Prevalence of distress and changes over time among patients with progressive fibrosing interstitial lung disease

Prevalence of distress and changes over time among patients with progressive fibrosing interstitial lung disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Prevalence of distress and changes over time among patients with progressive fibrosing interstitial lung disease Tomoko Yamada, Koji Sugano, Kei Matsuno, Saori Hotta, Mitsuhiro Fujii, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4590296/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Patients with progressive fibrosing interstitial lung disease (PF-ILD) frequently experience respiratory symptoms and decline in activities of daily living (ADL) and quality of life (QOL) with disease progression. However, no effective treatment or palliative care strategy has been established for patients with PF-ILD. This study aimed to clarify the degree of physical and psychological distress in patients with PF-ILD and to evaluate symptom changes over a one-year period in patients with idiopathic pulmonary fibrosis (IPF) and those with other PF-ILDs (non-IPF). Methods Consecutive patients diagnosed with PF-ILD were recruited. The participants were divided into two groups and evaluated at registration (T0), 26 weeks (T1), and 52 weeks (T2) after registration. They were also followed-up for symptoms, ADL, QOL, depressive condition, laboratory findings, and other factors from study registration to 52 weeks (T2). Results Of the 70 patients with PF-ILD, 32 had IPF and 38 did not. The IPF and non-IPF groups showed no noticeable differences in clinical symptoms or laboratory findings on multivariate analysis at T0. The repeated-measures analysis of variance used to observe the changes over the course of the year in both groups showed that dyspnea in patients with IPF worsened from T1 to T2. In contrast, cough, which is one of the major symptoms in non-IPF patients, worsened, especially from T0 to T1 and T0 to T2. The QOL of non-IPF patients also declined from T0 to T1. Conclusions Patients with PF-ILD demonstrated several clinical signs and symptoms. In this one-year follow-up study, dyspnea tended to be worse in patients with IPF and cough in non-IPF patients, and QOL was temporarily worse in non-IPF patients. Respiratory symptoms are directly related to the patient's daily life and led to reduced QOL. Therefore, further long-term studies in this population are required. progressive fibrosing interstitial lung disease palliative care dyspnea activities of daily living quality of life Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Progressive fibrosing interstitial lung disease (PF-ILD) is characterized by decreased respiratory function, worsening symptoms, and lung fibrosis on chest high-resolution computed tomography (HRCT). The term “PF-ILD” is used to refer to a group of diseases with poor prognoses that lead to death through exacerbation of the disease despite therapy [ 1 , 2 ]. PF-ILD includes idiopathic pulmonary fibrosis (IPF), other unexplained interstitial pneumonia, the so-called idiopathic interstitial pneumonias (IIPs), interstitial lung disease associated with connective tissue (CTD-ILD), chronic hypersensitivity pneumonitis, and various interstitial lung diseases such as sarcoidosis and organizing pneumonia [ 3 , 4 ]. IPF is commonly characterized by chronic and progressive fibrosis of unknown cause [ 1 ] and demonstrates a radiological pattern known as usual interstitial pneumonia (UIP) on HRCT scans. IPF shows a particularly rapid progression and poor prognosis among PF-ILD, with an average time from diagnosis to death of ≤ 5 years [ 3 ]. In Japan, the total number of patients with IPF is estimated to be approximately 34,000 based on the number of recipients of designated intractable diseases for each primary disease, disease incidence surveys, and publications [ 5 ]. Patients with PF-ILD frequently show respiratory symptoms such as cough, sputum, and unbearable dyspnea with disease progression [ 6 ], which decreases their activities of daily living (ADL) and quality of life (QOL) [ 7 ]. In addition, patients in the end-of-life (EOL) phase experience psychological, social, and existential distress as the disease progresses and show reduced ADL, resulting in a decline in QOL [ 8 ]. In these patients, pulmonary function tests may reveal reduced forced vital capacity (FVC), total lung capacity (TLC), and diffusing capacity of the lungs for carbon monoxide (DL CO ) [ 2 ]. Management of PF-ILD requires a combination of pharmacological and nonpharmacological treatments [ 9 ]. Antifibrotic drugs inhibit the progression of the decline in lung function and prevent acute exacerbations [ 10 , 11 ]. Acute exacerbations may occur with specific triggers, such as infection, surgical invasion, drug toxicity, and aspiration, or without specific triggers, and are characterized by sudden and usually severe respiratory deterioration with new bilateral opacities on HRCT scans [ 4 , 12 ]. Patients showing acute exacerbations are primarily treated with systemic steroids; however, their prognosis is poor. Pulmonary rehabilitation can improve functional exercise capacity and QOL and relieve distressing symptoms such as dyspnea in the short term, potentially offering benefits in patients with IPF [ 13 , 14 ]. Oxygen therapy is essential for patients with advanced disease and respiratory failure [ 15 ]. The comprehensive care of patients with PF-ILD should include disease treatment, symptom management, patient education, and self-management based on a strong relationship of trust between healthcare providers and patients [ 16 ]. Nevertheless, treating patients with PF-ILD in the actual clinical setting is often difficult because evidence supporting symptom management is limited [ 17 ]. Moreover, in comparison with other lung diseases, such as lung cancer, no effective treatments for the progression of fibrosis and palliative care for PF-ILD have been established [ 18 ]. Few clinical studies on patients with IPF have clarified effective treatments and palliative care regimens [ 19 ]. A previous study also reported inadequate EOL care in patients with PF-ILD, since early intervention is often difficult because of a lack of symptoms, disease awareness, and variability in the clinical course [ 20 ]. Despite the known importance of changes requiring early intervention, previous studies have not demonstrated the point at the disease course at which the symptoms are likely to appear or change. No study has compared the clinical course of IPF with that of other PF-ILD (non-IPF), focusing not only on respiratory symptoms but also psychological symptoms. Rapid determination of the presence or absence of any symptom changes within a short period in the disease trajectory may facilitate the provision of effective management and highly satisfactory palliative care at an appropriate time or at an early stage. Therefore, this study aimed to clarify the degree of physical and psychological distress in patients with PF-ILD and to evaluate symptom changes in IPF patients with non-IPF patients over a one-year period. Methods Ethical approval This study was approved by the Ethics Committee of the Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan, and was conducted in accordance with the Declaration of Helsinki. Study participants This study included patients with interstitial pneumonia who visited or were admitted to several affiliated hospitals, including our university hospital. The patients had been diagnosed with interstitial pneumonia and met the definition of PF-ILD. PF-ILD was defined by the spread of fibrosis in more than 10% of the chest HRCT scans and disease progression within 24 months meeting the following criteria: 10% or more decrease in FVC, 5%-10% decrease in FVC and progression of image findings, 5%-10% decrease in FVC and progression of symptoms, or progression of image findings and symptoms. IPF was defined as a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause and was associated with the histopathological and/or radiologic patterns of UIP [1]. Non-IPF was defined as other unexplained interstitial pneumonia that could result in PF-ILD. We compared the findings for cases showing IPF, which has a poor prognosis and often cause severe symptoms in clinical settings, with those that did not show IPF. Exclusion criteria: Clinical diagnosis of severe mental or cognitive disorders, inability to fully understand the contents of the study protocol for the interview and examination, or inability to participate in the study as judged by the attending physician. Criteria for discontinuation: The study was discontinued when the patient declined to participate in the study or withdrew consent, when the patient died, or when the attending physician determined that the patient is not suitable for participation in the study for other reasons. Written consent was obtained from each eligible patient after a thorough explanation of the purpose and methods of the study. When the participants could not fully understand the contents of the study protocol, the patients’ oral consent and their surrogates’ written consent were obtained. All participants were orally explained the details of PF-ILD by their primary physicians. Procedures Patients diagnosed with PF-ILD were consecutively recruited for one year, starting in June 2021, with a one-year follow-up after enrollment. Research registration was performed within three weeks of consent. Each patient was observed at registration and 26 and 52 weeks after registration. “T0” was defined as the point of registration, “T1” as the point 26 weeks after registration, and “T2” as the point 52 weeks after registration. A margin of error of four weeks before and after treatment was allowed for T1 and T2. Respiratory symptoms, ADL, QOL, depressive conditions, and other possible explanatory factors were evaluated using validated measurements at each point. The research team performed the assessments described below at each point. The research team also noted the reasons for dropouts during the study period. The physician set the patient identification code at the time of registration, linked it to the patient chart number, and ensured that leakage of personal information was avoided. All documents and data related to this study were carefully stored and protected at each medical institution until the end of the study. Measurements We evaluated the changes in the symptoms and other factors of the participants. Physical evaluations were as follows: respiratory symptoms of dyspnea were evaluated by the modified British Medical Research Council (mMRC) scale [21] and rated on a 5-point scale from 0 (the mildest degree of dyspnea) to 4 (the most severe). Symptoms of cough and sputum were evaluated by visual analogue scale (VAS) [22,23], which records patients’ assessment of symptom severity on a 100-mm linear scale ranging from “no cough or sputum” (0 mm) to “worst cough or sputum” (100 mm). ADL was evaluated using the Barthel Index [24]. In the Barthel Index, each of the 10 items of exertion, which included eating, dressing, bathing, walking, climbing stairs, changing clothes, and toileting, were rated on a 100-point scale. In this study, the Barthel Index was categorized as 60 points or less (2), 61–90 points (1), and 91 points or more (0), and categories 1 or 2 were considered to indicate disability while 0 indicated the absence of disability. Blood tests included measurement of the white blood cell count and the levels of C-reactive protein (CRP), total protein, albumin, liver function, renal function, creatine phosphokinase, markers of interstitial pneumonia (Krebs von den Lungen-6 [KL-6] and surfactant protein-D [SP-D]), and collagen disease-related antibodies, and arterial blood gas analysis. Respiratory function tests included measurement of FVC, forced expiratory volume in 1 s (FEV1.0), DL CO , TLC, and residual volume. The imaging tests included chest radiography and HRCT. QOL was evaluated using the EuroQol 5-dimensions 3-levels (EQ-5D-3L). The EQ-5D-3L is a self-reported survey that measures QOL across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain was scored on a 3-level severity ranking ranging from 1 (no problems) to 3 (extreme problems) [25]. The psychological domain of depressive symptoms was assessed using the Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms. The validity of the Japanese version of the questionnaire has been verified. This measure consisted of nine items with the same four response options for each item: 0 (not at all) to 3 (nearly every day) [26]. Medical and demographic data were obtained from the patients and medical records. Participants were also checked for vital signs, body height, and weight, in addition to completing a self-administered questionnaire. Blood examinations (including arterial blood gas analysis), 6-minute walk tests, respiratory function tests, and imaging tests were performed at T0, T1 and T2, which were performed after considering their general condition. Statistical analysis Univariate analysis was performed to explore potential explanatory factors associated with IPF and non-IPF at baseline. Intergroup differences in the categorical, non-parametric, and continuous variables were tested by the chi-square test (or Fisher’s exact test), Wilcoxon’s rank-sum test, and unpaired t-test, respectively. Factors with p < 0.10 were included in the multiple logistic regression analysis with forced entry. A significance level of p < 0.05 was adopted for all statistical analysis and P values reported were 2-tailed. Repeated-measures analysis of variance was also performed to evaluate disease progression in IPF and non-IPF patients at each point during the observation period. All analyses were conducted using SPSS software, version 29.0 J for Windows (SPSS Inc., 2022). Results Demographic and clinical characteristics Seventy potential participants were included in this study. Sixteen patients were excluded due to missing data. Table 1 showed the demographic and clinical characteristics of the patients. The patients were classified into those showing IPF (IPF group) and those showing PF-ILD other than IPF (non-IPF group). The mean (±SD) and median age of the participants in the IPF group were 78.5 (±6.9) and 79 years, respectively. Some patients receiving home oxygen therapy were unable to perform the respiratory function tests adequately. Note that in Table 1, ADL indicates the number of patients with even a slight decline. Factors differing between IPF and non-IPF on T0: univariate and multivariate analyses In comparison with non-IPF participants, those with IPF were more likely to have a smoking history, be hypertensive, have less complicated cancer, have more severe cough, have lower ADL, have lower %FVC levels, and receive treatment with antifibrotic drugs and home oxygen therapy. Table 2 showed the factors associated with IPF at T0. A multiple logistic regression analysis showed that cancer complications were more common in non-IPF patients; however, among patients with cancer, the proportion of those showing lung cancer was not significantly different between the IPF and non-IPF groups. The two groups showed no other significant differences in clinical symptoms or laboratory findings. Changes observed in both groups over the course of a year Multiple patients dropped out of the study during the 1-year follow-up period: ten patients dropped out before reaching T1, five patients died, including one with acute exacerbation, two patients were transferred to home or a facility, and three withdrew study consent. Thirteen patients dropped out of the study before reaching T2: six patients died, including one with acute exacerbation, four were transferred, and three were unable to continue the study. Patients who were eligible to continue the study were evaluated for changes in the following factors during the study period: cough, sputum, dyspnea, ADL, depression, QOL, and LDH, KL-6, and SP-D levels. Figure 1 demonstrated that dyspnea assessed by the mMRC scale in patients with IPF worsened from T1 to T2 ( p = 0.02, 95%CI 0.09 to 1.19) but not from T0 to T1, while the patients in the non-IPF group showed no worsening of dyspnea from T0 to T1 to T2. Patients with IPF did not show worsening of cough, whereas non-IPF patients showed worsening of cough over time from T0 to T1 ( p = 0.01, 95%CI 2.38 to 23.61) and T2 ( p = 0.02, 95%CI 2.18 to 27.76) (Figure 2). In addition, patients with IPF did not show any changes in QOL over time; however, non-IPF patients showed a decline in QOL from T0 to T1 ( p = 0.03, 95%CI 0.009 to 0.211), and this decline was prolonged from T1 to T2 (Figure 5). In contrast, both IPF and non-IPF groups showed no changes in sputum production, ADL, and depression over time (Figure 3, 4, and 6). Discussion To clarify the degree of distress in patients with PF-ILD, we examined each factor at the beginning of the study and evaluated the changes in symptoms over the course of one year in the IPF and non-IPF groups. Since IPF has a poor prognosis, tends to show variable respiratory symptoms or distress, and often results in acute exacerbations in daily clinical practice, we decided to evaluate the symptom changes separately in IPF and non-IPF groups in the present study. Patients with IPF tended to have a strong cough, history of smoking, and fewer cancer complications at baseline. In contrast, the two groups showed no significant differences in other background factors, including lung cancer complications, other symptoms, or laboratory results. However, our study demonstrated that while patients with IPF showed only worsening of dyspnea, those with non-IPF showed worsening of cough and reduced QOL during the one-year follow-up period. IPF accounts for approximately half of all cases of progressive pulmonary fibrosis and has a stronger and poorer prognosis than other PF-ILD [3]. PF-ILD is characterized by respiratory symptoms and disease progression, which result in a decline in ADL and QOL [8]. Our study showed worsening of dyspnea in patients with IPF from six months to one year after recruitment. No notable changes in the administration of steroid-containing medications for respiratory symptoms were noted during the research period; however, half of the patients with IPF had been receiving home oxygen therapy since the start of this study. Despite the lack of clarity regarding the therapeutic usefulness of treatment including steroids, opioids, or respiratory rehabilitation, background factors, and individual characteristics, the finding showing worsening of dyspnea over six months may be an indicator for follow-up period and symptom management. In contrast to the findings for the IPF group, non-IPF patients showed worsening cough and a temporary decline in QOL in our study. Cough is a common symptom of chronic pulmonary diseases, and PF-ILD is no exception. Chronic coughing increases the disease burden in patients. A previous study found that cough predicts disease progression in patients with IPF [6]. Although the cause of cough in non-IPF patients has not yet been understood, underlying inflammation or fibrosis and comorbidities may be involved. Another study showed that the mechanism underlying cough in IPF may involve mechanical distortion associated with lung parenchymal fibrosis [27]. The role of some forms of airway inflammation or the physical condition and surrounding environmental factors at the time of the assessment was also undeniable. Although one report on cough in patients with IPF indicated the important roles of increased cough reflex sensitivity, gastroesophageal reflex, and airway inflammation [27], the specific management of cough in patients with PF-ILD has not been reported in previous studies. To the best of our knowledge, general antitussive therapy does not improve the chronic cough caused by PF-ILD. Although a persistent cough is an extremely important factor worth consideration in the palliative care phase, evidence regarding the effectiveness of therapeutic agents, including opioids, is insufficient, and a comprehensive multidisciplinary approach consisting of treatment and care is required. The QOL in patients with non-IPF declined six months after the start of the study and showed no trend of improvement within the study period. In contrast, no reduction in QOL was observed in the patients with IPF in our study. Reductions in QOL can be attributed to several reasons, but cough may have had an impact in our study. Nevertheless, prolonged coughing eventually leads to a loss of strength and secondary sarcopenia, which may occur in both IPF and non-IPF patients. Half of the patients with pulmonary sarcoidosis, which is included in PF-ILD, had chronic cough, which is associated with a poor QOL [28]. Other studies have shown that non-IPF patients with cough had higher odds of lower cough-specific QOL than patients with IPF [29]. Our study suggests that this trend may be applicable to non-IPF patients over a relatively short period. The results indicated that the trajectory of PF-ILD may be similar to that of cancer, which deteriorates in a relatively short period of time during the final stages of the disease [30]. Although a previous study investigated QOL in patients with PF-ILD [8], none of the existing studies have reported significant reductions. The decline in QOL for each disease that constituted PF-ILD could not be examined individually in the present study; however, some of the non-IPF patients who entered the study were diagnosed with nonspecific interstitial pneumonia or CTD-ILD. Thus, while the medical condition of the primary disease may have had an impact, other factors could not be identified in our study. Symptoms of sputum, ADL, and depression did not differ over time in IPF and non-IPF patients. One reason for this is that patients with IPF as well as the non-IPF patients, such as those with IIPs and sarcoidosis, experienced a persistent dry cough with low sputum volume [3,31], making it difficult to be aware of changes in sputum symptoms over time. Another reason is that patients with IPF tended to have lower ADL at the time of registration, whereas the non-IPF patients often had a background of cancer. IPF is often associated with lung cancer, and no prospective studies have reported significantly more lung cancer complications in patients with non-IPF than in those with IPF. Although non-IPF may also be strongly associated with smoking and exposure to carcinogens, like in IPF [32], we could not determine why the non-IPF group had more cancers. Although some patients were receiving home respiratory rehabilitation as part of their nonpharmacological treatment, we could not exclude the possibility that the addition of respiratory care may have already influenced the findings at the beginning of this study or the absence of symptom changes over the course of one year. This study has several limitations. First, the sample size was small. The number of registered patients did not increase owing to a decrease in the number of outpatients and difficulties in coming to the hospital because of the coronavirus disease 2019 (COVID-19) pandemic. Moreover, respiratory function tests could not be performed in some cases due to changes in physical symptoms, and in some cases, patients refused to undergo the tests due to COVID-19. Second, patients with missing values who dropped out of the study were also excluded. Since the hospital with the largest number of enrolled cases was a medical institution specializing in the elderly, comorbidities such as cognitive decline or household-related factors may have affected the data collection. Furthermore, since the study included patients with PF-ILD, some participants dropped out during the one-year follow-up because they died or were unable to visit the hospital due to disease progression. Third, to ensure that the findings were more aligned to real-world conditions, we did not set strict inclusion criteria. Although almost all outpatients were enrolled, some may have had advanced disease and may have already undergone home oxygen therapy or rehabilitation, potentially causing a selection bias. Therefore, the changes in symptoms during the follow-up period may not have been not reflected in the data. Finally, we assessed dyspnea and QOL using the mMRC and EQ-5D, respectively. Considering the researchers’ workload, we used an evaluation scale that is commonly used in daily clinical practice. Although this was a validated assessment method, we considered the St. George’s Respiratory Questionnaire, which is commonly used in research. Conclusions PF-ILD is characterized by progressive respiratory symptoms and is highly distressing to patients; no sufficiently effective therapeutic strategies have been established to date. Respiratory symptoms are directly related to the patient's daily life and lead to reduced QOL. Although a variety of treatments and care are being provided in clinical settings, evidence supporting the suitability of these modalities for individual patients may be unavailable. This study, in which several symptoms were assessed over a short period, highlighted the significance of identifying and assessing the patient's distress as early as possible. Additional research is required to understand how PF-ILD affect the lives of patients over time. Abbreviations ADL activities of daily living COVID-19 coronavirus disease 2019 CTD-ILD interstitial lung disease associated with connective tissue DL CO diffusing capacity of the lungs for carbon monoxide EOL end-of-life EQ-5D EuroQol 5-dimensions FVC forced vital capacity HRCT high-resolution computed tomography IIP idiopathic interstitial pneumonias IPF idiopathic pulmonary fibrosis KL-6 Krebs von den Lungen 6 PHQ-9 Patient Health Questionnaire-9 QOL quality of life SP-D surfactant protein-D TLC total lung capacity UIP usual interstitial pneumonia VAS visual analogue scale Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of the Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan, and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all the participants. Consent for publication Not applicable. Availability of data and materials The data analyzed in this study are available from the corresponding author upon request. Competing interests The authors declare that they have no competing interests. Funding The authors declare no funding. Authors’ contributions Conceived and designed the experiments: TY, KS, KT Performed the experiments: TY, KS, KM, SH, MF, HI Analyzed the data: TY, KS, KM, SH, MF, HI, KT Wrote the paper: TY, KS, KM, SH, MF, HI, KT Acknowledgments The authors gratefully acknowledge the support of the study participants, their families, medical staff, and physicians. We also would like to thank Editage (www.editage.jp) for English language editing. References Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An Official ATS/ERS/JRS/ALAT Statement: idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med. 2011;183:788-824. Lederer DJ, Martinez FJ. 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Vigeland CL, Hughes AH, Horton MR. Etiology and treatment of cough in idiopathic pulmonary fibrosis. Respir Med. 2017 Feb;123:98-104. Naccache JM, Gibiot Q, Monnet I, Antoine M, Wislez M, Chouaid C, et al. Lung cancer and interstitial lung disease: a literature review. J Thorac Dis. 2018;10:3829-44. Tables Table 1. Demographic and clinical characteristics of the patients ( n = 70) 95% CI Sample characteristics IPF ( n = 32) non-IPF ( n = 38) p value Lower Higher Male sex, n (%) 23 (72%) 22 (58%) 0.23 -0.09 0.37 Age, years 78.53±6.90[54-87] 79.37±5.68[69-90] 0.58 -3.84 2.16 mean：79.0 mean：80.0 BMI (kg/㎡) 22.70±3.58 23.22±3.25 0.52 -2.17 1.11 Smoking history, n(%) 28 (88%) 24 (63%) 0.02 0.03 0.44 Medical history COPD, n(%) 6 (19%) 10 (26%) 0.46 -0.27 0.12 Asthma, n(%) 4 (13%) 8 (21%) 0.35 -0.26 0.09 Myocardial infarction, n(%) 9 (28%) 12 (32%) 0.75 -0.25 0.18 CKD, n(%) 2 (6%) 5 (13%) 0.34 -0.21 0.07 Hypertension, n(%) 26 (81%) 21 (55%) 0.01 0.04 0.47 Diabetes mellitus, n(%) 10 (31%) 13 (34%) 0.79 -0.25 0.19 Collagen disease, n(%) 4 (13%) 8 (21%) 0.35 -0.26 0.09 Cancer, n(%) 4 (13%) 11 (29%) 0.08 -0.35 0.02 Lung, n(%) 2 (6%) 5 (13%) 0.34 -0.21 0.07 Dyspnea 2 1.58 0.13 -0.13 0.96 Table 1. (Continued) 95% CI Sample characteristics IPF ( n = 32) non-IPF ( n = 38) p value Lower Higher Cough 34.90±24.63[0-88] 22.67±18.22[0-79] 0.02 1.75 22.72 mean: 33 mean: 16 0.4 -0.17 0.42 Sputum 29.81±25.79[0-90] 21.57±22.32[0-80] 0.16 -3.59 20.06 mean: 17 mean: 11 0.02 1.75 22.72 ADL, n(%) 7 (22%) 3 (8%) 0.1 -0.03 0.3 QOL 0.72 0.78 0.15 -0.14 0.02 Depression, n(%) 8 (27%) 7 (21%) 0.4 -0.17 0.42 Vital signs Heart rate, bpm 80.19±13.79 80.51±9.64 0.9 -5.98 5.33 Respiration rate, bpm 18.83±1.92 18.97±2.43 0.25 -1.26 0.97 Arterial blood gas analysis PaO 2 , breathing air, mmHg 80.02±16.95 81.90±25.00 0.72 -12.48 8.72 PaCO 2 , breathing air, mmHg 39.34±4.33 39.43±5.92 0.94 -2.66 2.47 Blood examination WBC (10 3 /µL) 7.88±3.08 7.67±2.42 0.75 -1.1 1.52 CRP (mg/dL) 0.58±0.70 0.56±1.05 0.92 -0.41 0.45 Table 1. (Continued) 95% CI Sample characteristics IPF ( n = 32) non-IPF ( n = 38) p value Lower Higher Blood examination LDH (IU/L) 244.28±46.86 234.84±55.21 0.44 -15.25 34.13 KL-6 (IU/L) 1080.85±672.55 1007.85±802.03 0.68 -284.07 430.06 SP-D (mg/dl) 269.52±224.06 201.72±130.14 0.12 -18.83 154.43 Pulmonary function FVC (L) 1.95±0.55 2.07±0.78 0.47 -0.47 0.22 FVC, %, predicted 67.33±19.10 76.94±25.31 0.1 -21.26 2.02 DL CO , %, predicted 26.98±18.12 26.90±19.46 0.56 -12.89 7.06 Treatment Steroids, n (%) 7 (22%) 12 (32%) 0.37 -0.31 0.11 Immunosuppressive drugs, n (%) 1 (3%) 2 (5%) 0.66 -0.12 0.07 Antifibrotic drugs, n (%) 5 (16%) 1 (3%) 0.07 -0.01 0.27 Home oxygen therapy, n (%) 15 (47%) 10 (26%) 0.07 -0.02 0.43 Dyspnea was evaluated on the basis of the modified British Medical Research Council scale (mMRC), while cough and sputum production were evaluated using a visual analogue scale (VAS). ADL was evaluated by applying the Barthel Index, which indicated those who were judged to be slightly impaired. QOL and depression were evaluated using the EuroQol 5-dimensions 3-levels (EQ-5D) and the Patient Health Questionnaire-9 (PHQ-9), respectively. Abbreviation: ADL, activities of daily living; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DLco, diffusing capacity of the lung for carbon monoxide; FVC, forced vital capacity; IPF, idiopathic pulmonary fibrosis; KL-6, Krebs von den Lungen 6; LDH, lactate dehydrogenase; PaCO 2 , partial pressure of carbon dioxide; PaO 2 , partial pressure of oxygen; QOL, quality of life; SP-D, surfactant protein D; WBC, white blood cell Table 2. Factors associated with IPF at baseline: Logistic regression analysis ( n = 32) 95% CI Independent variable Beta Standard Error p value Adjusted OR Lower Higher Smoking history 1.71 0.82 0.06 5.57 1.10 28.25 Hypertension 0.33 0.72 0.64 1.39 0.33 5.74 Cancer -2.11 0.92 0.02 0.12 0.02 0.73 Cough 0.02 0.01 0.10 1.02 0.99 1.06 ADL 0.48 1.15 0.67 1.61 0.17 15.43 FVC, %, predicted -0.02 0.01 0.14 0.97 0.94 1.00 Antifibrotic drugs 1.95 1.31 0.13 7.05 0.53 92.71 Home oxygen therapy 0.72 0.86 0.93 1.07 0.19 5.86 Abbreviation: ADL, activities of daily living; FVC, forced vital capacity; IPF, idiopathic pulmonary fibrosis Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4590296","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":315868108,"identity":"85972af3-f80e-4df4-a163-2ad6ca93fb35","order_by":0,"name":"Tomoko Yamada","email":"","orcid":"","institution":"Juntendo University Faculty of Medicine and Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Yamada","suffix":""},{"id":315868110,"identity":"34794294-8ae7-46c5-8edb-fabd11d1bf38","order_by":1,"name":"Koji Sugano","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYBACCSgtx9gApplRhfFpMQZqAekiQUsiUDmSFnxAsv+M8YufO2zSm2fkHn/wcYe1HAP74QcMljtwa5GWyDGz7D2Tlts4Iy+xceaZdGMGnjQDBskzuLXISfCYGfC2HQZqyTFsBjKALswBWt6GRwv/GTPDv22H0xlBWv6CtPC/wa9FmiHH+DHQ8ASwFkaQFgkCtkjOSCtjlm1LM2zseWM4s7ct3ZhN4pnBAXx+kTh/ePPHt2028obtOQYffrZZy/HzJz98LIknxICADRw3hg0wLhAflmzApRoMmD+ASHlkIcaP+LWMglEwCkbByAIAZrJPbUzTHT4AAAAASUVORK5CYII=","orcid":"","institution":"Juntendo University Faculty of Medicine and Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Koji","middleName":"","lastName":"Sugano","suffix":""},{"id":315868111,"identity":"311dab2c-ee91-4ae7-878b-818aae24a012","order_by":2,"name":"Kei Matsuno","email":"","orcid":"","institution":"Juntendo Tokyo Koto Geriatric Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Matsuno","suffix":""},{"id":315868113,"identity":"f4d5b346-55ac-49db-90ad-bfd3a5b9c8ea","order_by":3,"name":"Saori Hotta","email":"","orcid":"","institution":"Juntendo Tokyo Koto Geriatric Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Saori","middleName":"","lastName":"Hotta","suffix":""},{"id":315868114,"identity":"6e47ecf5-2c50-4d11-b051-a99e5ffbd319","order_by":4,"name":"Mitsuhiro Fujii","email":"","orcid":"","institution":"Koto Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mitsuhiro","middleName":"","lastName":"Fujii","suffix":""},{"id":315868116,"identity":"e76ca2a8-44d4-4d8c-98aa-8cb19481ef95","order_by":5,"name":"Hiroaki Ihara","email":"","orcid":"","institution":"Koto Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Ihara","suffix":""},{"id":315868117,"identity":"2090476a-3fbd-4b11-8503-c87307bc9aae","order_by":6,"name":"Kazuhisa Takahashi","email":"","orcid":"","institution":"Juntendo University Faculty of Medicine and Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kazuhisa","middleName":"","lastName":"Takahashi","suffix":""}],"badges":[],"createdAt":"2024-06-16 15:32:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4590296/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4590296/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60426759,"identity":"9aba6f8f-2d1c-47ec-ac23-ffd6c73f414c","added_by":"auto","created_at":"2024-07-16 15:47:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":734214,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in dyspnea in the idiopathic pulmonary fibrosis (IPF) (left) and non-IPF (right) groups. Dyspnea at T0, T1, and T2 were assessed by the modified British Medical Research Council (mMRC) scale.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/061fdcd2b10547ec5e0cf390.jpg"},{"id":60429530,"identity":"9c3ad986-2090-4688-9170-1859a1663290","added_by":"auto","created_at":"2024-07-16 16:03:31","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":722046,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in cough in the idiopathic pulmonary fibrosis (IPF) (left) and non-IPF (right) groups. Cough at T0, T1, and T2 were assessed by the visual analogue scale (VAS).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/1da23f8711fa97699fe2de30.jpg"},{"id":60426761,"identity":"549091b2-dc49-405f-ba4c-ad977e004706","added_by":"auto","created_at":"2024-07-16 15:47:31","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":700247,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in sputum in the idiopathic pulmonary fibrosis (IPF) (left) and non-IPF (right) groups. Sputum at T0, T1, and T2 were assessed by visual analogue scale (VAS).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/9c9e7d41b8e41f07120a6753.jpg"},{"id":60428217,"identity":"2f8dc330-2697-4ce3-b833-331f82921f04","added_by":"auto","created_at":"2024-07-16 15:55:31","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":723852,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in activities of daily living (ADL) in the idiopathic pulmonary fibrosis (IPF) (left) and non-IPF (right) groups. ADL at T0, T1, and T2 were assessed by Barthel Index.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/8dd9bd526dda44aaec5533f5.jpg"},{"id":60428219,"identity":"a77774df-0722-4d96-ac64-9b64c1f16b68","added_by":"auto","created_at":"2024-07-16 15:55:31","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":759530,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in quality of life (QOL) in the idiopathic pulmonary fibrosis (IPF) (left) and non-IPF (right) groups. QOL at T0, T1, and T2 were assessed by EuroQol 5-dimensions 3-levels (EQ-5D).\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/1f14714799a65c150875a468.jpg"},{"id":60426765,"identity":"f0d97ac4-48d3-4f12-af08-b7fedbad14a7","added_by":"auto","created_at":"2024-07-16 15:47:32","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":726037,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in depression in the idiopathic pulmonary fibrosis(IPF) (left) and non-IPF (right) groups. Depression at T0, T1, and T2 was assessed by Patient Health Questionnaire-9 (PHQ-9).\u003c/p\u003e","description":"","filename":"Figure6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/07c282ff46356ea7fc6c4f14.jpg"},{"id":83437422,"identity":"d40e8b2f-a745-4d19-8316-e3c02d1ff136","added_by":"auto","created_at":"2025-05-26 08:46:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5263956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4590296/v1/55c874d4-d233-414e-9ff0-f907009780ed.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prevalence of distress and changes over time among patients with progressive fibrosing interstitial lung disease","fulltext":[{"header":"Background","content":"\u003cp\u003eProgressive fibrosing interstitial lung disease (PF-ILD) is characterized by decreased respiratory function, worsening symptoms, and lung fibrosis on chest high-resolution computed tomography (HRCT). The term \u0026ldquo;PF-ILD\u0026rdquo; is used to refer to a group of diseases with poor prognoses that lead to death through exacerbation of the disease despite therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. PF-ILD includes idiopathic pulmonary fibrosis (IPF), other unexplained interstitial pneumonia, the so-called idiopathic interstitial pneumonias (IIPs), interstitial lung disease associated with connective tissue (CTD-ILD), chronic hypersensitivity pneumonitis, and various interstitial lung diseases such as sarcoidosis and organizing pneumonia [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. IPF is commonly characterized by chronic and progressive fibrosis of unknown cause [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and demonstrates a radiological pattern known as usual interstitial pneumonia (UIP) on HRCT scans. IPF shows a particularly rapid progression and poor prognosis among PF-ILD, with an average time from diagnosis to death of \u0026le;\u0026thinsp;5 years [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In Japan, the total number of patients with IPF is estimated to be approximately 34,000 based on the number of recipients of designated intractable diseases for each primary disease, disease incidence surveys, and publications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with PF-ILD frequently show respiratory symptoms such as cough, sputum, and unbearable dyspnea with disease progression [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], which decreases their activities of daily living (ADL) and quality of life (QOL) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In addition, patients in the end-of-life (EOL) phase experience psychological, social, and existential distress as the disease progresses and show reduced ADL, resulting in a decline in QOL [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In these patients, pulmonary function tests may reveal reduced forced vital capacity (FVC), total lung capacity (TLC), and diffusing capacity of the lungs for carbon monoxide (DL\u003csub\u003eCO\u003c/sub\u003e) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eManagement of PF-ILD requires a combination of pharmacological and nonpharmacological treatments [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Antifibrotic drugs inhibit the progression of the decline in lung function and prevent acute exacerbations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Acute exacerbations may occur with specific triggers, such as infection, surgical invasion, drug toxicity, and aspiration, or without specific triggers, and are characterized by sudden and usually severe respiratory deterioration with new bilateral opacities on HRCT scans [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Patients showing acute exacerbations are primarily treated with systemic steroids; however, their prognosis is poor. Pulmonary rehabilitation can improve functional exercise capacity and QOL and relieve distressing symptoms such as dyspnea in the short term, potentially offering benefits in patients with IPF [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Oxygen therapy is essential for patients with advanced disease and respiratory failure [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The comprehensive care of patients with PF-ILD should include disease treatment, symptom management, patient education, and self-management based on a strong relationship of trust between healthcare providers and patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNevertheless, treating patients with PF-ILD in the actual clinical setting is often difficult because evidence supporting symptom management is limited [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Moreover, in comparison with other lung diseases, such as lung cancer, no effective treatments for the progression of fibrosis and palliative care for PF-ILD have been established [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Few clinical studies on patients with IPF have clarified effective treatments and palliative care regimens [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A previous study also reported inadequate EOL care in patients with PF-ILD, since early intervention is often difficult because of a lack of symptoms, disease awareness, and variability in the clinical course [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Despite the known importance of changes requiring early intervention, previous studies have not demonstrated the point at the disease course at which the symptoms are likely to appear or change. No study has compared the clinical course of IPF with that of other PF-ILD (non-IPF), focusing not only on respiratory symptoms but also psychological symptoms. Rapid determination of the presence or absence of any symptom changes within a short period in the disease trajectory may facilitate the provision of effective management and highly satisfactory palliative care at an appropriate time or at an early stage. Therefore, this study aimed to clarify the degree of physical and psychological distress in patients with PF-ILD and to evaluate symptom changes in IPF patients with non-IPF patients over a one-year period.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan, and was conducted in accordance with the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy participants\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included patients with interstitial pneumonia who visited or were admitted to several affiliated hospitals, including our university hospital. The patients had been diagnosed with interstitial pneumonia and met the definition of PF-ILD. PF-ILD was defined by the spread of fibrosis in more than 10% of the chest HRCT scans and disease progression within 24 months meeting the following criteria: 10% or more decrease in FVC, 5%-10% decrease in FVC and progression of image findings, 5%-10% decrease in FVC and progression of symptoms, or progression of image findings and symptoms. IPF was defined as a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause and was associated with the histopathological and/or radiologic patterns of UIP [1]. Non-IPF was defined as other unexplained interstitial pneumonia that could result in PF-ILD. We compared the findings for cases showing IPF, which has a poor prognosis and often cause severe symptoms in clinical settings, with those that did not show IPF.\u003c/p\u003e\n\u003cp\u003eExclusion criteria: Clinical diagnosis of severe mental or cognitive disorders, inability to fully understand the contents of the study protocol for the interview and examination, or inability to participate in the study as judged by the attending physician.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCriteria for discontinuation: The study was discontinued when the patient declined to participate in the study or withdrew consent, when the patient died, or when the attending physician determined that the patient is not suitable for participation in the study for other reasons.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWritten consent was obtained from each eligible patient after a thorough explanation of the purpose and methods of the study. When the participants could not fully understand the contents of the study protocol, the patients’ oral consent and their surrogates’ written consent were obtained. All participants were orally explained the details of PF-ILD by their primary physicians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eProcedures\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients diagnosed with PF-ILD were consecutively recruited for one year, starting in June 2021, with a one-year follow-up after enrollment. Research registration was performed within three weeks of consent. Each patient was observed at registration and 26 and 52 weeks\u0026nbsp;after\u0026nbsp;registration. “T0” was defined as the point of registration, “T1” as the point 26 weeks after registration, and “T2” as the point 52 weeks after registration. A margin of error of four weeks before and after treatment was allowed for T1 and T2. Respiratory symptoms, ADL, QOL, depressive conditions, and other possible explanatory factors were evaluated using validated measurements at each point. The research team performed the assessments described below at each point. The research team also noted the reasons for dropouts during the study period. The physician set the patient identification code at the time of registration, linked it to the patient chart number, and ensured that leakage of personal information was avoided.\u0026nbsp;All documents and data related to this study were carefully stored and protected at each medical institution until the end of the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMeasurements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe evaluated the changes in the symptoms and other factors of the participants. Physical evaluations were as follows: respiratory symptoms of dyspnea were evaluated by the modified British Medical Research Council (mMRC) scale [21] and rated on a 5-point scale from 0 (the mildest degree of dyspnea) to 4 (the most severe). Symptoms of cough and sputum were evaluated by visual analogue scale (VAS) [22,23], which records patients’ assessment of symptom severity on a 100-mm linear scale ranging from “no cough or sputum” (0 mm) to “worst cough or sputum” (100 mm). ADL\u0026nbsp;was\u0026nbsp;evaluated using the Barthel Index [24]. In the Barthel Index, each of the 10 items of exertion, which included eating, dressing, bathing, walking, climbing stairs, changing clothes, and toileting, were rated on a 100-point scale. In this study, the Barthel Index was categorized as 60 points or less (2), 61–90 points (1), and 91 points or more (0), and categories 1 or 2 were considered to indicate disability while 0 indicated the absence of disability. Blood tests included measurement of the white blood cell count and the levels of C-reactive protein\u0026nbsp;(CRP), total protein, albumin, liver function, renal function, creatine phosphokinase, markers of interstitial pneumonia (Krebs von den Lungen-6 [KL-6] and surfactant protein-D [SP-D]), and collagen disease-related antibodies, and arterial blood gas analysis. Respiratory function tests included measurement of FVC, forced expiratory volume in 1 s (FEV1.0), DL\u003csub\u003eCO\u003c/sub\u003e, TLC, and residual volume. The imaging tests included chest radiography and HRCT. QOL was evaluated using the EuroQol 5-dimensions 3-levels (EQ-5D-3L). The EQ-5D-3L is a self-reported survey that measures QOL across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain was scored on a 3-level severity ranking ranging from 1 (no problems) to 3 (extreme problems) [25]. The psychological domain of depressive symptoms was assessed using the Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms. The validity of the Japanese version of the questionnaire has been verified. This measure consisted of nine items with the same four response options for each item: 0 (not at all) to 3 (nearly every day) [26]. Medical and demographic data were obtained from the patients and medical records. Participants were also checked for vital signs, body height, and weight, in addition to completing a self-administered questionnaire. Blood examinations (including arterial blood gas analysis), 6-minute walk tests, respiratory function tests, and imaging tests were performed at T0, T1 and T2, which were performed after considering their general condition.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate analysis was performed to explore potential explanatory factors associated with IPF and non-IPF at baseline. Intergroup differences in the categorical, non-parametric, and continuous variables were tested by the chi-square test (or Fisher’s exact test), Wilcoxon’s rank-sum test, and unpaired t-test, respectively. Factors with \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.10 were included in the multiple logistic regression analysis with forced entry. A significance level of \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 was adopted for all statistical analysis and \u003cem\u003eP\u003c/em\u003e values reported were 2-tailed. Repeated-measures analysis of variance was also performed to evaluate disease progression in IPF and non-IPF patients at each point during the observation period. All analyses were conducted using SPSS software, version 29.0 J for Windows (SPSS Inc., 2022).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDemographic and clinical characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeventy potential participants were included in this study. Sixteen patients were excluded due to missing data. Table 1 showed the demographic and clinical characteristics of the patients. The patients were classified into those showing IPF (IPF group) and those showing PF-ILD other than IPF (non-IPF group). The mean (±SD) and median age of the participants in the IPF group were 78.5 (±6.9) and 79 years, respectively. Some patients receiving home oxygen therapy were unable to perform the respiratory function tests adequately. Note that in Table 1, ADL indicates the number of patients with even a slight decline.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFactors differing between IPF and non-IPF on T0: univariate and multivariate analyses\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn comparison with\u0026nbsp;non-IPF\u0026nbsp;participants, those with IPF were more likely to have a smoking history, be hypertensive, have less complicated cancer, have more severe cough, have lower ADL, have lower %FVC levels, and receive treatment with antifibrotic drugs and home oxygen therapy. Table 2 showed the factors associated with IPF at T0. A multiple logistic regression analysis showed that cancer complications were more common in non-IPF patients; however, among patients with cancer, the proportion of those showing lung cancer was not significantly different between the IPF and non-IPF groups. The two groups showed no other significant differences in clinical symptoms or laboratory findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eChanges observed in both groups over the course of a year\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultiple patients dropped out of the study during the 1-year follow-up period: ten patients dropped out before reaching T1, five patients died, including one with acute exacerbation, two patients were transferred to home or a facility, and three withdrew study consent.\u0026nbsp;Thirteen patients dropped out of the study before reaching T2: six patients died, including one with acute exacerbation, four were transferred, and three were unable to continue the study.\u0026nbsp;Patients who were eligible to continue the study were evaluated for changes in the following factors\u0026nbsp;during the study period: cough, sputum, dyspnea, ADL, depression, QOL, and LDH, KL-6, and SP-D levels.\u003c/p\u003e\n\u003cp\u003eFigure 1 demonstrated that dyspnea assessed by the mMRC scale in patients with IPF worsened from T1 to T2 (\u003cem\u003ep\u003c/em\u003e = 0.02, 95%CI 0.09 to 1.19) but not\u0026nbsp;from T0 to T1, while the patients in the non-IPF group showed no worsening of dyspnea from T0 to T1 to T2.\u0026nbsp;Patients with IPF did not show worsening of cough, whereas\u0026nbsp;non-IPF patients\u0026nbsp;showed\u0026nbsp;worsening of cough over time from T0 to T1 (\u003cem\u003ep\u003c/em\u003e = 0.01, 95%CI 2.38 to 23.61) and T2 (\u003cem\u003ep\u003c/em\u003e = 0.02, 95%CI 2.18 to 27.76) (Figure 2). In addition, patients with IPF did not show any changes in QOL over time; however,\u0026nbsp;non-IPF patients\u0026nbsp;showed a decline in QOL from T0 to T1\u0026nbsp;(\u003cem\u003ep\u003c/em\u003e = 0.03, 95%CI 0.009 to 0.211), and this decline was prolonged from T1 to T2 (Figure 5). In contrast, both IPF and non-IPF groups showed no changes in sputum production, ADL, and depression over time (Figure 3, 4, and 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo clarify the degree of distress in patients with PF-ILD, we examined each factor at the beginning of the study and evaluated the changes in symptoms over the course of one year in the IPF and non-IPF\u0026nbsp;groups.\u0026nbsp;Since IPF has a poor prognosis, tends to show variable respiratory symptoms or distress, and often results in acute exacerbations in daily clinical practice, we decided to evaluate the symptom changes separately in IPF and non-IPF groups in the present study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients with IPF tended to have a strong cough, history of smoking, and fewer cancer complications at baseline. In contrast, the two groups showed no significant differences in other background factors, including lung cancer complications, other symptoms, or laboratory results. However, our study demonstrated that while patients with IPF showed only worsening of dyspnea, those with non-IPF showed worsening of cough and reduced QOL during the one-year follow-up period. IPF accounts for approximately half of all\u0026nbsp;cases of progressive pulmonary fibrosis and has a stronger and poorer prognosis than other PF-ILD [3]. PF-ILD is characterized by respiratory symptoms and\u0026nbsp;disease progression, which result in a decline in ADL and QOL [8]. Our study showed worsening of dyspnea in patients with IPF from six months to one year after recruitment. No notable changes in the administration of steroid-containing medications\u0026nbsp;for respiratory symptoms were noted during\u0026nbsp;the research period; however, half of\u0026nbsp;the patients with IPF had been receiving home oxygen therapy since the start of this study. Despite the lack of clarity regarding the therapeutic usefulness of treatment including steroids, opioids, or respiratory rehabilitation, background factors, and individual characteristics, the finding showing worsening of dyspnea over six months may be an indicator for follow-up period and symptom management.\u003c/p\u003e\n\u003cp\u003eIn contrast to the findings for the IPF group,\u0026nbsp;non-IPF patients showed worsening cough and\u0026nbsp;a temporary decline in QOL in our study. Cough is a common symptom of chronic pulmonary diseases, and PF-ILD is no exception.\u0026nbsp;Chronic coughing increases the disease burden in patients. A previous study found that cough predicts disease progression in patients\u0026nbsp;with IPF [6]. Although the cause of cough in non-IPF patients has not yet been understood, underlying inflammation or fibrosis and comorbidities may be involved. Another study showed that\u0026nbsp;the mechanism underlying cough in IPF may involve mechanical distortion associated with lung parenchymal fibrosis [27]. The role of some forms of airway inflammation or the physical condition and surrounding environmental factors at the time of the assessment was also undeniable.\u0026nbsp;Although one report on cough in patients with IPF indicated the important roles of increased cough reflex sensitivity, gastroesophageal reflex, and airway inflammation [27],\u0026nbsp;the specific management of cough in patients\u0026nbsp;with PF-ILD has not been reported in previous studies. To\u0026nbsp;the best of our knowledge, general antitussive therapy does not improve the chronic cough caused by PF-ILD. Although\u0026nbsp;a persistent cough is an extremely important factor worth consideration in the palliative care phase, evidence regarding the effectiveness of therapeutic agents, including opioids, is insufficient, and a comprehensive multidisciplinary approach consisting of treatment and care is required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe QOL in patients with\u0026nbsp;non-IPF declined six months after the start of the study and showed no trend of improvement within the study period.\u0026nbsp;In contrast, no reduction in QOL was observed in the patients with IPF in our study. Reductions in QOL can be attributed to\u0026nbsp;several\u0026nbsp;reasons, but cough\u0026nbsp;may have\u0026nbsp;had an impact in our study. Nevertheless, prolonged coughing eventually leads to\u0026nbsp;a loss of strength and secondary sarcopenia, which may occur in both IPF and non-IPF patients.\u0026nbsp;Half of the patients with pulmonary sarcoidosis, which is included in PF-ILD, had chronic cough, which is associated with a poor QOL [28].\u0026nbsp;Other studies have shown that non-IPF patients with cough had higher odds of lower cough-specific QOL than patients with IPF [29]. Our study suggests that this trend may be applicable to non-IPF patients over a relatively short period.\u003c/p\u003e\n\u003cp\u003eThe results indicated that the trajectory of PF-ILD may be similar to that of cancer, which deteriorates in a relatively short period of time during the final stages of the disease\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[30]. Although a previous study investigated QOL in patients with PF-ILD [8], none of the existing studies have reported significant reductions. The decline in QOL for each disease that constituted PF-ILD could not be examined individually in the present study;\u0026nbsp;however, some of the non-IPF patients who entered the study were diagnosed with nonspecific interstitial pneumonia or CTD-ILD. Thus, while the medical condition of the primary disease may have\u0026nbsp;had an impact, other factors could not be identified in our study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSymptoms of sputum, ADL, and depression did not differ over time in IPF and non-IPF patients.\u0026nbsp;One reason for this is that patients with IPF as well as the non-IPF patients, such as\u0026nbsp;those with IIPs and sarcoidosis, experienced a persistent dry cough with low sputum volume [3,31], making it difficult to be aware of changes in sputum symptoms over time. Another reason is that patients with IPF tended to have lower ADL at the time of registration, whereas the non-IPF patients often had\u0026nbsp;a background of cancer.\u0026nbsp;IPF is often associated with lung cancer, and no prospective studies have reported significantly more lung cancer complications in patients with non-IPF than in those with IPF. Although non-IPF may also be strongly associated with smoking and exposure to carcinogens, like in IPF [32], we could not determine why the non-IPF group had more cancers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough some patients were receiving home respiratory rehabilitation as part of their nonpharmacological treatment, we could not exclude the possibility that the addition of respiratory care may have already influenced the findings at the beginning of this study or\u0026nbsp;the absence of symptom changes over the course of one year.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the sample size was small. The number of registered patients did not increase owing to a decrease in the number of outpatients and difficulties in coming to the hospital because of the coronavirus disease 2019 (COVID-19) pandemic. Moreover, respiratory function tests could not be performed in some cases due to changes in physical symptoms, and in some cases, patients refused to undergo the tests due to COVID-19. Second, patients with missing values who dropped out of the study were also excluded. Since the hospital with the largest number of enrolled cases was a medical institution specializing in the elderly, comorbidities such as cognitive decline or household-related factors may have affected the data collection. Furthermore, since the study included patients with PF-ILD, some participants dropped out during the one-year follow-up because they died or were unable to visit the hospital due to disease progression. Third, to ensure that the findings were more aligned to real-world conditions, we did not set strict inclusion criteria. Although almost all outpatients were enrolled, some may have had advanced disease and may have already undergone home oxygen therapy or rehabilitation, potentially causing a selection bias. Therefore, the changes in symptoms during the follow-up period may not have been not reflected in the data. Finally, we assessed dyspnea and QOL using the mMRC and EQ-5D, respectively. Considering the researchers\u0026rsquo; workload, we used an evaluation scale that is commonly used in daily clinical practice. Although this was a validated assessment method, we considered the St. George\u0026rsquo;s Respiratory Questionnaire, which is commonly used in research.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePF-ILD is characterized by progressive respiratory symptoms and\u0026nbsp;is highly\u0026nbsp;distressing to patients; no sufficiently effective therapeutic strategies have been established to date. Respiratory symptoms are directly related to the patient\u0026apos;s daily life and lead to reduced QOL. Although a variety of treatments and care are being provided in clinical settings, evidence supporting the suitability of these modalities for individual patients may be unavailable. This study, in which several symptoms were assessed over a short period, highlighted the significance of identifying and assessing the patient\u0026apos;s distress as early as possible.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAdditional research is required to understand how PF-ILD affect the lives of patients over time.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADL\u0026nbsp;activities of daily living\u003c/p\u003e\n\u003cp\u003eCOVID-19\u0026nbsp;coronavirus disease 2019\u003c/p\u003e\n\u003cp\u003eCTD-ILD\u0026nbsp;interstitial lung disease associated with connective tissue\u003c/p\u003e\n\u003cp\u003eDL\u003csub\u003eCO\u0026nbsp;\u003c/sub\u003ediffusing capacity of the lungs for carbon monoxide\u003c/p\u003e\n\u003cp\u003eEOL\u0026nbsp;end-of-life\u003c/p\u003e\n\u003cp\u003eEQ-5D\u0026nbsp;EuroQol 5-dimensions\u003c/p\u003e\n\u003cp\u003eFVC\u0026nbsp;forced vital capacity\u003c/p\u003e\n\u003cp\u003eHRCT\u0026nbsp;high-resolution computed tomography\u003c/p\u003e\n\u003cp\u003eIIP\u0026nbsp;idiopathic interstitial pneumonias\u003c/p\u003e\n\u003cp\u003eIPF\u0026nbsp;idiopathic pulmonary fibrosis\u003c/p\u003e\n\u003cp\u003eKL-6\u0026nbsp;Krebs von den Lungen 6\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePHQ-9\u0026nbsp;Patient Health Questionnaire-9\u003c/p\u003e\n\u003cp\u003eQOL\u0026nbsp;quality of life\u003c/p\u003e\n\u003cp\u003eSP-D\u0026nbsp;surfactant protein-D\u003c/p\u003e\n\u003cp\u003eTLC\u0026nbsp;total lung capacity\u003c/p\u003e\n\u003cp\u003eUIP\u0026nbsp;usual interstitial pneumonia\u003c/p\u003e\n\u003cp\u003eVAS visual analogue scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan, and was conducted in accordance with the Declaration of Helsinki.\u0026nbsp;Written informed consent was obtained from all the participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data analyzed in this study are available from the corresponding author upon request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceived and designed the experiments: TY, KS, KT\u003c/p\u003e\n\u003cp\u003ePerformed the experiments: TY, KS, KM, SH, MF, HI\u003c/p\u003e\n\u003cp\u003eAnalyzed the data: TY, KS, KM, SH, MF, HI, KT\u003c/p\u003e\n\u003cp\u003eWrote the paper: TY, KS, KM, SH, MF, HI, KT\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully acknowledge the support of the study participants, their families, medical staff, and physicians. We also would like to thank Editage (www.editage.jp) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRaghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An Official ATS/ERS/JRS/ALAT Statement: idiopathic Pulmonary Fibrosis: Evidence-based Guidelines for Diagnosis and Management. Am J Respir Crit Care Med. 2011;183:788-824.\u003c/li\u003e\n\u003cli\u003eLederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med. 2018;378:1811-23.\u003c/li\u003e\n\u003cli\u003eCottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, et al. Presentation. diagnosis, and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27:180076.\u003c/li\u003e\n\u003cli\u003eWong AW, Ryerson CJ, Guler SA. Progression of fibrosing interstitial lung disease. Respir Res. 2020;21:32.\u003c/li\u003e\n\u003cli\u003eKondoh Y, Suda T, Hongo Y, Yoshida M, Hiroi S, Iwasaki K, et al. Prevalence of idiopathic pulmonary fibrosis in Japan based on a claims database analysis. Respir Res. 2022;23:24. \u003c/li\u003e\n\u003cli\u003eBirring SS, Kavanagh JE, Irwin RS, Keogh KA, Lim KG, Ryu JH, et al. Treatment of Interstitial Lung Disease Associated Cough: CHEST Guideline and Expert Panel Report. Chest. 2018;154:904-17.\u003c/li\u003e\n\u003cli\u003eSwigris JJ, Kuschner WG, Jacobs SS, Wilson SR, Gould MK. Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review. Thorax. 2005;60:588-94.\u003c/li\u003e\n\u003cli\u003eDe Vries JD, Kessels BL, Drent M. Quality of life of idiopathic pulmonary fibrosis patients. Eur Respir J. 2001;17:954-61.\u003c/li\u003e\n\u003cli\u003eDiamantopoulos A, Wright E, Vlahopoulou K, Cornic L, Schoof N, Maher TM. The burden of illness of idiopathic pulmonary fibrosis: A comprehensive evidence review. Pharmacoeconomics. 2018;36:779-807.\u003c/li\u003e\n\u003cli\u003eSwigris JJ, Brown KK, Abdulqawi R, Buch K, Dilling DF, Koschel D, et al. Patients\u0026rsquo; perceptions and patient-reported outcomes in progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27:180075.\u003c/li\u003e\n\u003cli\u003eNasser M, Larrieu S, Si-Mohamed S, Ahmad K, Boussel L, Brevet M, et al. Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS study). Eur Respir J. 2021;57:2002718.\u003c/li\u003e\n\u003cli\u003eCollard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am J Respir Crit Care Med. 2016;194:265-75.\u003c/li\u003e\n\u003cli\u003eKreuter M, Bendstrup E, Russell AM, Bajwah S, Lindell K, Adir Y, et al. Palliative care in interstitial lung disease: living well. Lancet Respir Med. 2017 Dec;5:968-80.\u003c/li\u003e\n\u003cli\u003eDowman L, Hill CJ, Holland AE. Pulmonary rehabilitation for interstitial lung disease. Cochrane Database Syst Rev. 2021;2:CD006322.\u003c/li\u003e\n\u003cli\u003eEgan JJ. Follow- up and nonpharmacological management of the idiopathic pulmonary fibrosis patient. Eur Respir Rev. 2011;20:114-7.\u003c/li\u003e\n\u003cli\u003eLindell KO, Nouraie M, Klesen MJ, Klein S, Gibson KF, Kass DJ, et al. Randomised clinical trial of an early palliative care intervention (SUPPORT) for patients with idiopathic pulmonary fibrosis (IPF) and their caregivers: protocol and key design considerations. BMJ Open Respir Res. 2018;5:e000272.\u003c/li\u003e\n\u003cli\u003eGibson P, Wang G, McGarvey L, Vertigan AE, Altman KW, Birring SS, et al. Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report. Chest. 2016;149:27-44.\u003c/li\u003e\n\u003cli\u003eAhmadi Z, Wysham NG, Lundstr\u0026ouml;m S, Janson C, Currow DC, Ekstr\u0026ouml;m M. End- of- life care in oxygen- dependent ILD compared with lung cancer: a national population- based study. Thorax. 2016;71:510-6.\u003c/li\u003e\n\u003cli\u003eIgai Y. A narrative literature review of palliative care regarding patients with idiopathic pulmonary fibrosis. Nurs Open. 2018;5:536-45.\u003c/li\u003e\n\u003cli\u003eKoyauchi T, Suzuki Y, Sato K, Hozumi H, Karayama M, Furuhashi K, et al. Quality of dying and death in patients with interstitial lung disease compared with lung cancer: an observational study. Thorax. 2021;76:248-55.\u003c/li\u003e\n\u003cli\u003eMahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 1988 Mar;93:580-6.\u003c/li\u003e\n\u003cli\u003eFreyd M. The Graphic Rating scale. J Educ Psychol. 1923;14:83-102.\u003c/li\u003e\n\u003cli\u003eNguyen AM, Bacci ED, Vernon M, Birring SS, Rosa CL, Muccino D, et al. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis. 2021;15:1-13.\u003c/li\u003e\n\u003cli\u003eMahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Med J. 1965;14:61-5.\u003c/li\u003e\n\u003cli\u003eEuroQol Group. EuroQol--a new facility for the measurement of health-related quality of life. Health Policy. 1990 Dec;16:199-208.\u003c/li\u003e\n\u003cli\u003eKroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16:606-13.\u003c/li\u003e\n\u003cli\u003eJones RM, Hilldrup S, Hope-Gill BD, Eccles R, Harrison NK. Mechanical induction of cough in idiopathic pulmonary fibrosis. Cough. 2011;7:2.\u003c/li\u003e\n\u003cli\u003eSinha A, Lee KK, Rafferty GF, Yousaf N, Pavord ID, Galloway J, et al. Predictors of objective cough frequency in pulmonary sarcoidosis. Eur Respir J. 2016;47:1461-71.\u003c/li\u003e\n\u003cli\u003eLee J, White E, Freiheit E, Scholand MB, Strek ME, Podolanczuk AJ, et al. Cough-Specific Quality of Life Predicts Disease Progression Among Patients With Interstitial Lung Disease: Data From the Pulmonary Fibrosis Foundation Patient Registry. Chest. 2022;162:603-13.\u003c/li\u003e\n\u003cli\u003eLynn J. Perspectives on care at the close of life. Serving patients who may die soon and their families: the role of hospice and other services. JAMA. 2001;285:925-32.\u003c/li\u003e\n\u003cli\u003eVigeland CL, Hughes AH, Horton MR. Etiology and treatment of cough in idiopathic pulmonary fibrosis. Respir Med. 2017 Feb;123:98-104. \u003c/li\u003e\n\u003cli\u003eNaccache JM, Gibiot Q, Monnet I, Antoine M, Wislez M, Chouaid C, et al. Lung cancer and interstitial lung disease: a literature review. J Thorac Dis. 2018;10:3829-44.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Demographic and clinical characteristics of the patients (\u003cem\u003en\u003c/em\u003e = 70)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25984251968504%\" colspan=\"2\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eSample characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eIPF (\u003cem\u003en\u003c/em\u003e = 32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003enon-IPF (\u003cem\u003en\u003c/em\u003e = 38)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003eHigher\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eMale sex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e23 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e22 (58%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\" rowspan=\"2\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e78.53\u0026plusmn;6.90[54-87]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e79.37\u0026plusmn;5.68[69-90]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" rowspan=\"2\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" rowspan=\"2\"\u003e\n \u003cp\u003e-3.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" rowspan=\"2\"\u003e\n \u003cp\u003e2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003emean：79.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003emean：80.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eBMI (kg/㎡)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e22.70\u0026plusmn;3.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e23.22\u0026plusmn;3.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-2.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eSmoking history, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e28 (88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e24 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eMedical history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e COPD, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e6 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e10 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Asthma, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e4 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e8 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Myocardial infarction, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e9 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e12 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e CKD, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e2 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e5 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Hypertension, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e26 (81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e21 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Diabetes mellitus, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e10 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e13 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Collagen disease, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e4 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e8 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Cancer, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e4 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e11 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Lung, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e2 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e5 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eDyspnea \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e1.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. (Continued)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25984251968504%\" colspan=\"2\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eSample characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eIPF (\u003cem\u003en\u003c/em\u003e = 32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003enon-IPF (\u003cem\u003en\u003c/em\u003e = 38)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003eHigher\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\" rowspan=\"2\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e34.90\u0026plusmn;24.63[0-88]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e22.67\u0026plusmn;18.22[0-79]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e22.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56508422664625%\"\u003e\n \u003cp\u003emean: 33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.56508422664625%\"\u003e\n \u003cp\u003emean: 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.926493108728943%\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.39509954058193%\"\u003e\n \u003cp\u003e-0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548238897396631%\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\" rowspan=\"2\"\u003e\n \u003cp\u003eSputum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e29.81\u0026plusmn;25.79[0-90]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e21.57\u0026plusmn;22.32[0-80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-3.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e20.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"27.56508422664625%\"\u003e\n \u003cp\u003emean: 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.56508422664625%\"\u003e\n \u003cp\u003emean: 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.926493108728943%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.39509954058193%\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.548238897396631%\"\u003e\n \u003cp\u003e22.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eADL, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e7 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e3 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eQOL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eDepression, n(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e8 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e7 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eVital signs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Heart rate, bpm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e80.19\u0026plusmn;13.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e80.51\u0026plusmn;9.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-5.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e5.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Respiration rate, bpm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e18.83\u0026plusmn;1.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e18.97\u0026plusmn;2.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eArterial blood gas analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e PaO\u003csub\u003e2\u003c/sub\u003e, breathing air, mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e80.02\u0026plusmn;16.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e81.90\u0026plusmn;25.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-12.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e8.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e PaCO\u003csub\u003e2\u003c/sub\u003e, breathing air, mmHg\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e39.34\u0026plusmn;4.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e39.43\u0026plusmn;5.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-2.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e2.47\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eBlood examination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e WBC (10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e7.88\u0026plusmn;3.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e7.67\u0026plusmn;2.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e1.52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e CRP (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e0.58\u0026plusmn;0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e0.56\u0026plusmn;1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. (Continued)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25984251968504%\" colspan=\"2\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eSample characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eIPF (\u003cem\u003en\u003c/em\u003e = 32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003enon-IPF (\u003cem\u003en\u003c/em\u003e = 38)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003eHigher\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eBlood examination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e LDH (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e244.28\u0026plusmn;46.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e234.84\u0026plusmn;55.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-15.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e34.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e KL-6\u0026nbsp;(IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e1080.85\u0026plusmn;672.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e1007.85\u0026plusmn;802.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-284.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e430.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e SP-D (mg/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e269.52\u0026plusmn;224.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e201.72\u0026plusmn;130.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-18.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e154.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003ePulmonary function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e FVC (L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e1.95\u0026plusmn;0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e2.07\u0026plusmn;0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e FVC, %, predicted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e67.33\u0026plusmn;19.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e76.94\u0026plusmn;25.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-21.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e2.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e DL\u003csub\u003eCO\u003c/sub\u003e, %, predicted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e26.98\u0026plusmn;18.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e26.90\u0026plusmn;19.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-12.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e7.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Steroids, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e7 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e12 (32%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Immunosuppressive drugs, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e1 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e2 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Antifibrotic drugs, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e5 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e1 (3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.5466816647919%\"\u003e\n \u003cp\u003e Home oxygen therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e15 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003e10 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.69853768278965%\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e-0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eDyspnea was evaluated on the basis of the modified British Medical Research Council scale (mMRC), while cough and sputum production were evaluated using a visual analogue scale (VAS). ADL was evaluated by applying the Barthel Index, which indicated those who were judged to be slightly impaired. QOL and depression were evaluated using the EuroQol 5-dimensions 3-levels (EQ-5D) and the Patient Health Questionnaire-9 (PHQ-9), respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviation:\u0026nbsp;ADL, activities of daily living;\u0026nbsp;CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DLco, diffusing capacity of the lung for carbon monoxide;\u0026nbsp;FVC, forced vital capacity;\u0026nbsp;IPF, idiopathic pulmonary fibrosis;\u0026nbsp;KL-6, Krebs von den Lungen 6; LDH, lactate dehydrogenase; PaCO\u003csub\u003e2\u003c/sub\u003e, partial pressure of carbon dioxide; PaO\u003csub\u003e2\u003c/sub\u003e, partial pressure of oxygen; QOL, quality of life; SP-D, surfactant protein D; WBC, white blood cell\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Factors associated with IPF at baseline: Logistic regression analysis (\u003cem\u003en\u003c/em\u003e = 32)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"888\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25984251968504%\" colspan=\"2\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eIndependent variable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003eBeta\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003eStandard Error\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003eAdjusted OR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003eHigher\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e1.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e5.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e28.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e1.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e5.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eCancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e-2.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eCough\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eADL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e1.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e15.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eFVC, %, predicted\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e-0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eAntifibrotic drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e1.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e1.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e7.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e92.71\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.247469066366705%\"\u003e\n \u003cp\u003eHome oxygen therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.84814398200225%\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.835770528683915%\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.973003374578179%\"\u003e\n \u003cp\u003e1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.573678290213723%\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.686164229471316%\"\u003e\n \u003cp\u003e5.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: ADL, activities of daily living; FVC, forced vital capacity; IPF, idiopathic pulmonary fibrosis\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"progressive fibrosing interstitial lung disease, palliative care, dyspnea, activities of daily living, quality of life","lastPublishedDoi":"10.21203/rs.3.rs-4590296/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4590296/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePatients with progressive fibrosing interstitial lung disease (PF-ILD) frequently experience respiratory symptoms and decline in activities of daily living (ADL) and quality of life (QOL) with disease progression. However, no effective treatment or palliative care strategy has been established for patients with PF-ILD. This study aimed to clarify the degree of physical and psychological distress in patients with PF-ILD and to evaluate symptom changes over a one-year period in patients with idiopathic pulmonary fibrosis (IPF) and those with other PF-ILDs (non-IPF).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eConsecutive patients diagnosed with PF-ILD were recruited. The participants were divided into two groups and evaluated at registration (T0), 26 weeks (T1), and 52 weeks (T2) after registration. They were also followed-up for symptoms, ADL, QOL, depressive condition, laboratory findings, and other factors from study registration to 52 weeks (T2).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 70 patients with PF-ILD, 32 had IPF and 38 did not. The IPF and non-IPF groups showed no noticeable differences in clinical symptoms or laboratory findings on multivariate analysis at T0. The repeated-measures analysis of variance used to observe the changes over the course of the year in both groups showed that dyspnea in patients with IPF worsened from T1 to T2. In contrast, cough, which is one of the major symptoms in non-IPF patients, worsened, especially from T0 to T1 and T0 to T2. The QOL of non-IPF patients also declined from T0 to T1.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePatients with PF-ILD demonstrated several clinical signs and symptoms. In this one-year follow-up study, dyspnea tended to be worse in patients with IPF and cough in non-IPF patients, and QOL was temporarily worse in non-IPF patients. Respiratory symptoms are directly related to the patient's daily life and led to reduced QOL. Therefore, further long-term studies in this population are required.\u003c/p\u003e","manuscriptTitle":"Prevalence of distress and changes over time among patients with progressive fibrosing interstitial lung disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 15:47:26","doi":"10.21203/rs.3.rs-4590296/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6405b478-ba8a-44c5-9486-73e53c1111f7","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-26T08:38:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-16 15:47:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4590296","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4590296","identity":"rs-4590296","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}