Prognostic impact of erector spinae muscle cross-sectional area in patients with pleuroparenchymal fibroelastosis

Prognostic impact of erector spinae muscle cross-sectional area in patients with pleuroparenchymal fibroelastosis | 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 Article Prognostic impact of erector spinae muscle cross-sectional area in patients with pleuroparenchymal fibroelastosis Shinsuke Kitahara, Mitsuhiro Abe, Chiyoko Kono, Noriko Sakuma, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3201258/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Oct, 2023 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Pleuroparenchymal fibroelastosis (PPFE) progresses slowly but sometimes relatively quickly, leading to decreased activities of daily living (ADL) and muscle weakness. Skeletal muscle atrophy and muscle weakness in patients with chronic obstructive pulmonary disease (COPD) may be caused by cachexia and are associated with reduced ADLs and increased risk of death. However, the association between skeletal muscle mass and the prognosis of patients with PPFE remains unknown. We retrospectively analysed the clinical significance of the erector spinae muscle cross-sectional area (ESM CSA ), a skeletal muscle index, and predictors of mortality within 3 years in 51 patients with PPFE and 62 patients with COPD. Patients with PPFE had significantly lower ESM CSA than those with COPD, and lower ESM CSA (< 22.57 cm 2 ) was associated with prognosis within 3 years (log-rank test; p = 0.006), whereas lower body mass index (BMI) showed no association. Multivariate analysis showed that ESM CSA was an independent predictor of mortality within 3 years in patients with PPFE (hazard ratio, 0.900; 95% confidence interval: 0.834–0.964, p = 0.003). These results suggest the importance of monitoring ESM CSA in patients with PPFE and that assessing skeletal muscle mass in patients with PPFE could be a more useful prognostic indicator than BMI. Health sciences/Diseases Health sciences/Medical research Health sciences/Risk factors Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Among types of idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis (IPF) is the most frequent, causing chronic progressive fibrosis predominantly at the lung base [ 1 – 2 ]. Pleuroparenchymal fibroelastosis (PPFE) is another chronic pulmonary fibrosis proposed by Frankel et al. in 2004 [ 3 ]. PPFE differs from IPF in that there is more fibrosis in the upper lobe, and the histopathology shows fibrosis in the alveolar space, aggregation of elastic fibres in the alveolar walls, and fibrous thickening of the visceral pleura. The European Respiratory Society (ERS), American Thoracic Society (ATS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) 2013 guidelines [ 2 ] rank idiopathic PPFE (IPPFE) as a rare type of interstitial lung disease (ILD). PPFE is generally considered to progress slowly; however, the rapid onset of dyspnoea sometimes leads to a decline in activities of daily living (ADL), making hospital visits difficult. IPPFE typically presents with changes in body composition, and patients often complain of an emaciated physique with weight loss [ 4 ]; this weight loss includes frailty. Frailty is a concept that encompasses physical changes such as weight loss, fatigue, decreased mobility, and activity, and mental changes such as decreased energy [ 5 – 7 ]; sarcopenia and cachexia are associated with frailty [ 8 ]. Regarding respiratory diseases, frailty is occasionally associated with chronic obstructive pulmonary disease (COPD) [ 9 ]. Skeletal muscle dysfunction caused by frailty is a major cause of being bedridden and requiring other care types [ 10 ]. Skeletal muscle atrophy and loss of muscle mass in COPD have been associated with decreased ADL and risk of death [ 11 ]. However, only a few studies have compared skeletal muscle mass with the prognosis of PPFE, although a lower body mass index (BMI) has been implicated as a poor prognostic factor [ 4 ]. Recently, computed tomography (CT) has made it possible to assess skeletal muscle loss quantitatively, and the erector spinae muscle cross-sectional area (ESM CSA ) is considered a strong predictor of survival in COPD and IPF [ 12 – 14 ]. Therefore, we investigated the association of the quantification of skeletal muscle obtained by CT with PPFE. Results Characteristics The baseline characteristics of the included patients (PPFE [n = 51], COPD [n = 62]) are shown in Table 1 . PPFE included 14 patients with secondary PPFE (secondary causes comprised hypersensitivity pneumonitis [n = 4], non-tuberculous mycobacteria [n = 4], haematopoietic stem cell transplantation [n = 3], asbestos [n = 2], and ulcerative colitis [n = 1]); secondary factors were determined by pathology or clinical diagnosis. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage of patients with COPD was I/II/III/IV in 12/22/19/9 patients. Most patients with PPFE were underweight and tended to be thinner than those with COPD. Laboratory findings showed a mild increase in Krebs von den Lunge-6 (KL-6) and an increase in surfactant protein D. The pulmonary function test results, %forced vital capacity (FVC), and % diffusing capacity of the lung carbon monoxide (D LCO ) were not reduced, but residual volume/total lung capacity (%RV/TLC) was increased. Table 1 Clinical characteristics of 51 patients with PPFE and 62 patients with COPD . PPFE (n = 51) COPD (n = 62) General Age, years 64 [55–70] 69 [62–76] Gender, male/female 28/23 52/10 Observation period, days 1743 [980.5-2807.5] NA Smoking, pack-years 0 [0-23.75] 46.9 [30.8–70.5] Height, cm 163.0 [156.0-169.5] 165.1 [159.1-169.9] Weight, kg 49.9 [40.0-57.3] 63.2 [54.0–70.0] BMI, kg/m 2 18.6 [16.5–19.7] 23.1 [21.1–25.1] ESM CSA , cm 2 24.38 [19.62–28.75] IPPFE: 23.03 [19.57–28.19] (n = 37) SPPFE: 25.88 [20.68–29.25] (n = 14) 30.58 [25.82–35.99] GOLD I/II: 32.36 [25.96–36.66] (n = 34) GOLD III/IV: 29.31 [25.80-34.61] (n = 28) Laboratory findings KL-6, U/mL 387.6 [310.0-567.3] (n = 50) NA SP-D, ng/mL 198.0 [118.3-305.8] (n = 38) NA Pulmonary function test FVC, %-pred 72.2 [58.7–90.4] (n = 49) 93.5 [80.8-107.6] D LCO , % 74.9 [63.2–89.9] (n = 38) NA RV/TLC 45.5 [35.8–51.3] (n = 39) NA RV/TLC, %-pred 139.5 [119.7-168.2] (n = 39) NA Data are presented as median [interquartile range]. Abbreviations: BMI; body mass index, COPD; chronic obstructive pulmonary disease, D LCO ; diffuse capacity of the lung for carbon monoxide, ESM CSA ; erector spinae muscle cross-sectional area, FVC; forced vital capacity, KL-6; Krebs von den Lunge-6, IPPFE; idiopathic pleuroparenchymal fibroelastosis, SPPFE; secondary pleuroparenchymal fibroelastosis, SP-D; surfactant protein-D, RV; residual volume, TLC; total lung capacity, NA; not available Image analysis The distributions of the ESM CSA and BMI are shown in Fig. 1 and Supplementary Fig. 1. The ESM CSA of patients with PPFE was significantly smaller than that of patients with COPD (PPFE; 24.38 [19.62–28.75] cm 2 , COPD; 30.58 [25.82–35.99] cm 2 (GOLD I/II; 32.36 [25.96–36.66] cm 2 , GOLD III/IV; 29.31 [25.80–34.61] cm 2 ); COPD vs PPFE: p < 0.001, COPD GOLD I/II vs PPFE: p < 0.001 and COPD GOLD III/IV vs PPFE: p = 0.003). BMI was significantly lower in the patients with PPFE than in those with COPD (PPFE; 18.6 [16.5–19.7] kg/m 2 , COPD; 23.1 [21.1–25.1] kg/m 2 ; COPD vs PPFE: p < 0.001, COPD GOLD I/II vs PPFE: p < 0.001 and COPD GOLD III/IV vs PPFE: p = 0.005). The correlations among ESM CSA , BMI, and clinical parameters are shown in Fig. 2 and Table 2 . In patients with PPFE, there was a significant correlation between ESM CSA and BMI (r = 0.543, p < 0.001) but no correlation with KL-6 or %FVC. Table 2 Correlations analyses of ESM CSA Variables PPFE [n = 51] r P-value Age, years -0.337 0.002 Smoking, pack-years 0.454 < 0.001 Weight, kg 0.719 < 0.001 BMI, kg/m 2 0.543 < 0.001 KL-6, U/mL -0.076 0.600 SP-D, ng/mL 0.036 0.830 FVC, %-pred 0.27 0.061 D LCO , % 0.266 0.106 RV/TLC -0.509 < 0.001 RV/TLC, %-pred -0.483 0.002 Abbreviations: BMI; body mass index, D LCO ; diffuse capacity of the lung for carbon monoxide, ESM CSA ; erector spinae muscle cross-sectional area, FVC; forced vital capacity, KL-6; Krebs von den Lunge-6, PPFE; pleuroparenchymal fibroelastosis, RV; residual volume, SP-D; surfactant protein-D, TLC; total lung capacity. Prognostic value of ESM CSA and BMI in PPFE Over 3 years, 12 patients with PPFE died (the causes of death in patients with PPFE were respiratory failure [n = 5], acute exacerbation [n = 2], and unknown [n = 5]). The prognosis of patients with PPFE was evaluated using the Kaplan-Meier method and log-rank test, based on the ESM CSA cutoff value determined by the receiver operating characteristic curve to detect the risk of death (Fig. 3 ) and on the BMI value (WHO definition of underweight status). The cutoff value for ESM CSA was 22.57 cm 2 , with a sensitivity of 0.83, specificity of 0.31, and area under the curve of 0.801 (95% confidence interval: 0.663–0.940). In patients with PPFE, a significant difference was observed in the 3-year prognosis for ESM CSA <22.57 cm 2 at diagnosis but not for BMI < 18.5 kg/m 2 (Fig. 4 ). Univariate and multivariate analyses of ESM CSA in PPFE To determine the prognostic impact of measurements related to skeletal muscle changes, a preliminary Cox proportional hazards regression analysis was performed. In the univariate analysis of patients with PPFE, ESM CSA , age, KL-6 level, %FVC, and RV/TLC were associated with mortality within 3 years. In the multivariate analyses, ESM CSA , KL-6, and %FVC were independently associated with mortality within 3 years in patients with PPFE (Table 3 ). Table 3 Prediction of 3-year mortality in patients with PPFE by univariate and multivariate Cox proportional-hazard regression analyses PPFE [n = 51] HR [95% CI] P-value Univariate analysis General Age, years 1.107 [1.026–1.194] 0.009 Gender, male 0.567 [0.180–1.787] 0.333 Smoking, pack-years 1.005 [0.987–1.023] 0.590 Weight, kg 0.949 [0.896–1.006] 0.078 BMI, kg/m 2 0.846 [0.683–1.047] 0.123 ESM CSA , cm 2 0.877 [0.817–0.942] < 0.001 Laboratory KL-6, U/mL 1.001 [1.000-1.002] 0.028 SP-D, ng/mL 1.000 [0.997–1.004] 0.830 Pulmonary function test FVC, %-pred 0.956 [0.928–0.985] 0.003 DLCO, % 0.974 [0.946–1.002] 0.066 RV/TLC 1.109 [1.020–1.205] 0.015 RV/TLC, %-pred 1.015 [0.999–1.031] 0.059 Multivariate analysis ESM CSA , cm 2 0.900 [0.840–0.964] 0.003 KL-6, U/mL 1.002 [1.000-1.003] 0.016 FVC, %-pred 0.941 [0.899–0.985] 0.009 Abbreviations: BMI; body mass index, D LCO ; diffuse capacity of the lung for carbon monoxide, ESM CSA ; erector spinae muscle cross-sectional area, FVC; forced vital capacity, KL-6; Krebs von den Lunge-6, PPFE; pleuroparenchymal fibroelastosis, RV; residual volume, SP-D; surfactant protein-D, TLC; total lung capacity. Discussion This study is one of the few to compare changes in skeletal muscle mass with prognosis in patients with PPFE. This study highlights the importance of these two evaluation aspects. First, a decrease in ESM CSA was associated with prognosis in patients with PPFE. Second, the assessment of skeletal muscle mass in PPFE may reflect a better prognosis than BMI. It has been suggested that a lower ESM CSA may be associated with the prognosis of PPFE, including secondary PPFE (SPPFE). SPPFE is caused by haematopoietic stem cell transplantation, hypersensitivity pneumonitis, non-tuberculous mycobacterial infection, and chemotherapy [ 16 ]. However, it is possible that such comorbidities may simply be comorbid and not affect the patient and that IPPFE is included in the SPPFE. There were no significant differences in the laboratory data, respiratory complications, or survival rates between the idiopathic and secondary PPFE groups [ 17 ]. Known prognostic factors for IPPFE include older age, male, lower BMI, elevated KL-6, and lower FVC [ 4 , 18 ]. This study also found that older age, elevated KL-6 levels, and lower FVC were associated with prognosis; however, no previous reports have shown an association between lower ESM CSA and prognosis. Suzuki et al. also reported an association between PPFE and ESM CSA , but no significant difference was found in prognosis. The reasons for the different results are unclear but could be explained as follows. First, both studies included small numbers of patients and may have observed different phenotypes. Second, approximately half of the patients with PPFE enrolled in this study were underweight, whereas most patients with PPFE reported by Suzuki et al. were underweight, with a BMI of < 18.5 kg/m 2 . Therefore, it is possible that the patients with PPFE in the report by Suzuki et al. had a longer disease-modifying period than those in this study and already had a more reduced skeletal muscle mass. The ESM CSA in this study was independent of laboratory findings and pulmonary function tests in the multivariate analysis. Therefore, it is important to monitor ESM CSA in patients with PPFE. In this study, ESM CSA was significantly correlated with age and BMI but not with %FVC or KL-6 values. The correlation of ESM CSA with age and BMI could be related to a decrease in skeletal muscle mass with increasing age or decreasing body weight [ 19 ]. However, it is noteworthy that despite a significant difference in survival within 3 years for ESM CSA , there was no significant difference in BMI. This finding may be related to body weight components. Body weight comprises muscle mass, body fat mass, and the amount of inorganic matter in the skeleton. The lack of a significant difference in prognosis with respect to BMI may be because BMI is calculated based on body weight, including body fat and muscle mass. Weight loss can occur for various reasons, including starvation caused by reduced food intake preserving skeletal muscle mass and cachexia resulting in reduced skeletal muscle mass [ 20 ]. Cachexia is caused by increased energy expenditure due to inflammatory-induced cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6, decreased appetite and increased protein catabolism associated with leptin and ghrelin, and skeletal muscle atrophy due to angiotensin II [ 21 , 22 ]. Cachexia occurs in cancer patients and is a cause of reduced skeletal muscle mass in COPD patients [ 9 ]. Compared to healthy controls, patients with COPD, IPF, and PPFE have lower ESM CSA [ 12 , 14 ], and those with PPFE have even lower amounts of ESM CSA than those with IPF [ 14 ]. In this study, the patients with PPFE had an even lower ESM CSA than those with COPD. This suggests that PPFE may be more strongly affected by cachexia than COPD or IPF. Oral nutritional supplements are often used to treat cachexia, and the ghrelin receptor agonist, anamorelin, has recently proved effective in cancer patients [ 23 , 24 ]. Ghrelin is an appetite-enhancing peptide secreted from the stomach, which binds to the growth hormone secretagogue receptor-1a (GHSR-1a) and regulates appetite and energy metabolism [ 25 , 26 ]. Ghrelin and its analogues exhibit appetite-stimulating effects by promoting the expression of agouti-related neuropeptides and neuropeptide Y [ 27 – 29 ] and preventing weight loss [ 30 ]. In addition to its appetite-enhancing effects, ghrelin also suppresses energy expenditure by suppressing leptin-induced inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which are central to the pathogenesis of cachexia [ 31 ], and reduces skeletal muscle catabolism induced by angiotensin II [ 32 ]. Ghrelin may also be effective for PPFE patients with possible skeletal muscle loss due to cachexia. However, non-cancer cachexia is still difficult to study compared to major diseases because of issues such as research funding and lack of public awareness. Therefore, the relationship between PPFE and cachexia, including inflammatory cytokines, remains uncertain and there are few reports on nutritional therapy and anamorelin in interstitial pneumonia, including PPFE. The symptoms of cachexia, such as severe weight loss, anorexia, early satiety, and oedema, are not clear in the early stages of the disease, and the time required for symptom onset greatly depends on the rate of progression of the underlying disease and host responses, such as activation of the systemic inflammatory response and metabolic, immune, and neuroendocrine changes [ 33 ]. It is difficult to correct undernutrition in advanced cachexia, and prevention at an early stage is considered important [ 34 ]. Although body weight and BMI are often used to assess cachexia [ 35 , 36 ], the quantitative analysis of body composition using ESM CSA is a better prognostic parameter than body weight or BMI [ 12 ]. The results of this study suggest that in PPFE, as in COPD, ESM CSA may be a stronger prognostic factor than BMI. This study has several limitations. First, it was a retrospective study; thus, it was impossible to assess patients' clinical symptoms, such as dyspnoea, or ADLs at the time of diagnosis of PPFE. Second, although this was not a single-centre study, the number of patients included was relatively small. Third, the study included patients with PPFE who were not pathologically diagnosed. Although pathological evaluation is necessary for a definitive diagnosis of IPPFE, surgical lung biopsy is often not performed due to the risk of postoperative lung leaks, pneumothorax, and acute exacerbation [ 37 , 38 ]. Therefore, Watanabe et al. [ 15 ] proposed a method for diagnosis without surgical biopsy. Finally, the cross-sectional area of the erector spinae muscle was measured as an antigravity muscle that may influence ADL; however, other antigravity muscles, such as the iliopsoas and quadriceps muscles [ 39 ], were not assessed. Future prospective studies are required to evaluate various skeletal muscles to overcome these limitations. In conclusion, we investigated the relationship between the quantification of skeletal muscles using CT and PPFE. This study highlights the importance of monitoring ESM CSA in predicting the prognosis of patients with PPFE. This suggests that ESM CSA may be a better prognostic factor for PPFE than BMI and may be more influenced by cachexia than by COPD. Methods Patients This retrospective study was conducted in a cohort of 51 consecutive patients with PPFE at Chiba University Hospital and JR Tokyo General Hospital between July 2004 and June 2023. To compare skeletal muscle mass, the study enrolled 62 patients with COPD who visited our institute as a control group, and they were evaluated using physical measurements, pulmonary function tests, and chest CT. The control group had no malignancy, ILD, resected lungs, active infection, diabetes, or neuromuscular disease. The study protocol was approved by the Ethics Committee of Chiba University Graduate School of Medicine (M10117) and JR Tokyo General Hospital (R03-23). This retrospective study was conducted in accordance with the amended Declaration of Helsinki, and informed consent was obtained from all participants. Image diagnosis The clinical diagnosis of PPFE was based on the following criteria [ 15 ]. Major criteria included (1) the presence of subpleural airspace consolidation with traction bronchiectasis of the upper lobe and (2) subpleural zonal or wedge-shaped dense fibrosis consisting of collapsed alveoli and collagen-filled alveoli with septal elastosis, with or without collagenous thickening of the visceral pleura in surgical lung biopsy specimens. Minor criteria included (1) bilateral upward migration of pulmonary hilar structures and/or volume loss in the upper lobes; (2) dry cough or exertional dyspnoea with insidious onset; and (3) RV/TLC% ≥115% and/or BMI ≤ 20 kg/m 2 plus RV/TLC% ≥80%. The presence of major criteria 1 and 2 indicated a diagnosis of definite PPFE, and the presence of major criteria 1 and minor criteria 1, 2 and/or 3 indicated a diagnosis of clinical PPFE. Image analysis Electronically stored CT images were used to assess skeletal muscle mass. All the CT images were obtained for diagnostic purposes during routine clinical practice. Chest CT was performed in the supine position with full inspiration breath-hold at 120 kV and approximately 200 mA. Scan data were analysed using the HOPE LifeMark-PACS (Fujitsu, Tokyo, Japan). Axial CT images (without contrast, 5 mm thick, 5 mm apart) taken at the inferior margin of the 12th thoracic vertebra were selected for ESM CSA measurements based on previous studies. The areas of the left and right ESMs were measured by manual tracing. The sum of the left and right muscle areas was defined as ESM CSA . All CT analyses were independently performed by trained individuals (SK, CK, and NS) blinded to the patients' survival statuses; the results were then averaged. Data collection Clinical data were obtained from the patients’ medical records. The laboratory findings and pulmonary function test results obtained at the time of diagnosis were recorded. Statistical analysis Survival time was measured from the date of PPFE diagnosis and differentiated between death within 3 years and 3-year survival as early prognosis deterioration. All data are expressed as the median [interquartile range]. The Mann-Whitney U test was used to evaluate differences in means between the two groups, and the Kruskal-Wallis test and post-hoc analyses were used for multiple comparisons. The relationships between continuous variables were evaluated using Spearman's rank correlation coefficients. Univariate and multivariate analyses were performed using Cox proportional hazards regression models to determine the effect of body composition changes on prognosis. The ESM CSA cutoff values for detecting the risk of death were determined using receiver operating characteristic curves, and BMI cutoff values were defined as underweight according to the World Health Organization. All statistical analyses were performed using R (R version 4.2.2, The R Foundation for Statistical Computing, Vienna, Austria), with p < 0.05 considered statistically significant. Declarations Acknowledgements We would like to thank Editage (www.editage.jp) for the English language editing. Author contributions S.K. designed the research; S.K., M.A., C.K., N.S., D.I., T.K., and J.I. conducted the research; S.K., M.A., C.K. and N.S. analysed the data; S.K. and M.A. wrote the manuscript; and T.S. had the primary responsibility for the final content. All authors read and approved the final manuscript. Competing interests The authors declare no competing interests. Data availability statement All data generated or analysed during this study are included in this published article (and its Supplementary Information files). References Raghu G, 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. 183, 788–824 (2011). Travis WD, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 188, 733–748 (2013). 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Supplementary Files SupplFigure1..jpg SupplFigureLegend.docx Cite Share Download PDF Status: Published Journal Publication published 12 Oct, 2023 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Major revision 07 Sep, 2023 Reviews received at journal 06 Sep, 2023 Reviewers agreed at journal 01 Sep, 2023 Reviews received at journal 15 Aug, 2023 Reviewers agreed at journal 07 Aug, 2023 Reviewers invited by journal 03 Aug, 2023 Editor assigned by journal 03 Aug, 2023 Editor invited by journal 28 Jul, 2023 Submission checks completed at journal 28 Jul, 2023 First submitted to journal 24 Jul, 2023 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-3201258","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":222321379,"identity":"26123825-6aa6-44c1-84c2-2d3879679a14","order_by":0,"name":"Shinsuke Kitahara","email":"","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shinsuke","middleName":"","lastName":"Kitahara","suffix":""},{"id":222321380,"identity":"494ea977-f53b-4b72-b3b5-d220afaec7ad","order_by":1,"name":"Mitsuhiro Abe","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYFACHgjFD2QchjAPENDBBtUi2UCyFoMDPAzMRDlLd37vsY8/ft2JNj5+9uDhghqGxAbGs/itMTvGlzybt+9Z7rYzeQmHZxwDamE4l0BAC48xM2PP4dxtN3gMDvOw/QdqOWNAUAvjT6CWzTNAWv4xEKeFgefH4dwNEkAtvG1EackxZuZtOJw740yOweGZfQzGbQT9cviMMeOPP4dz+9vPGH8u+MYg2y9BIMTAgLENicMmcYawDgaGP8gc/h5itIyCUTAKRsEIAgAbOk2ZF/AZtgAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Mitsuhiro","middleName":"","lastName":"Abe","suffix":""},{"id":222321381,"identity":"4d5b85cc-8fd3-47fe-bf3a-58e07ecfc5e6","order_by":2,"name":"Chiyoko Kono","email":"","orcid":"","institution":"Department of Respiratory Medicine, JR Tokyo General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chiyoko","middleName":"","lastName":"Kono","suffix":""},{"id":222321382,"identity":"96c3692d-2f69-4ef7-83d9-aff324f68189","order_by":3,"name":"Noriko Sakuma","email":"","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noriko","middleName":"","lastName":"Sakuma","suffix":""},{"id":222321383,"identity":"e54096c6-1658-494b-bb2f-33634767e102","order_by":4,"name":"Daisuke Ishi","email":"","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Ishi","suffix":""},{"id":222321384,"identity":"5439d876-1024-41da-a39c-0cb5553b8bd5","order_by":5,"name":"Takeshi Kawasaki","email":"","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Kawasaki","suffix":""},{"id":222321385,"identity":"bd54e18b-7168-4a4c-a7f5-64ba97712729","order_by":6,"name":"Jun Ikari","email":"","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Ikari","suffix":""},{"id":222321387,"identity":"d7bbd8e7-125f-4e30-977c-2236c391e3ec","order_by":7,"name":"Takuji Suzuki","email":"","orcid":"","institution":"Department of Respirology, Graduate School of Medicine, Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takuji","middleName":"","lastName":"Suzuki","suffix":""}],"badges":[],"createdAt":"2023-07-25 03:44:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3201258/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3201258/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-023-44138-y","type":"published","date":"2023-10-12T15:00:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":41022293,"identity":"a136017f-1972-41b4-8328-8a47867831a0","added_by":"auto","created_at":"2023-08-03 15:24:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":610344,"visible":true,"origin":"","legend":"\u003cp\u003eDistributions of the erector spinae muscle cross-sectional area (ESM\u003csub\u003eCSA\u003c/sub\u003e) and body mass index (BMI) in patients with pleuroparenchymal fibroelastosis (PPFE) and chronic obstructive pulmonary disease (COPD). Patients with PPFE had lower ESM\u003csub\u003eCSA\u003c/sub\u003e and BMI than COPD patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) I/II and GOLD III/IV. There was no significant difference in ESM\u003csub\u003eCSA\u003c/sub\u003e between COPD patients with GOLD I/II and GOLD III/IV, but BMI was lower in GOLD III/IV than in GOLD I/II.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/a6221222376e6e872c93a08e.jpg"},{"id":41022292,"identity":"9d9c2424-febe-4a3d-8f1b-213efac2a512","added_by":"auto","created_at":"2023-08-03 15:24:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":868287,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations between the erector spinae muscle cross-sectional area (ESM\u003csub\u003eCSA\u003c/sub\u003e) and body mass index (BMI), Krebs von den Lunge-6 (KL-6), and % forced vital capacity (FVC) in pleuroparenchymal fibroelastosis (PPFE). In patients with PPFE, there was a correlation between ESM\u003csub\u003eCSA\u003c/sub\u003e and BMI but not between ESM\u003csub\u003eCSA\u003c/sub\u003e and KL-6 or %FVC.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/8b3d1a32a0467b589e21fc5c.jpg"},{"id":41022296,"identity":"b1304e12-375c-4508-a571-b5d705c0632d","added_by":"auto","created_at":"2023-08-03 15:24:03","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":561281,"visible":true,"origin":"","legend":"\u003cp\u003eDetermination of the erector spinae muscle cross-sectional area (ESM\u003csub\u003eCSA\u003c/sub\u003e) cutoff value for the risk of death within 3 years using receiver operating characteristic curves. The area under the curve was 0.801, and the ESM\u003csub\u003eCSA\u003c/sub\u003e cutoff value was 22.57 cm\u003csup\u003e2\u003c/sup\u003e, with a sensitivity of 0.83 and a specificity of 0.31.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/b62df2ef93e514c9c95f406f.jpg"},{"id":41023596,"identity":"22d54f13-1eaa-4c26-ae49-6d42444484b1","added_by":"auto","created_at":"2023-08-03 15:32:03","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":893899,"visible":true,"origin":"","legend":"\u003cp\u003ePrognostic impact of the erector spinae muscle cross-sectional area (ESM\u003csub\u003eCSA\u003c/sub\u003e) and body mass index (BMI) in patients with pleuroparenchymal fibroelastosis (PPFE). Low ESM\u003csub\u003eCSA\u003c/sub\u003e was associated with death within 3 years in patients with PPFE. However, BMI showed no association with death within 3 years.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/8ee73c1e4452d98fa475f9c9.jpg"},{"id":44699801,"identity":"21021666-15b4-4994-9758-4a794d5d77e7","added_by":"auto","created_at":"2023-10-16 15:07:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":566450,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/e114329f-6b40-45c4-8e6f-56766b80763a.pdf"},{"id":41022297,"identity":"4f70d06c-cf3f-4a6d-a07f-d3a970293bf9","added_by":"auto","created_at":"2023-08-03 15:24:03","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":269051,"visible":true,"origin":"","legend":"","description":"","filename":"SupplFigure1..jpg","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/715c9e957685e424f7fa3df8.jpg"},{"id":41022294,"identity":"db443df0-320e-4469-9135-b915ccd6700f","added_by":"auto","created_at":"2023-08-03 15:24:02","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21853,"visible":true,"origin":"","legend":"","description":"","filename":"SupplFigureLegend.docx","url":"https://assets-eu.researchsquare.com/files/rs-3201258/v1/2480bedab783ba82858199ac.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic impact of erector spinae muscle cross-sectional area in patients with pleuroparenchymal fibroelastosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAmong types of idiopathic interstitial pneumonia, idiopathic pulmonary fibrosis (IPF) is the most frequent, causing chronic progressive fibrosis predominantly at the lung base [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Pleuroparenchymal fibroelastosis (PPFE) is another chronic pulmonary fibrosis proposed by Frankel et al. in 2004 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. PPFE differs from IPF in that there is more fibrosis in the upper lobe, and the histopathology shows fibrosis in the alveolar space, aggregation of elastic fibres in the alveolar walls, and fibrous thickening of the visceral pleura. The European Respiratory Society (ERS), American Thoracic Society (ATS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) 2013 guidelines [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] rank idiopathic PPFE (IPPFE) as a rare type of interstitial lung disease (ILD). PPFE is generally considered to progress slowly; however, the rapid onset of dyspnoea sometimes leads to a decline in activities of daily living (ADL), making hospital visits difficult. IPPFE typically presents with changes in body composition, and patients often complain of an emaciated physique with weight loss [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]; this weight loss includes frailty.\u003c/p\u003e \u003cp\u003eFrailty is a concept that encompasses physical changes such as weight loss, fatigue, decreased mobility, and activity, and mental changes such as decreased energy [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]; sarcopenia and cachexia are associated with frailty [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Regarding respiratory diseases, frailty is occasionally associated with chronic obstructive pulmonary disease (COPD) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Skeletal muscle dysfunction caused by frailty is a major cause of being bedridden and requiring other care types [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Skeletal muscle atrophy and loss of muscle mass in COPD have been associated with decreased ADL and risk of death [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, only a few studies have compared skeletal muscle mass with the prognosis of PPFE, although a lower body mass index (BMI) has been implicated as a poor prognostic factor [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Recently, computed tomography (CT) has made it possible to assess skeletal muscle loss quantitatively, and the erector spinae muscle cross-sectional area (ESM\u003csub\u003eCSA\u003c/sub\u003e) is considered a strong predictor of survival in COPD and IPF [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, we investigated the association of the quantification of skeletal muscle obtained by CT with PPFE.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics\u003c/h2\u003e \u003cp\u003eThe baseline characteristics of the included patients (PPFE [n\u0026thinsp;=\u0026thinsp;51], COPD [n\u0026thinsp;=\u0026thinsp;62]) are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. PPFE included 14 patients with secondary PPFE (secondary causes comprised hypersensitivity pneumonitis [n\u0026thinsp;=\u0026thinsp;4], non-tuberculous mycobacteria [n\u0026thinsp;=\u0026thinsp;4], haematopoietic stem cell transplantation [n\u0026thinsp;=\u0026thinsp;3], asbestos [n\u0026thinsp;=\u0026thinsp;2], and ulcerative colitis [n\u0026thinsp;=\u0026thinsp;1]); secondary factors were determined by pathology or clinical diagnosis. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage of patients with COPD was I/II/III/IV in 12/22/19/9 patients. Most patients with PPFE were underweight and tended to be thinner than those with COPD. Laboratory findings showed a mild increase in Krebs von den Lunge-6 (KL-6) and an increase in surfactant protein D. The pulmonary function test results, %forced vital capacity (FVC), and % diffusing capacity of the lung carbon monoxide (D\u003csub\u003eLCO\u003c/sub\u003e) were not reduced, but residual volume/total lung capacity (%RV/TLC) was increased.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of 51 patients with PPFE and 62 patients with COPD .\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePPFE (n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCOPD (n\u0026thinsp;=\u0026thinsp;62)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eGeneral\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 [55\u0026ndash;70]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 [62\u0026ndash;76]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, male/female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28/23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52/10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObservation period, days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1743 [980.5-2807.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, pack-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 [0-23.75]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46.9 [30.8\u0026ndash;70.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e163.0 [156.0-169.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e165.1 [159.1-169.9]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49.9 [40.0-57.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.2 [54.0\u0026ndash;70.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.6 [16.5\u0026ndash;19.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.1 [21.1\u0026ndash;25.1]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESM\u003csub\u003eCSA\u003c/sub\u003e, cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.38 [19.62\u0026ndash;28.75]\u003c/p\u003e \u003cp\u003eIPPFE: 23.03 [19.57\u0026ndash;28.19] (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003cp\u003eSPPFE: 25.88 [20.68\u0026ndash;29.25] (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.58 [25.82\u0026ndash;35.99]\u003c/p\u003e \u003cp\u003eGOLD I/II: 32.36 [25.96\u0026ndash;36.66] (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003cp\u003eGOLD III/IV: 29.31 [25.80-34.61] (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eLaboratory findings\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKL-6, U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e387.6 [310.0-567.3] (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSP-D, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e198.0 [118.3-305.8] (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003ePulmonary function test\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.2 [58.7\u0026ndash;90.4] (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93.5 [80.8-107.6]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003csub\u003eLCO\u003c/sub\u003e, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.9 [63.2\u0026ndash;89.9] (n\u0026thinsp;=\u0026thinsp;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRV/TLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.5 [35.8\u0026ndash;51.3] (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRV/TLC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139.5 [119.7-168.2] (n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003cp\u003eData are presented as median [interquartile range]. Abbreviations: BMI; body mass index, COPD; chronic obstructive pulmonary disease, D\u003csub\u003eLCO\u003c/sub\u003e; diffuse capacity of the lung for carbon monoxide, ESM\u003csub\u003eCSA\u003c/sub\u003e; erector spinae muscle cross-sectional area, FVC; forced vital capacity, KL-6; Krebs von den Lunge-6, IPPFE; idiopathic pleuroparenchymal fibroelastosis, SPPFE; secondary pleuroparenchymal fibroelastosis, SP-D; surfactant protein-D, RV; residual volume, TLC; total lung capacity, NA; not available\u003c/p\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eImage analysis\u003c/h2\u003e \u003cp\u003eThe distributions of the ESM\u003csub\u003eCSA\u003c/sub\u003e and BMI are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Supplementary Fig.\u0026nbsp;1. The ESM\u003csub\u003eCSA\u003c/sub\u003e of patients with PPFE was significantly smaller than that of patients with COPD (PPFE; 24.38 [19.62\u0026ndash;28.75] cm\u003csup\u003e2\u003c/sup\u003e, COPD; 30.58 [25.82\u0026ndash;35.99] cm\u003csup\u003e2\u003c/sup\u003e (GOLD I/II; 32.36 [25.96\u0026ndash;36.66] cm\u003csup\u003e2\u003c/sup\u003e, GOLD III/IV; 29.31 [25.80\u0026ndash;34.61] cm\u003csup\u003e2\u003c/sup\u003e); COPD vs PPFE: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, COPD GOLD I/II vs PPFE: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and COPD GOLD III/IV vs PPFE: p\u0026thinsp;=\u0026thinsp;0.003). BMI was significantly lower in the patients with PPFE than in those with COPD (PPFE; 18.6 [16.5\u0026ndash;19.7] kg/m\u003csup\u003e2\u003c/sup\u003e, COPD; 23.1 [21.1\u0026ndash;25.1] kg/m\u003csup\u003e2\u003c/sup\u003e; COPD vs PPFE: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, COPD GOLD I/II vs PPFE: p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and COPD GOLD III/IV vs PPFE: p\u0026thinsp;=\u0026thinsp;0.005). The correlations among ESM\u003csub\u003eCSA\u003c/sub\u003e, BMI, and clinical parameters are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In patients with PPFE, there was a significant correlation between ESM\u003csub\u003eCSA\u003c/sub\u003e and BMI (r\u0026thinsp;=\u0026thinsp;0.543, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but no correlation with KL-6 or %FVC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelations analyses of ESM\u003csub\u003eCSA\u003c/sub\u003e \u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePPFE [n\u0026thinsp;=\u0026thinsp;51]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003er\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.337\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, pack-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.454\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.719\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKL-6, U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.076\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSP-D, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.830\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eD\u003csub\u003eLCO\u003c/sub\u003e, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRV/TLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRV/TLC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003cp\u003eAbbreviations: BMI; body mass index, D\u003csub\u003eLCO\u003c/sub\u003e; diffuse capacity of the lung for carbon monoxide, ESM\u003csub\u003eCSA\u003c/sub\u003e; erector spinae muscle cross-sectional area, FVC; forced vital capacity, KL-6; Krebs von den Lunge-6, PPFE; pleuroparenchymal fibroelastosis, RV; residual volume, SP-D; surfactant protein-D, TLC; total lung capacity.\u003c/p\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePrognostic value of ESM\u003csub\u003eCSA\u003c/sub\u003e and BMI in PPFE\u003c/h2\u003e \u003cp\u003eOver 3 years, 12 patients with PPFE died (the causes of death in patients with PPFE were respiratory failure [n\u0026thinsp;=\u0026thinsp;5], acute exacerbation [n\u0026thinsp;=\u0026thinsp;2], and unknown [n\u0026thinsp;=\u0026thinsp;5]). The prognosis of patients with PPFE was evaluated using the Kaplan-Meier method and log-rank test, based on the ESM\u003csub\u003eCSA\u003c/sub\u003e cutoff value determined by the receiver operating characteristic curve to detect the risk of death (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) and on the BMI value (WHO definition of underweight status). The cutoff value for ESM\u003csub\u003eCSA\u003c/sub\u003e was 22.57 cm\u003csup\u003e2\u003c/sup\u003e, with a sensitivity of 0.83, specificity of 0.31, and area under the curve of 0.801 (95% confidence interval: 0.663\u0026ndash;0.940). In patients with PPFE, a significant difference was observed in the 3-year prognosis for ESM\u003csub\u003eCSA\u003c/sub\u003e \u0026lt;22.57 cm\u003csup\u003e2\u003c/sup\u003e at diagnosis but not for BMI\u0026thinsp;\u0026lt;\u0026thinsp;18.5 kg/m\u003csup\u003e2\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eUnivariate and multivariate analyses of ESM\u003csub\u003eCSA\u003c/sub\u003e in PPFE\u003c/h2\u003e \u003cp\u003eTo determine the prognostic impact of measurements related to skeletal muscle changes, a preliminary Cox proportional hazards regression analysis was performed. In the univariate analysis of patients with PPFE, ESM\u003csub\u003eCSA\u003c/sub\u003e, age, KL-6 level, %FVC, and RV/TLC were associated with mortality within 3 years. In the multivariate analyses, ESM\u003csub\u003eCSA\u003c/sub\u003e, KL-6, and %FVC were independently associated with mortality within 3 years in patients with PPFE (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrediction of 3-year mortality in patients with PPFE by univariate and multivariate Cox proportional-hazard regression analyses\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePPFE [n\u0026thinsp;=\u0026thinsp;51]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR [95% CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnivariate analysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eGeneral\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.107 [1.026\u0026ndash;1.194]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.567 [0.180\u0026ndash;1.787]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, pack-years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.005 [0.987\u0026ndash;1.023]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.590\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight, kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.949 [0.896\u0026ndash;1.006]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.846 [0.683\u0026ndash;1.047]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESM\u003csub\u003eCSA\u003c/sub\u003e, cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.877 [0.817\u0026ndash;0.942]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eLaboratory\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKL-6, U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.001 [1.000-1.002]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSP-D, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.000 [0.997\u0026ndash;1.004]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.830\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003ePulmonary function test\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.956 [0.928\u0026ndash;0.985]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLCO, %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.974 [0.946\u0026ndash;1.002]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRV/TLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.109 [1.020\u0026ndash;1.205]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRV/TLC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.015 [0.999\u0026ndash;1.031]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultivariate analysis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESM\u003csub\u003eCSA\u003c/sub\u003e, cm\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.900 [0.840\u0026ndash;0.964]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKL-6, U/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.002 [1.000-1.003]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC, %-pred\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.941 [0.899\u0026ndash;0.985]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: BMI; body mass index, D\u003csub\u003eLCO\u003c/sub\u003e; diffuse capacity of the lung for carbon monoxide, ESM\u003csub\u003eCSA\u003c/sub\u003e; erector spinae muscle cross-sectional area, FVC; forced vital capacity, KL-6; Krebs von den Lunge-6, PPFE; pleuroparenchymal fibroelastosis, RV; residual volume, SP-D; surfactant protein-D, TLC; total lung capacity.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is one of the few to compare changes in skeletal muscle mass with prognosis in patients with PPFE. This study highlights the importance of these two evaluation aspects. First, a decrease in ESM\u003csub\u003eCSA\u003c/sub\u003e was associated with prognosis in patients with PPFE. Second, the assessment of skeletal muscle mass in PPFE may reflect a better prognosis than BMI.\u003c/p\u003e \u003cp\u003eIt has been suggested that a lower ESM\u003csub\u003eCSA\u003c/sub\u003e may be associated with the prognosis of PPFE, including secondary PPFE (SPPFE). SPPFE is caused by haematopoietic stem cell transplantation, hypersensitivity pneumonitis, non-tuberculous mycobacterial infection, and chemotherapy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, it is possible that such comorbidities may simply be comorbid and not affect the patient and that IPPFE is included in the SPPFE. There were no significant differences in the laboratory data, respiratory complications, or survival rates between the idiopathic and secondary PPFE groups [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Known prognostic factors for IPPFE include older age, male, lower BMI, elevated KL-6, and lower FVC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This study also found that older age, elevated KL-6 levels, and lower FVC were associated with prognosis; however, no previous reports have shown an association between lower ESM\u003csub\u003eCSA\u003c/sub\u003e and prognosis. Suzuki et al. also reported an association between PPFE and ESM\u003csub\u003eCSA\u003c/sub\u003e, but no significant difference was found in prognosis. The reasons for the different results are unclear but could be explained as follows. First, both studies included small numbers of patients and may have observed different phenotypes. Second, approximately half of the patients with PPFE enrolled in this study were underweight, whereas most patients with PPFE reported by Suzuki et al. were underweight, with a BMI of \u0026lt;\u0026thinsp;18.5 kg/m\u003csup\u003e2\u003c/sup\u003e. Therefore, it is possible that the patients with PPFE in the report by Suzuki et al. had a longer disease-modifying period than those in this study and already had a more reduced skeletal muscle mass. The ESM\u003csub\u003eCSA\u003c/sub\u003e in this study was independent of laboratory findings and pulmonary function tests in the multivariate analysis. Therefore, it is important to monitor ESM\u003csub\u003eCSA\u003c/sub\u003e in patients with PPFE.\u003c/p\u003e \u003cp\u003eIn this study, ESM\u003csub\u003eCSA\u003c/sub\u003e was significantly correlated with age and BMI but not with %FVC or KL-6 values. The correlation of ESM\u003csub\u003eCSA\u003c/sub\u003e with age and BMI could be related to a decrease in skeletal muscle mass with increasing age or decreasing body weight [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, it is noteworthy that despite a significant difference in survival within 3 years for ESM\u003csub\u003eCSA\u003c/sub\u003e, there was no significant difference in BMI. This finding may be related to body weight components. Body weight comprises muscle mass, body fat mass, and the amount of inorganic matter in the skeleton. The lack of a significant difference in prognosis with respect to BMI may be because BMI is calculated based on body weight, including body fat and muscle mass. Weight loss can occur for various reasons, including starvation caused by reduced food intake preserving skeletal muscle mass and cachexia resulting in reduced skeletal muscle mass [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCachexia is caused by increased energy expenditure due to inflammatory-induced cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6, decreased appetite and increased protein catabolism associated with leptin and ghrelin, and skeletal muscle atrophy due to angiotensin II [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Cachexia occurs in cancer patients and is a cause of reduced skeletal muscle mass in COPD patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Compared to healthy controls, patients with COPD, IPF, and PPFE have lower ESM\u003csub\u003eCSA\u003c/sub\u003e [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and those with PPFE have even lower amounts of ESM\u003csub\u003eCSA\u003c/sub\u003e than those with IPF [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In this study, the patients with PPFE had an even lower ESM\u003csub\u003eCSA\u003c/sub\u003e than those with COPD. This suggests that PPFE may be more strongly affected by cachexia than COPD or IPF. Oral nutritional supplements are often used to treat cachexia, and the ghrelin receptor agonist, anamorelin, has recently proved effective in cancer patients [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Ghrelin is an appetite-enhancing peptide secreted from the stomach, which binds to the growth hormone secretagogue receptor-1a (GHSR-1a) and regulates appetite and energy metabolism [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Ghrelin and its analogues exhibit appetite-stimulating effects by promoting the expression of agouti-related neuropeptides and neuropeptide Y [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] and preventing weight loss [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In addition to its appetite-enhancing effects, ghrelin also suppresses energy expenditure by suppressing leptin-induced inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which are central to the pathogenesis of cachexia [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and reduces skeletal muscle catabolism induced by angiotensin II [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Ghrelin may also be effective for PPFE patients with possible skeletal muscle loss due to cachexia. However, non-cancer cachexia is still difficult to study compared to major diseases because of issues such as research funding and lack of public awareness. Therefore, the relationship between PPFE and cachexia, including inflammatory cytokines, remains uncertain and there are few reports on nutritional therapy and anamorelin in interstitial pneumonia, including PPFE. The symptoms of cachexia, such as severe weight loss, anorexia, early satiety, and oedema, are not clear in the early stages of the disease, and the time required for symptom onset greatly depends on the rate of progression of the underlying disease and host responses, such as activation of the systemic inflammatory response and metabolic, immune, and neuroendocrine changes [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. It is difficult to correct undernutrition in advanced cachexia, and prevention at an early stage is considered important [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Although body weight and BMI are often used to assess cachexia [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], the quantitative analysis of body composition using ESM\u003csub\u003eCSA\u003c/sub\u003e is a better prognostic parameter than body weight or BMI [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The results of this study suggest that in PPFE, as in COPD, ESM\u003csub\u003eCSA\u003c/sub\u003e may be a stronger prognostic factor than BMI.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it was a retrospective study; thus, it was impossible to assess patients' clinical symptoms, such as dyspnoea, or ADLs at the time of diagnosis of PPFE. Second, although this was not a single-centre study, the number of patients included was relatively small. Third, the study included patients with PPFE who were not pathologically diagnosed. Although pathological evaluation is necessary for a definitive diagnosis of IPPFE, surgical lung biopsy is often not performed due to the risk of postoperative lung leaks, pneumothorax, and acute exacerbation [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Therefore, Watanabe et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] proposed a method for diagnosis without surgical biopsy. Finally, the cross-sectional area of the erector spinae muscle was measured as an antigravity muscle that may influence ADL; however, other antigravity muscles, such as the iliopsoas and quadriceps muscles [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], were not assessed. Future prospective studies are required to evaluate various skeletal muscles to overcome these limitations.\u003c/p\u003e \u003cp\u003eIn conclusion, we investigated the relationship between the quantification of skeletal muscles using CT and PPFE. This study highlights the importance of monitoring ESM\u003csub\u003eCSA\u003c/sub\u003e in predicting the prognosis of patients with PPFE. This suggests that ESM\u003csub\u003eCSA\u003c/sub\u003e may be a better prognostic factor for PPFE than BMI and may be more influenced by cachexia than by COPD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted in a cohort of 51 consecutive patients with PPFE at Chiba University Hospital and JR Tokyo General Hospital between July 2004 and June 2023. To compare skeletal muscle mass, the study enrolled 62 patients with COPD who visited our institute as a control group, and they were evaluated using physical measurements, pulmonary function tests, and chest CT. The control group had no malignancy, ILD, resected lungs, active infection, diabetes, or neuromuscular disease.\u003c/p\u003e \u003cp\u003e The study protocol was approved by the Ethics Committee of Chiba University Graduate School of Medicine (M10117) and JR Tokyo General Hospital (R03-23). This retrospective study was conducted in accordance with the amended Declaration of Helsinki, and informed consent was obtained from all participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eImage diagnosis\u003c/h2\u003e \u003cp\u003eThe clinical diagnosis of PPFE was based on the following criteria [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Major criteria included (1) the presence of subpleural airspace consolidation with traction bronchiectasis of the upper lobe and (2) subpleural zonal or wedge-shaped dense fibrosis consisting of collapsed alveoli and collagen-filled alveoli with septal elastosis, with or without collagenous thickening of the visceral pleura in surgical lung biopsy specimens. Minor criteria included (1) bilateral upward migration of pulmonary hilar structures and/or volume loss in the upper lobes; (2) dry cough or exertional dyspnoea with insidious onset; and (3) RV/TLC% \u0026ge;115% and/or BMI\u0026thinsp;\u0026le;\u0026thinsp;20 kg/m\u003csup\u003e2\u003c/sup\u003e plus RV/TLC% \u0026ge;80%. The presence of major criteria 1 and 2 indicated a diagnosis of definite PPFE, and the presence of major criteria 1 and minor criteria 1, 2 and/or 3 indicated a diagnosis of clinical PPFE.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eImage analysis\u003c/h2\u003e \u003cp\u003eElectronically stored CT images were used to assess skeletal muscle mass. All the CT images were obtained for diagnostic purposes during routine clinical practice. Chest CT was performed in the supine position with full inspiration breath-hold at 120 kV and approximately 200 mA. Scan data were analysed using the HOPE LifeMark-PACS (Fujitsu, Tokyo, Japan). Axial CT images (without contrast, 5 mm thick, 5 mm apart) taken at the inferior margin of the 12th thoracic vertebra were selected for ESM\u003csub\u003eCSA\u003c/sub\u003e measurements based on previous studies. The areas of the left and right ESMs were measured by manual tracing. The sum of the left and right muscle areas was defined as ESM\u003csub\u003eCSA\u003c/sub\u003e. All CT analyses were independently performed by trained individuals (SK, CK, and NS) blinded to the patients' survival statuses; the results were then averaged.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eClinical data were obtained from the patients\u0026rsquo; medical records. The laboratory findings and pulmonary function test results obtained at the time of diagnosis were recorded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSurvival time was measured from the date of PPFE diagnosis and differentiated between death within 3 years and 3-year survival as early prognosis deterioration. All data are expressed as the median [interquartile range]. The Mann-Whitney U test was used to evaluate differences in means between the two groups, and the Kruskal-Wallis test and post-hoc analyses were used for multiple comparisons. The relationships between continuous variables were evaluated using Spearman's rank correlation coefficients. Univariate and multivariate analyses were performed using Cox proportional hazards regression models to determine the effect of body composition changes on prognosis. The ESM\u003csub\u003eCSA\u003c/sub\u003e cutoff values for detecting the risk of death were determined using receiver operating characteristic curves, and BMI cutoff values were defined as underweight according to the World Health Organization. All statistical analyses were performed using R (R version 4.2.2, The R Foundation for Statistical Computing, Vienna, Austria), with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.jp) for the English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.K. designed the research; S.K., M.A., C.K., N.S., D.I., T.K., and J.I. conducted the research; S.K., M.A., C.K. and N.S. analysed the data; S.K. and M.A. wrote the manuscript; and T.S. had the primary responsibility for the final content. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article (and its Supplementary Information files).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRaghu G, 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. 183, 788\u0026ndash;824 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTravis WD, et al. 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Spinal Cord. 58, 78\u0026ndash;85 (2020).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3201258/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3201258/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePleuroparenchymal fibroelastosis (PPFE) progresses slowly but sometimes relatively quickly, leading to decreased activities of daily living (ADL) and muscle weakness. Skeletal muscle atrophy and muscle weakness in patients with chronic obstructive pulmonary disease (COPD) may be caused by cachexia and are associated with reduced ADLs and increased risk of death. However, the association between skeletal muscle mass and the prognosis of patients with PPFE remains unknown. We retrospectively analysed the clinical significance of the erector spinae muscle cross-sectional area (ESM\u003csub\u003eCSA\u003c/sub\u003e), a skeletal muscle index, and predictors of mortality within 3 years in 51 patients with PPFE and 62 patients with COPD. Patients with PPFE had significantly lower ESM\u003csub\u003eCSA\u003c/sub\u003e than those with COPD, and lower ESM\u003csub\u003eCSA\u003c/sub\u003e (\u0026lt;\u0026thinsp;22.57 cm\u003csup\u003e2\u003c/sup\u003e) was associated with prognosis within 3 years (log-rank test; p\u0026thinsp;=\u0026thinsp;0.006), whereas lower body mass index (BMI) showed no association. Multivariate analysis showed that ESM\u003csub\u003eCSA\u003c/sub\u003e was an independent predictor of mortality within 3 years in patients with PPFE (hazard ratio, 0.900; 95% confidence interval: 0.834\u0026ndash;0.964, p\u0026thinsp;=\u0026thinsp;0.003). These results suggest the importance of monitoring ESM\u003csub\u003eCSA\u003c/sub\u003e in patients with PPFE and that assessing skeletal muscle mass in patients with PPFE could be a more useful prognostic indicator than BMI.\u003c/p\u003e","manuscriptTitle":"Prognostic impact of erector spinae muscle cross-sectional area in patients with pleuroparenchymal fibroelastosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-08-03 15:23:58","doi":"10.21203/rs.3.rs-3201258/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2023-09-07T10:47:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-09-06T07:48:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44874891-e61f-4d7e-8788-526ec1f6277d","date":"2023-09-01T06:11:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-08-15T17:25:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c12b77ec-4100-4cde-bb73-fc97d2d8b387","date":"2023-08-07T11:47:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-08-03T13:25:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-08-03T13:15:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-07-28T12:43:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-07-28T12:37:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-07-25T03:34:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"794b85b6-855e-4ea5-8526-ac2a309b7168","owner":[],"postedDate":"August 3rd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":23634837,"name":"Health sciences/Diseases"},{"id":23634838,"name":"Health sciences/Medical research"},{"id":23634839,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2023-10-16T15:04:07+00:00","versionOfRecord":{"articleIdentity":"rs-3201258","link":"https://doi.org/10.1038/s41598-023-44138-y","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2023-10-12 15:00:47","publishedOnDateReadable":"October 12th, 2023"},"versionCreatedAt":"2023-08-03 15:23:58","video":"","vorDoi":"10.1038/s41598-023-44138-y","vorDoiUrl":"https://doi.org/10.1038/s41598-023-44138-y","workflowStages":[]},"version":"v1","identity":"rs-3201258","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3201258","identity":"rs-3201258","version":["v1"]},"buildId":"ehx78VzkSd0WSzXnipQa-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}