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

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 chronic obstructive pulmonary disease (COPD) patients 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 PPFE patients remains unknown. We retrospectively analysed the clinical significance of the cross-sectional area of the erector spinae muscle (ESMCSA), a skeletal muscle index, and predictors of mortality within 3 years in PPFE 51 patients, idiopathic pulmonary fibrosis (IPF) 52 patients and COPD 62 patients. PPFE patients had significantly lower ESMCSA than IPF or COPD patients, and lower ESMCSA (< 22.57 cm2) 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 ESMCSA was an independent predictor of mortality within 3 years in PPFE patients (hazard ratio, 0.854; 95% confidence interval: 0.737–0.990, p = 0.036). These results suggest the importance of monitoring ESMCSA in PPFE patients and that assessing ESMCSA in PPFE patients could be a more useful prognostic indicator than BMI.


Prognostic impact of the cross-sectional area of the erector spinae muscle in patients with pleuroparenchymal fibroelastosis
Shinsuke Kitahara 1,2 , Mitsuhiro Abe 1* , Chiyoko Kono 2 , Noriko Sakuma 1,2 , Daisuke Ishii 1 , Takeshi Kawasaki 1 , Jun Ikari 1 & Takuji Suzuki 1 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 chronic obstructive pulmonary disease (COPD) patients 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 PPFE patients remains unknown.We retrospectively analysed the clinical significance of the cross-sectional area of the erector spinae muscle (ESM CSA ), a skeletal muscle index, and predictors of mortality within 3 years in PPFE 51 patients, idiopathic pulmonary fibrosis (IPF) 52 patients and COPD 62 patients.PPFE patients had significantly lower ESM CSA than IPF or COPD patients, 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 PPFE patients (hazard ratio, 0.854; 95% confidence interval: 0.737-0.990,p = 0.036).These results suggest the importance of monitoring ESM CSA in PPFE patients and that assessing ESM CSA in PPFE patients could be a more useful prognostic indicator than BMI.
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 often includes muscle weakness.Skeletal muscle atrophy and loss of muscle mass in COPD have been associated with decreased ADL and risk of death 5 .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 .Antigravity muscles have been reported to reflect physical activity more readily than other muscle groups 6 .The cross-sectional area of the erector spinae muscle (ESM CSA ), part of the antigravity muscles, can recently be quantitatively assessed using computed tomography (CT) and is considered a strong predictor of survival in COPD and IPF [7][8][9] .Therefore, we investigated the association of the quantification of ESM CSA obtained by CT with PPFE.Most patients with PPFE were underweight and tended to be thinner than those with IPF or 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.

Image analysis
The distributions of the ESM CSA and BMI are shown in Fig. 1 and Supplementary Figures 1 and 2 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) or RV/TLC (r = −0.509,p < 0.001), but no correlation with KL-6 or %FVC.).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 (p = 0.006) at diagnosis but not for BMI < 18.5 kg/m 2 (p = 0.129) (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, albumin, KL-6, %FVC, and RV/TLC were associated with mortality within 3 years.In the multivariate analyses, ESM CSA was independently associated with mortality within 3 years in patients with PPFE (Table 3).

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 11 .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 12 .Known prognostic factors for IPPFE include older age, male, lower BMI, elevated KL-6, and lower FVC 4,13 .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.There are two possible reasons for the different results.First, the diagnostic criteria are different.Both studies had small numbers of patients and may have observed different phenotypes.Second, the disease behaviour could be different.Many of the patients in the present study were diagnosed by imaging, which means that the time axis has not been assessed.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, BMI, and RV/TLC 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 14 .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,  www.nature.com/scientificreports/including starvation caused by reduced food intake preserving skeletal muscle mass and cachexia resulting in reduced skeletal muscle mass 15 .
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 16,17 .Cachexia occurs in cancer patients and is a cause of reduced skeletal muscle mass in COPD patients 18 .Compared to healthy controls, patients with COPD, IPF, and PPFE have lower ESM CSA 6,8 , and those with PPFE have even lower amounts of ESM CSA than those with IPF 8 .In this study, the patients with PPFE had an even lower ESM CSA than those with COPD or IPF.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 19,20 .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 21,22 .Ghrelin and its analogues exhibit appetite-stimulating effects by promoting the expression of agouti-related neuropeptides and neuropeptide Y [23][24][25] and preventing weight loss 26 .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 27 , and reduces skeletal muscle catabolism induced by angiotensin II 28 .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 29 .It is difficult to correct undernutrition in advanced cachexia, and prevention at an early stage is considered important 30 .Although body weight and BMI are often used to assess cachexia 31,32 , the quantitative analysis of body composition using ESM CSA is a better prognostic parameter than body weight or BMI 8 .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 www.nature.com/scientificreports/ 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 33,34 .Therefore, Watanabe et al. 35 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 36 , were not assessed.Future prospective studies are required to evaluate various skeletal muscles to overcome these limitations.
In conclusion, we investigated the relationship between ESM CSA 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.

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 52 patients with IPF and 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, resected lungs, active infection, 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 35 .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.

Figure 1 .
Figure 1.Distributions of the cross-sectional area of the erector spinae muscle (ESM CSA ) (A) and body mass index (BMI) (B) in patients with pleuroparenchymal fibroelastosis (PPFE), idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).Patients with PPFE had lower ESM CSA and BMI than patients with IPF or COPD.

Figure 3 .
Figure 3. Determination of the cross-sectional area of the erector spinae muscle (ESM CSA ) 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 CSA cutoff value was 22.57 cm 2 , with a sensitivity of 0.83 and a specificity of 0.31.

Figure 4 .
Figure 4. Prognostic impact of the cross-sectional area of the erector spinae muscle (ESM CSA ) (A) and body mass index (BMI) (B) in patients with pleuroparenchymal fibroelastosis (PPFE).Low ESM CSA was associated with death within 3 years in patients with PPFE.However, BMI showed no association with death within 3 years.

Table 1 .
The baseline characteristics of the included patients (PPFE [n = 51], IPF [n = 52], COPD [n = 62]) are shown in In this study, eight definite PPFE cases were diagnosed by surgical lung biopsy, and 33 PPFE cases had fibrosis in the lower lobes.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 Japanese severity classification of patients with IPF 10 , consisting of arterial partial pressure of oxygen and oxygen saturation during exercise, was Stage I/II/III/IV in 11/1/12/28 patients.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.

Table 1 .
The correlations among ESM CSA , BMI, and clinical parameters are shown in Clinical characteristics of 51 patients with PPFE, 52 patients with IPF and 62 patients with COPD.

Table 3 .
Prediction of 3-year mortality in patients with PPFE by univariate and multivariate Cox proportional-hazard regression analyses.Abbreviations: BMI; body mass index, D LCO ; diffuse capacity of the lung for carbon monoxide, ESM CSA ; The cross-sectional area of the erector spinae muscle, 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.