepared recombinant human periostin protein using Drosophila S2 cells, as previously described [29], and then purified monomeric periostin using the affinity purification method, as previously reported [24]. We generated eleven kinds of mAbs against periostin (SS16A, SS17B, SS18A, SS19A, SS19B, SS19C, SS19D, SS20A, SS21A, SS23A, and SS27D) by immunizing rats or mice with recombinant human periostin, as previously described [24].

ELISAs for periostin

We used five kinds of periostin ELISA systems: (1) the original ELISA system recognizing the total periostin composed of SS18A and SS17B (Shino-Test Corporation, Tokyo, Japan) [27]; (2) an ELISA system recognizing only the monomeric periostin composed of SS20A and SS19D (Shino-Test Corporation, Tokyo, Japan) [24]; (3) a modified ELISA system recognizing the total periostin composed of SS16A and SS17B established in this study; and two commercially available ELISA kits supplied by R&D Systems (Minneapolis, MN, USA) and Biomedica (Vienna, Austria). The commercially available ELISA kits were used according to the manufacturers’ instructions. We diluted serum by 100 fold for the R&D kit and by 51 fold for the Biomedica kit, respectively. In the reducing condition for the original and modified ELISA systems, we diluted serum by 500 fold using sample diluent (0.5% Casein in Tris buffer saline pH 8.0) and added DTT to set the final concentration of 1 mM. For the R&D and Biomedica kits, we added DTT to set the final concentrations at 2 mM and 2.9 mM, respectively, due to the different dilution ratios. We confirmed that these DTT concentrations could dissociate the complex of periostin and IgA but did not affect the ELISA systems.

We validated the assay performance of the modified ELISA system established in this study according to CLSI guidelines. The modified ELISA system showed good representative calibration curves (Fig. S1a). The lower limits of blank (LOB), of detection (LOD), and of quantification (LOQ) of the modified ELISA system were 2.0, 4.0, and 34 pg/mL, respectively. The intra- and inter-assay CV values ranged from 1.8–2.2% (n = 15) and from 1.9–2.3% (n = 15), respectively (Table S1). Recoveries of periostin ranged from 99–102%. Serially diluted analyses showed close linearity in each sample (r > 0.997). There was no substantial interference from hemoglobin (< 500 mg/dL), bilirubin (< 50 mg/dL), IgA (< 5 mg/mL), βIG-H3 (< 500 ng/mL), ascorbic acid (< 20 mg/dL), chyle (< 3000 FTU), or DTT (< 0.1 mM), indicating that the assay was resistant to interference from a wide range of biological constituents (Table S2).

Serum samples

We purchased pooled human serum and 50 serum samples obtained from individual subjects from Cosmo Bio Co., Ltd., (Tokyo, Japan) and VERITAS Corporation (Tokyo, Japan), respectively.

Immunoprecipitation and Western blotting

We carried out immunoprecipitation and Western blotting as previously described [24, 28]. In the reducing condition, we diluted the samples by tenfold using PBS with 0.05% Tween-20 (PBS-T) at a final concentration of 4 mM DTT. We calculated periostin concentrations of immunoprecipitated samples by comparing the signals with those of recombinant periostin standards using Image J software.

Subject IIP patients and diagnosis of IIP

Ours is a post-hoc study of the previously published one combining the CoDD-PF study and the Kurume study. The details of the subject IIP patients and diagnosis of IIP were described in the previous report [24]. Sixty-two eligible patients were selected from 137 cases in the CoDD-PF study. These included 27 IPF patients, 11 possible IPF patients, six fNSIP patients, one cNSIP patient, and 17 unclassified IP patients (Fig. 1). Fifteen eligible patients were selected in the Kurume study, all IPF patients. Biomarkers were evaluated at day 0. We used the criteria for PF-ILD for 77 IIP patients in total.

Diagnosis of PF-ILD

In this study, we used the criteria for PF-ILD proposed by the Erice ILD working group [13]. Since we did not have the data on respiratory symptoms in the CoDD-PF study or the Kurume study, we adopted the following three criteria: (1) the relative decline of ≥ 10% of %FVC within one year, (2) the relative decline of 5–10% of %FVC and the relative decline of ≥ 15% of D_{L, CO} within one year, or (3) the relative decline of 5–10% of %FVC and the increased extent of fibrotic changes in HRCTs within one year. We defined the increased extent of fibrotic changes in HRCTs as increased scores of reticulation, honeycombing, or traction bronchiectasis. We selected 25 and 52 IIP patients as PF-ILD patients and patients with IIP other than PF-ILD, respectively (Fig. 1). The PF-ILD patients included 18 IPF patients, three possible IPF patients, and four unclassified IP patients, whereas patients with IIP other than PF-ILD included 24 IPF patients, eight possible IPF patients, six fNSIP patients, one cNSIP patient, and 13 unclassified IP patients.

Statistics

Differences were examined by the Student t-test or the Mann-Whitney U-test. Results are shown as mean ± SD. The correlation between different analytes or methods were arrived at using nonparametric spearman rank correlations. A linear relationship between two analytes was evaluated by a linear regression model. Differences were considered statistically significant if P < 0.05. All statistical analysis was performed by SPSS software version.26.

Effect of formation of the IgA complex on periostin measurement by the original ELISA method

We recently demonstrated that periostin forms a complex with IgA in the non-reducing condition in serum, whereas this formation is dissociated in the reducing condition [28]. We first examined whether formation of the complex with IgA affects periostin measurement using the original ELISA method. When we added 1.0 mM DTT in serum, periostin forming the complex with IgA migrated at around 240 kDa was dissociated into the monomeric periostin migrated at 79 kDa, as we previously demonstrated. (Fig. 2a) [28]. When we measured the periostin concentration of pooled serum by the original ELISA method, those of the non-reducing and reducing conditions were 52 ng/mL and 783 ng/mL, respectively, which means that the value at the reducing condition is 15 fold higher than that of the non-reducing condition (Fig. 2b). Such an increase of the periostin values in the reducing compared to the non-reducing condition was observed also with the two kinds of ELISA kits commercially available (Fig. S2). These results demonstrate that formation of the complex with IgA affects periostin measurement by the original ELISA method.

We next addressed which primary Ab (SS18A) or secondary Ab (SS17B) comprising the original ELISA method causes the difference in periostin measurement of the non-reducing and reducing conditions. SS18A immunoprecipitated comparable amounts of periostin from recombinant periostin that did not form a complex with IgA in both the non-reducing and reducing conditions, whereas SS17B showed an only slightly weaker ability to immunoprecipitate periostin in the reducing than in the non-reducing condition (Fig. 2c). When we immunoprecipitated periostin from pooled serum, SS18A was more effective in the reducing than in the non-reducing condition, where SS17B was the opposite. These results demonstrate that the increase of periostin values measured by the original ELISA method in the reducing compared to the non-reducing condition is attributable to SS18A, not to SS17B.

Identification of the periostin domains that affect periostin measurement by the original ELISA method

Since it is known that eleven cysteine residues are located at the EMI, R1, R2, and R3 domains and that SS18A recognizes the R1 domain [28], the epitope of SS18A is likely to be affected by formation of the complex with IgA via intermolecular disulfide bonds. We next examined how each domain of periostin affects periostin measurement. We prepared ten kinds of anti-periostin mAbs that recognize the EMI, R1, R2, R3, R4, and C-terminal domains (Fig. 3a), examining their abilities to immunoprecipitate periostin from either recombinant periostin or pooled serum in the non-reducing and reducing conditions. Both SS20A and SS18A recognizing the EMI and R1 domains, respectively, immunoprecipitated more periostin in the reducing condition of pooled serum, but not of recombinant periostin, than in the non-reducing condition (Fig. 3b-d). SS21A and SS19B in addition to SS17B showed weaker abilities to immunoprecipitate periostin in the reducing than in the non-reducing condition. The four mAbs—SS19C, SS23A, SS16A, and SS27D—recognizing the R2 or R3 domain immunoprecipitated comparable amounts of periostin from pooled serum in the reducing and non-reducing conditions. These results demonstrate that both the EMI and R1 domains rich in cysteine residues contribute to formation of the complex with IgA, affecting the abilities of the mAbs recognizing these domains to bind to periostin.

Establishment of a modified ELISA system that can measure periostin independently of the IgA complex

In order to establish an ELISA system that could measure periostin independently of the IgA complex, we chose as the primary mAb SS16A recognizing the R3 domain that does not change the ability to immunoprecipitate periostin in the reduction condition and established a novel ELISA system combining SS17B as the secondary mAb. We validated the accuracy of the ELISA system in the presence or absence of formation of the IgA complex by comparing the values in the reducing and non-reducing conditions for the original and modified ELISA systems. The periostin concentrations measured by the original ELISA system provided values approximately tenfold higher in the reducing than the non-reducing condition (r = 0.76, y = 8.80x + 209.41), whereas the modified ELISA system showed almost the same values (r = 0.92, y = 1.03x + 184.46) in the non-reducing and reducing conditions (Fig. 4a). Estimation of periostin concentrations by immunoprecipitation also showed a good correlation with what had been estimated by the modified ELISA system (Fig. 4b). These results demonstrate that the modified ELISA system using SS16A instead of SS18A as the primary mAb can measure periostin independently of the IgA complex.

Application of the periostin ELISA systems to differentiate PF-ILD patients in IIP patients

We next applied our periostin ELISA systems—(1) the modified ELISA system that can measure total periostin independently of the IgA complex (SS16A × SS17B), (2) the original ELISA system recognizing total periostin (SS18A × SS17B), and (3) the ELISA system recognizing only the monomer periostin (SS20A × SS19D)—to serum from IIP patients to determine which one could best differentiate PF-ILD from non–PF-ILD patients. All periostin values found by the three systems were significantly higher in PF-ILD patients than in healthy subjects (the modified ELISA system: P < 0.001, the original system: P < 0.001, the monomer system: P < 0.001) in addition to SP-D (P < 0.001) and KL-6 (P < 0.001, Fig. 5). Moreover, all the periostin values could differentiate PF-ILD patients from patients with IIP other than PF-ILD, in the order of the monomer system (P < 0.001), the modified system (P = 0.006), and the original system (P = 0.009). Neither SP-D nor KL-6 could differentiate PF-ILD patients from patients with IIP other than PF-ILD (P = 0.387, P = 1.000, respectively). These results demonstrate that serum periostin, but not SP-D and KL-6, differentiates PF-ILD from non–PF-ILD and that the monomer ELISA system has the highest ability to do so.

Application of the periostin ELISA systems to predict lung function in PF-ILD patients

We next used our periostin ELISA systems to establish which periostin ELISA system could predict decline of lung function in PF-ILD patients. The periostin values by all three systems showed significant correlations with decline of %VC, in order of the monomer system (P < 0.001, r = -0.409), the modified system (P = 0.003, r = -0.335), and the original system (P = 0.005, r = -0.317, Fig. 6a). Neither SP-D nor KL-6 showed a significant correlation with decline of %VC (P = 0.057, r = -0.218, P = 0.668, r = 0.050, respectively).

We then examined correlations of the periostin values with decline of D_{L, CO}. The periostin value by the monomer system showed the highest correlation (P < 0.001, r = -0.445) and the values by the modified (P = 0.005, r = -0.345) and original (P = 0.014, r = -0.306) systems ranked second and third (Fig. 6b). Neither SP-D nor KL-6 showed a positive correlation with decline of D_{L, CO} (P = 0.300, r = -0.132, P = 0.606, r = -0.066, respectively). Taking these results together, periostin can predict decline of lung function in PF-ILD patients, and the monomer periostin ELISA system is the best at doing so.

The concept of PF-ILD is rapidly and widely being accepted. Even patients with fibrosing ILDs other than IPF share commonalities in pathogenic mechanisms and diseases behavior with IPF, whereas the clinical course of IPF itself is variable [1–6]. This concept has been further supported by the findings that nintedanib and pirfenidone showed beneficial effects as treatments for PF-ILD as well as IPF patients [7–9]. However, only a few studies thus far have discussed which biomarkers are useful in treating these patients. It has been recently reported that serum human epididymis protein 4 is high in PF-ILD patients and that high levels can predict poor survival, although the correlation between its levels and decline of lung function remains unclear [30]. In this article, we demonstrate that serum periostin is a useful biomarker in treating PF-ILD patients in that serum periostin is significantly correlated with decline of %VC and %D_{L, CO} suggesting that serum periostin can predict the short-term prognosis of PF-ILD and that in correlation with this ability, serum periostin potentially differentiates PF-ILD from non–PF-ILD in advance.

Although thus far the definition of PF-ILD has not been universally agreed on, it will include the relative decline of %FVC in combination with the relative decline of %D_{L, CO}, worsened respiratory symptoms, and/or increased extent of fibrotic changes on HRCT [10–15]. But these components are what can be seen retrospectively, not what can be forecast at the onset of the disease. It is a tough challenge to differentiate PF-ILD from non–PF-ILD in advance, one that requires a multidisciplinary approach combining clinical presentation, specific history assessment, smoking status, lung function evaluation, serological tests, imaging, and, in some cases, lung biopsy [1, 5]. Since the decline of lung function is central to the definition of PF-ILD and serum periostin is significantly correlated with it, we can reasonably expect that serum periostin can differentiate PF-ILD from non–PF-ILD in advance, based on our present results.

If we can diagnose PF-ILD in advance, we can begin appropriate treatment at once. Possible PF-ILD patients would start to receive aggressive treatment including administration of anti-fibrotic agents immediately after their diagnosis and would continue with it. Although it is known that nintedanib and pirfenidone are tolerable, IPF patients receiving these drugs frequently show adverse effects such as gastrointestinal disorders and photosensitivity/rash; 10–20% of the patients discontinue the drugs [31–34]. Serum periostin, as a biomarker to predict short-term prognosis of lung function, would be useful in deciding whether to continue.

In this study, we prepared three kinds of ELISA systems for periostin, as described above in Methods, to apply to the serum IIP patients, finding that the values by the monomer system have the highest abilities to differentiate PF-ILD from IIP other than PF-ILD and to predict short-term prognosis of lung functions in PF-ILD patients. It is reasonable that the modified system would be superior to the original system, because the former is not affected by formation of the complex with IgA and therefore directly reflects periostin production. However, the finding that the values by the monomer system showed the highest ability among the three systems surprised us. Thus far, we do not know how monomeric periostin is produced or why the monomeric periostin levels are high in IIP patients. We assume that aberrant redox status in IIP may first affect the inter- or intra-molecular disulfide bonds of periostin and then the formation of the complex of periostin with IgA via its intermolecular disulfide bonds. Although the underlying mechanism of high production of the monomeric periostin in IIP is unclear, the present article again suggests that formation of monomeric periostin would reflect the pathogenesis of PF-ILD as well as IPF.

The first limitation of this study is that since we did not acquire the data on respiratory symptoms of the subjects, some PF-ILD patients may be included in patients with IIP other than PF-ILD based on the criteria of PF-ILD [13]. The second is that since we observed the subjects at the latest one year, not two years, after entry, some PF-ILD patients may be included in patients with IIP other than PF-ILD based on the criteria of PF-ILD as well [13]. The final limitation is that we targeted only IIP patients for PF-ILD and non–PF-ILD patients and did not include secondary interstitial pneumonia patients, who should be included in future studies.

Serum periostin, particularly monomeric periostin, is a useful biomarker in treating PF-ILD patients in that it is significantly correlated with decline of %VC and %D_{L, CO} suggesting that serum periostin can predict short-term prognosis of PF-ILD. In correlation with this ability, serum periostin has the potential to differentiate PF-ILD from non–PF-ILD in advance.

ILD: interstitial lung disease

PF-ILD: progressive fibrosing ILD

IPF: idiopathic pulmonary fibrosis

HRCT: high-resolution computed tomography

Ab: antibody

ELISA: enzyme-linked immunosorbent assay

IIP: idiopathic interstitial pneumonia

mAb: monoclonal Ab

Ethics approval and concet to participate

This study was conducted by the Consortium for Development of Diagnostics for Pulmonary Fibrosis Patients (CoDD-PF) after approval by the local institutional review boards of the composed facilities.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

Funding

This work was supported in part by JSPS KAKENHI Grant Number #JP21K08476 (to KI).

Competing interests

MT, JO, and AK are employees of Shino-Test Corporation. KI received research grants from Shino-Test Corporation. The other authors declare no conflict of interest.

Author Contributions

MT, JO, and AK made the kit and analyzed the samples. MT, JO, MO, KF, AA, and KI designed the work. MO, KF, and TH managed the enrollment of the patients and the analyses of clinical data. MT and KI wrote the paper. All authors contributed to drafting the article and approved the published version of the article.

Acknowledgements

We thank the members of CoDD-PF for collecting the samples from IIP patients. The members of CoDD-PF not already listed as co-authors include Drs. Shigeru Kohno, Noriho Sakamoto (Nagasaki University of School of Medicine), Shinichiro Hayashi, Koichiro Takahashi (Saga Medical School), Masayuki Hanaoka, Hiroshi Yamamoto (Shinshu University School of Medicine), Jun-ichi Kadota, Hisako Kushima, Hiroshi Ishii (Oita University Faculty of Medicine), Hironori Sagara, Keiichi Akasaka (Dokkyo Medical University Koshigaya Hospital), and Takeshi Johkoh (Kinki Central Hospital of Mutual Aid Association of Public Treachers). We also thank Dr. Dovie R. Wylie for the critical review of this manuscript.

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Periostin: A Biomarker Useful in Treating Patients with Progressive Fibrosing Interstitial Lung Diseases

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Abstract

Figures

Background

Methods

Periostin protein and anti-periostin monoclonal Abs (mAbs)

ELISAs for periostin

Serum samples

Immunoprecipitation and Western blotting

Subject IIP patients and diagnosis of IIP

Diagnosis of PF-ILD

Statistics

Results

Effect of formation of the IgA complex on periostin measurement by the original ELISA method

Identification of the periostin domains that affect periostin measurement by the original ELISA method

Establishment of a modified ELISA system that can measure periostin independently of the IgA complex

Application of the periostin ELISA systems to differentiate PF-ILD patients in IIP patients

Application of the periostin ELISA systems to predict lung function in PF-ILD patients

Discussion

Conclusions

Abbreviations

Declarations

References

Supplementary Files

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