Significance of clinical parameters and biomarkers to predict nintedanib-induced diarrhea: an interview-based retrospective study

Introduction

Background

Idiopathic pulmonary fibrosis (IPF) is a fibrotic interstitial lung disease (ILD) with a poor prognosis and unknown etiology (1). There has been no evidence-based effective drug for a long time; however, nintedanib (2) and pirfenidone (3) have proven to be useful in large-scale randomized trials. For other ILDs, anti-inflammatory therapy, including corticosteroids, has been mainly used; however, progressive pulmonary fibrosis (PPF), occurring in ILDs other than IPF, can be treated with nintedanib (4). A systemic sclerosis-associated ILD is another target ILD for nintedanib under the evaluation by high-resolution computed tomography (5,6). Effectiveness of nintedanib has been extensively validated by manly clinical studies (7). Hence, chronic fibrotic ILDs can be treated with nintedanib, and the prognosis of the disease should be improved (5,6). However, management of adverse events is the important problem to maintain administration of nintedanib (7).

Rationale and knowledge gap

Diarrhea is the most common adverse event caused by nintedanib. Over 60% of patients reported diarrhea in the INPULSIS trial for IPF and INBUILD trial for PPF (2,4). Nintedanib is a tyrosine kinase inhibitor (TKI) that suppresses signal transduction via the receptors of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) (8). The mechanism of nintedanib-induced diarrhea has not yet been ascertained; blocking PDGF and FGF with nintedanib might induce epithelial apoptosis or injury (8-10). Furthermore, VEGF inhibition may induce epithelial injury through mucosal ischemia due to the inhibition of vascular growth in the intestinal mucosa (8,9). Antidiarrheal drugs, including loperamide, can control diarrhea in some patients. However, many patients frequently experience diarrhea after antidiarrheal treatment. For approximately 30% of patients in the INBUILD trial who experienced diarrhea at least once, dose reduction or discontinuation of nintedanib was required (11). We have reported that ramosetron might be useful for intractable diarrheal treatment (9); however, its efficacy is limited considering the response rate against diarrhea-predominant irritable bowel syndrome (IBS) (12). Hence, controlling diarrhea remains a significant challenge because nintedanib is thought to improve the prognosis of IPF and PPF (13,14), and its withdrawal might lead to a poor prognosis. If the onset of diarrhea can be predicted, we could also recommend other antifibrotic drugs, such as pirfenidone, or we might be able to manage diarrhea early. Tsuneyoshi et al. reported that the peripheral blood monocyte count at the start of nintedanib treatment might suggest the necessity of dose reduction or drug discontinuation (15). Biomarkers, including monocyte count, might be important in predicting nintedanib-induced diarrhea.

Objective

Herein, we aimed to identify significant factors, including clinical parameters and biomarkers, that predict the occurrence of nintedanib-induced diarrhea. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-938/rc).

Methods

Study design and participants

This was an interview-based, single-center, retrospective study. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the NHO Kinki Chuo Chest Medical Center Institutional Review Board (approval number Rin2023-122, approval date 2024/3/25). We enrolled patients with ILD, who were initiated on nintedanib treatment between April 2022 and March 2024 and whom we had been managing until April 2024. Interview about diarrhea was performed between April 2024 and August 2024 after we obtained informed consent for the inclusion in this study from the patients. Patients included those with IPF and non-IPF ILDs meeting PPF criteria (hereafter “PPF”) after standard management.

After the interview, we have selected the patients for the analysis to predict diarrhea at the commencement of nintedanib-induced diarrhea; we have selected patients, for whom presence or absence of diarrhea within 3 months was confirmed by the interview (Figure 1). Hence, patients whose nintedanib administration period was ≥3 months and patients with nintedanib administration period <3 months who experienced diarrhea in the period could be enrolled. Patients with nintedanib administration period <3 months and without diarrhea occurrence were excluded because the patients might have experienced diarrhea with additional administration period of nintedanib exceeding 3 months. The necessary administration period of nintedanib, 3 months, was determined because approximately 20–30% of patients discontinued nintedanib within 3 months (16) and more patients within 6 months in Japanese post-marketing surveillance and about 70% of diarrhea happened after the commencement of nintedanib within 3 months (11). The more the necessary observation period is prolonged, the more patients would be excluded. Hence, we have adopted diarrhea events with the interval from the first dose of nintedanib to the onset ≤3 months as primary outcome of this study.

Figure 1 Patient flow. We have selected patients, for whom presence or absence of diarrhea within 3 months was confirmed by the interview. Hence, patients whose nintedanib administration period was ≥3 months and patients with nintedanib administration period <3 months who experienced diarrhea in the period were analyzed population. Patients with nintedanib administration period <3 months and without diarrhea occurrence were excluded because the patients might have experienced diarrhea with additional administration period of nintedanib exceeding 3 months. Patients with nintedanib administration period ≥3 months who took antibiotics within 1-week prior diarrhea were excluded, either. mos, months.

We have excluded the patients who experienced diarrhea and took antibiotics within one week before diarrhea. Proton pump inhibitors (PPIs) can cause diarrhea; however, patients who took PPIs at the commencement of nintedanib were not excluded because corticosteroids-treated ILD patients frequently take PPIs (17) and the frequency of PPI-induced diarrhea is reported to be not so high (18). Patients with inflammatory bowel diseases (IBDs) (19) and IBS (20) should be excluded; however, patients who were not diagnosed as IBDs and IBS, and who experienced frequent bowel movements were included in the analysis.

Diagnosis of ILDs

IPF was diagnosed according to the 2022 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) guidelines for IPF (1). PPF was diagnosed following the 2022 ATS/ERS/JRS/ALAT guideline (1). ILDs other than IPF included idiopathic interstitial pneumonia (IIP) other than IPF (non-IPF IIPs) (21), fibrotic hypersensitivity pneumonitis (FHP) (22), connective tissue disease-related ILDs (CTD-ILDs) (23-26), pulmonary alveolar proteinosis related pulmonary fibrosis (27), and asbestosis.

Clinical findings of enrolled patients with ILD at the start of nintedanib

Clinical findings, including age, sex, administered drugs, comorbidities, body mass index (BMI, kg/m²), smoking status, modified Medical Research Council (mMRC) score (28), pulmonary function test results, including percent predicted value of forced vital capacity (%FVC) and percent predicted value of diffusing capacity of carbon monoxide (%DLco), and laboratory test results [albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT)] at the time of ILD diagnosis were obtained retrospectively from medical records. Body surface area (BSA, m²) was calculated using the Du-Bois equation (29).

Biomarker measurements

Monocyte counts of peripheral blood were measured using hematology analyzer, UniXel DxH 900 (Beckman Coulter, Brea, CA, USA), which was calibrated by Coulter 6C Cell Control (Beckman Coulter) twice every day. Serum levels of Krebs von Lungen-6 (KL-6, U/mL) were measured by Nanopia KL-6 (Sekisui Medical, Takyo, Japan) and serum levels of surfactant protein-D (SP-D, ng/mL) by commercially available Enzyme linked Immunosorbent Assay Kit (Yamasa, Tokyo, Japan) (30). Cutoffs of KL-6 and SP-D were 500 U/mL and 110 ng/mL, respectively (30). These three biomarkers were measured at the multiple points and values at the nearest points before initiation of nintedanib were used in this study. Allowed interval between biomarker measurement and nintedanib administration was one months for monocyte counts and three months for KL-6 and SP-D. The actual interval was a median of 1 day [interquartile range (IQR), 0–3 days] for monocytes and a median of 3 days (IQR, 0–16 days) for KL-6 and SP-D.

Frequency of stool before nintedanib usage and occurrence of nintedanib-induced diarrhea

We interviewed each participant regarding the frequency of stool formation before administering nintedanib, the occurrence of diarrhea after administering nintedanib, the interval between nintedanib administration and the onset of diarrhea, the daily frequency of diarrhea, and the stool form.

Frequency of diarrhea was described using the Common Terminology Criteria for Adverse Events (CTCAE) grade (31); increase of <4 stool per day over baseline (Grade 1), increase of 4–6 stools per day over baseline (Grade 2), and increase of ≥7 stools per day over baseline (Grade 3). CTCAE grade was evaluated at the severest time point. Stool form was classified as watery, formless and loose, or soft stool, with watery stool being the most severe form of diarrhea (20). The interval between the administration of nintedanib and the onset of diarrhea was classified into ≤2 days, ≥3 days and ≤7 days, >1 week and ≤2 weeks, >2 weeks and ≤1 month, >1 month and ≤2 months, >2 months and ≤3 months, and >3 months.

Statistical analysis

Distribution of continuous variables was examined by Kolmogorov-Smirnov normality test. Normally distributed variables were expressed as mean ± standard deviation. Continuous variables, which were not normally distributed, were expressed as median (IQR). Categorical variables were presented as numbers. Non-normally distributed continuous variables in the two groups were compared using the Mann-Whitney U test and normally distributed variables were compared using Student’s t-test. Categorical variables were compared using Pearson’s Chi-squared test for parameters with an expected value more than 5 in all items and using Fisher’s exact test for those with an expected value less than 5 in any item. %FVC was classified into within normal range (≥80%) or not (32) because clinical significance of absolute %FVC could be different according to the types of ILDs in detail. For example, %FVC is reported to be significantly lower in idiopathic pleuroparenchymal fibroelastosis (I-PPFE) than that in IPF; however, %DLco and arterial oxygen tension was similar between the two diseases (33). Similar %FVC does not always suggest similar severity in IPF and I-PPFE. Afterwards, multivariate logistic regression analysis (forced entry method) using parameters with P<0.10 by univariate analysis and other clinically important parameters (%FVC, nintedanib dose per BSA, age and gender), was performed. Cox proportional hazard regression analysis was not performed because the exact date of onset of diarrhea was unknown according to our method.

Cutoff values of each biomarker to predict nintedanib-induced diarrhea were examined using receiver operating characteristic (ROC) curve analysis, and levels of each biomarker were classified into higher and lower using the cutoff values. Odds ratios (ORs) to predict diarrhea within three months using higher levels of each parameter were examined by univariate logistic regression analysis and 95% confidence interval (CI) of the ORs were confirmed by the bootstrap method. The Significance of higher levels of each biomarker to predict diarrhea were adjusted by multivariate analysis using significant clinical parameters.

All statistical analyses were performed using SPSS Statistics for Macintosh v.29 (IBM Corp., Armonk, NY, USA). Statistical significance was set at P<0.05.

Results

Patient demographics

Overall, 134 patients with ILD were treated with nintedanib, 34 were excluded before this study because of death (n=14), no follow-up at NHO Kinki Chuo Chest Medical Center (n=13), and no informed consent (n=7); the remaining 100 patients were enrolled in this study after obtaining informed consent. Of the 100 patients, 21 were excluded because of antibiotic administration at the onset of diarrhea (n=10), no recollection of diarrhea (n=3), and nintedanib treatment period was <3 months (n=8) (Figure 1), and all eight patients were alive for >3 months. Therefore, 79 patients were included in this analysis (Table 1). The median age was 73 years, and 57 patients were men. The underlying ILDs included IPF (n=39) and PPF (n=40). %FVC was <80% in 31 out of 79 patients (39.2%). Only 6 of the 79 patients had died at the end of March 2025.

Background data were compared between the IPF and PPF patients (Table 2). Patients with IPF included significantly more patients with %FVC ≥80% than PPF patients. No patient with IPF was treated with corticosteroids; however, 14 of 40 PPF patients were treated with corticosteroids.

Predictive factors of the incidence of diarrhea within 3 months for all patients

Univariate analysis was performed to predict diarrhea within 3 months of nintedanib administration. IPF, 300 mg daily nintedanib administration, higher nintedanib dose per BSA, and corticosteroid therapy at the onset of treatment were significant predictors (Table 3). Age, gender, bowel habits before nintedanib administration, smoking status, and %FVC <80%, were not associated with diarrhea.

Multivariate analysis revealed that corticosteroid therapy [OR 0.114 (95% CI: 0.018–0.724), P=0.02], higher nintedanib dose per BSA [OR 1.025 (95% CI: 1.005–1.047), P=0.02], IPF [OR 3.737 (95% CI: 1.008–13.849), P=0.049], and %FVC <80% [OR 8.103 (95% CI: 1.642–40.003), P=0.01] were significant predictive factors of diarrhea occurrence (Table 3).

Biomarkers to predict the occurrence of induced diarrhea

Serum biomarkers, including KL-6 and SP-D, and monocyte counts in the peripheral blood were examined to predict the occurrence of diarrhea (Table 4) using ROC analysis. Five patients with KL-6 and SP-D missing were excluded from the analysis for the two biomarkers. Monocyte counts and serum SP-D possess P values <0.10. The categorical variables were made using the cutoffs of these continuous variables to predict diarrhea (monocyte counts >650/µL and serum SP-D >157.5 ng/mL, respectively). Both monocyte counts >650/µL and serum SP-D >157.5 ng/mL were significant predictors of diarrhea incidence by univariate logistic regression analysis [OR 0.270 (95% CI: 0.101–0.723) and OR 3.889 (95% CI: 1.397–10.829), respectively] (Table 5). Using bootstrap method, 95% CI of OR was confirmed: 0.093–0.681 (P=0.009) for monocyte counts >650/µL and 1.370–13.263 (P=0.008) for SP-D >157.5 ng/mL. The predictive values of the two parameters were also significant after the adjustment by multivariate logistic analysis using the four general significant predictors shown in Table 3. Using bootstrap method, 95% CI of adjusted OR was confirmed: 0.046–0.882 (P=0.02) for monocyte counts >650/µL and 1.094–22.331 (P=0.04) for SP-D >157.5 ng/mL.

Discussion

The incidence of diarrhea after initiating nintedanib treatment was evaluated as 82% in patients with IPF and 50% in patients with PPF in the real-world setting of our study. We examined the predictive factors for nintedanib-induced diarrhea in patients with IPF or PPF from other ILDs. IPF, no corticosteroid therapy, a higher dose of nintedanib per BSA, and a lower %FVC were associated with diarrhea within 3 months of initiating nintedanib administration. Bowel habits (i.e., daily stool frequency) before nintedanib administration were not associated with the occurrence of nintedanib-induced diarrhea, although, this is an important point in the selection of nintedanib as an antifibrotic drug for patients with ILD. Additionally, we have shown that lower monocyte counts in the peripheral blood and higher levels of serum SP-D was a potential predictor of the occurrence of diarrhea.

Approximately 70% of the patients with IPF in the INPULSIS trial (2) and those with PPF in the INBUILD trial (4) experienced diarrhea in the nintedanib arm. Hence, we hypothesized that no difference exists in the frequency of diarrhea between patients with IPF and PPF. However, we have shown that patients with IPF experience diarrhea more frequently than those with PPF. There were many differences in the background characteristics between the IPF and PPF groups. Recently, nintedanib administration has been recommended for early IPF (34), whereas apparent progression is needed to initiate treatment with nintedanib for PPF. Hence, the severity of PPF, as shown by %FVC, was significantly worse than that of IPF in our study, and corticosteroids were administered only for PPF. An IPF diagnosis was a significantly associated with nintedanib-induced diarrhea after the adjustment with other important parameters.

We have shown that the use of corticosteroids significantly determined the occurrence of diarrhea by multivariate analysis. Kato et al. also reported that the absence of corticosteroid treatment could significantly predict the occurrence of diarrhea in patients with nintedanib-treated IPF (35). Their results might support our study results; however, their analysis did not include the duration of nintedanib treatment and duration between the commencement of nintedanib and onset of diarrhea different from our study. Hence, additional studies are required to confirm that no corticosteroid therapy significantly predicts diarrhea. Effectiveness of budesonide for nintedanib-induced colitis in a patient with IPF (36), reported by Amini et al., is consistent with our finding that not using corticosteroids for ILD significantly determines the occurrence of nintedanib-induced diarrhea. A colonoscopy revealed an erythematous, friable, and granular mucosa in the cecum in the patient; however, whether similar colonoscopy findings of mucosal inflammation is observed in all patients with diarrhea is unclear.

As for generally important factors in patients with ILD, %FVC and smoking are our focus. Ogura et al. revealed that patients with IPF with <70% FVC demonstrated significantly more frequent discontinuation of nintedanib (16). This result was consistent with our finding that a lower FVC significantly predicts nintedanib-induced diarrhea. IBDs are associated with smoking (37). Ulcerative colitis (UC) is more common in non-smokers than in those who recently quit smoking. Additionally, the disease course is worse in patients with UC who quit smoking than in those who continue smoking (37). However, we established that smoking was not associated with nintedanib-induced diarrhea. Bowel habits (i.e., daily stool frequency) before nintedanib administration were not associated with the occurrence of nintedanib-induced diarrhea. Furthermore, this is an important point in the selection of nintedanib as an antifibrotic drug for patients with ILD.

We have shown that a lower monocyte count was significantly associated with diarrhea. This might be inconsistent with a previous report that higher monocyte counts suggest adverse events requiring nintedanib dose reduction (15). Their study was performed retrospectively, and we assumed that the incidence of diarrhea might not have been strictly evaluated, as shown by the comparably low frequency of 37 of 111 patients (33.3%). The relationship between of diarrhea and monocyte count has not been examined directly and all adverse events might not be similarly associated with monocyte counts. Understanding the pathophysiological role of monocytes in pulmonary fibrosis and diarrhea is essential for discussing monocyte count as a predictor of nintedanib-induced diarrhea.

Monocytes in peripheral blood can exert profibrotic effects by differentiating into M2 macrophages in IPF (38) and bleomycin-induced lung fibrosis model mice (39), although M2 macrophages are reported to promote the repair of epithelial injury and the resolution of inflammation (38,40). Higher monocyte counts significantly predict poor survival (41) and acute exacerbation (17,42) in IPF. Higher monocyte counts (>650/µL) also suggested poor survival of fibrotic ILDs (43). In a bleomycin-induced lung fibrosis model, the depletion of peripheral monocytes reduced pulmonary fibrosis by lowering the number and altering the population of lung macrophages (39).

Monocyte counts are supposed to have additional association with pathophysiology of colitis. In patients with IBD (19,44) and in a mouse model of colitis (45,46), M1-predominant macrophage polarization and proinflammatory monocytes are reported to be associated with disease activity through pro-inflammatory effects. Based on these pathophysiological roles of monocytes in ILDs and colitis, in ILD patients, monocytes in the peripheral blood, which can differentiate into M2 macrophages, possibly migrate into the mucosal lesions of intestinal epithelial injury caused by nintedanib, reduce inflammation, induce mucosal injury repair, and resolve or suppression of diarrhea. Inhibitory effects of corticosteroids on the occurrence of nintedanib-induced diarrhea might be explained by its suppressive effects on M1 macrophage polarization (47,48). As for immunosuppressants, tacrolimus ameliorated bleomycin-induced pulmonary fibrosis in vivo by inhibiting M2 macrophage polarization (49) and we hypothesized that tacrolimus aggravates nintedanib-induced diarrhea; however, tacrolimus did not affect the occurrence of nintedanib-induced diarrhea in our study.

Based on our hypothesis that lower monocyte counts are associated with diarrhea, and previous studies showing that lower monocyte counts are associated with better survival, patients with nintedanib-induced diarrhea could survive longer than those without diarrhea. From the standpoint of nintedanib responsiveness, nintedanib is shown to suppress monocyte differentiation to M2 macrophage (50) and nintedanib-induced diarrhea might happen in nintedanib responsive patients through M1 polarization. In other words, diarrhea might be easy to occur in patients with good prognosis, who shows good response to nintedanib. This hypothesis is supported by the positive association confirmed between the efficacy of the epidermal growth factor TKI erlotinib and rash, an adverse event in patients with lung cancer (51). However, in nintedanib-treated patients with IPF, occurrence of diarrhea did not suggest better efficacy in the post-hoc analysis of the INPILSIS trial (52). Kato et al. reported worse survival in nintedanib-treated patients with IPF and diarrhea than in those without diarrhea (35) although duration of nintedanib use was not described in detail. Further studies are needed to clarify the prognostic value of nintedanib-induced diarrhea in patients with ILD.

Unpredictably, association between serum SP-D levels and nintedanib-induced diarrhea was suggested in this study. SP-D is produced in the intestinal epithelial cells (53) in addition to alveolar epithelial cells, well-known producing cells. Association between SP-D polymorphisms and UC susceptibility (54) and between SP-D positivity of immunohistochemistry on IBD surgical specimens and disease activity (55) supports possible pathophysiological role of SP-D in nintedanib-induced diarrhea. Osteoclast-associated receptor (OSCAR) binds to the SP-D collagenous domain and is expressed on the surface of C-C chemokine receptor type 2 (CCR2)⁺ monocytes in the peripheral blood. OSCR⁺CCR2⁺ monocytes in the peripheral blood are activated by SP-D and produce inflammatory cytokines (56). Hence, in patients with higher SP-D levels, we suppose that inflammatory monocytes activated by SP-D possibly aggravate intestinal injury leading to severe and frequent nintedanib-induced diarrhea. Inflammatory effects of SP-D have also been reported in lung diseases. Intratracheal anti-SP-D antibody administration attenuates the severity of acute lung injury (57). The significant value of higher SP-D in a stable state in predicting poor survival of acute exacerbation in ILD (58), might also be consistent with the inflammatory function of serum SP-D.

This study has certain limitations. This was a retrospective, single-center study, and a limited number of patients were included. However, the incidence and severity of diarrhea were re-evaluated through additional interviews. Our method using interview to the patients might include recall bias as a matter off course; however, we suppose the documents on diarrhea in the medical records of daily clinical practice were also insufficient. Our interview-based study supposedly reflected the occurrence of nintedanib-induced diarrhea more accurately than the medical record-based study. Second, we had to exclude the patients, who has already died, who has moved to other hospitals, and from whom informed consent could not be obtained due to our interview-based method. We could not avoid selection bias especially due to the exclusion of dead patients, who was supposed to be severe. Third, the study did not include a completely validated cohort. We confirmed the significance of each parameter using multivariate analysis with forced entry method, especially monocyte count and serum SP-D levels. Fourth, the cutoff value for nintedanib-induced diarrhea was determined using ROC curve analysis. Monocyte >650/µL is like the monocyte >600/µL, which suggests poor survival of IPF in the clinical trials (41) and in our previous study (42). The cutoff for each biomarker might be better updated in another large-scale study. The pathophysiological roles of monocytes and SP-D in nintedanib-induced diarrhea should be confirmed in future clinical and basic research. Fifth, many drugs, viral infection, diet, and many other factors might be complicated with diarrhea. All factors could not be collected and included in the analysis. More number of patients are needed to perform detailed analysis using all the parameters.

Conclusions

Nintedanib-induced diarrhea is significantly associated with various complex factors. IPF, no corticosteroid therapy, a higher nintedanib dose per BSA, and a lower %FVC were associated with the occurrence of diarrhea within 3 months of initiating nintedanib therapy. Lower monocyte counts and higher levels of serum SP-D at the initiation of nintedanib might suggest occurrence of diarrhea. This is the first report showing potential biomarker suggesting nintedanib-induced diarrhea. Although large-scale studies are needed to draw definite conclusions regarding our hypothesis, the results of our study and hypothesis of nintedanib-induced diarrhea might suggest future research direction and lead to new management of nintedanib-induced diarrhea.

Acknowledgments

We thank Ms. Natsumi Matsumura, Ms. Miho Umehara, and Ms. Chihiro Inotani (Department of Nutrition School of Human Life and Ecology, Osaka Metropolitan University, Osaka, Japan) for their interviews with each patient. We are grateful for the data acquisition from the medical records of Ms. Sayaka Tanaka (Clinical Research Center, NHO Kinki Chuo Chest Medical Center, Sakai, Osaka, Japan).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-938/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-938/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-938/prf

Funding: This work was partially supported by the Study Group on Diffuse Lung Disease and Scientific Research on Intractable Diseases of the JMHLW (Program Grant Number JPMH20FC1030, to T.A.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-938/coif). T.A. received funding support by the Study Group on Diffuse Lung Disease and Scientific Research on Intractable Diseases of the JMHLW (Program Grant Number JPMH20FC1030); received the lecture fees from Boehringer Ingelheim, Shionogi, AstraZeneca, Sekisui Medical, and funds from Sekisui Medical and Sysmex for activities not connected to the submitted work. M.M. received lecture fees from Boehringer Ingelheim and Shionogi. T.T. received lecture fees from Shionogi. Masaki Hirose has received grants from Japanese Respiratory Society Boehringer Ingelheim Research Grant and Grants-in-Aid for Scientific Research (24K11332). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the NHO Kinki Chuo Chest Medical Center Institutional Review Board (approval number Rin2023-122, approval date 2024/3/25). Informed consent for the inclusion in this study was obtained from the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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