Clinical features and risk factors of invasive pulmonary aspergillosis in interstitial lung disease patients

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The purpose of this study is to analyze the clinical features and risk factors of IPA in patients with ILD. Methods 353 hospitalized ILD patients admitted in Nanjing Drum Tower Hospital from March 2023 and April 2024 were enrolled. The enrolled patients were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups. Results Among 353 patients with ILD, 58 who suffered from IPA were identified. Among them, 2 (3.4%) episodes of proven IPA and 56 (96.6%) of probable IPA were diagnosed. The median age was 68.4 ± 8.6 years, and 35 patients were men. The forms of ILD included idiopathic pulmonary fibrosis (n = 21), interstitial pneumonia with autoimmune features (n = 13), rheumatoid arthritis related interstitial pneumonia (n = 11) and Sjögren′s syndrome (n = 4). The clinical features of IPA in ILD were cough (100.0%), dyspnea (93.1%) and fever (55.2%). Chest CT images showed traction bronchiectasis (84.5%), GGO (77.6%), honeycombing (69.0%), consolidation (44.8%) and pleural effusion (24.1%). The incidence of honeycombing and consolidation were higher in ILD patients with IPA compared to control group ( P < 0.05). The main pathogens were A. fumigatus (50.0%) and A. flavus (29.3%). Following the diagnosis of IPA, all patients were treated with antifungal drugs. The overall survival rate after 90 days was 74.1%. Multivariate conditional Logistic regression analysis showed that lymphopenia (OR = 2.745, 95% CI 1.344–5.607) and honeycombing (OR = 2.915, 95% CI 1.429–5.949) were the risk factors of ILD with IPA ( P < 0.05). Conclusion IPA is one of the major complications of ILD and its prognosis is poor. Lymphopenia and honeycombing increased the risk of IPA in ILD patients. interstitial lung disease invasive pulmonary aspergillosis risk factor honeycombing Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Invasive pulmonary aspergillosis (IPA) primarily occurs in severely immunocompromised patients, including those with neutropenia, a history of hematopoietic stem-cell transplantation, solid-organ transplantation or prolonged and/or high dose corticosteroid treatment [ 1 ]. IPA progresses rapidly, and the mortality rate is high. Underlying lung disease like chronic obstructive pulmonary disease (COPD) is a well-known risk factor of IPA [ 2 ]; however, interstitial lung disease (ILD) has not been recognized as a risk factor of IPA. Several case reports on ILD with aspergillosis have been published recently [ 3 – 5 ]. The comorbid occurrence of IPA in patients with ILD severely impacts their short-term outcomes. Unfortunately, reports of these cases are few, the clinical presentation and imaging features of such patients are relatively rare. Therefore, we conducted a retrospective study of patients diagnosed with IPA associated with ILD in order to investigate the clinical features and risk factors of this condition. Methods Subjects and study design Medical records of all patients treated for ILD with or without IPA, who were admitted to Nanjing Drum Tower Hospital between March 2023 and April 2024 were retrospectively reviewed. This study was approved from the institutional review board of Nanjing Drum Tower Hospital, which waived the need for patient approval or informed consent because the study involved a retrospective review of clinical records. To diagnose ILD, we used the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus classification [ 6 ]. In patients with histological evidence, the diagnosis of ILD was dependent on pathological findings. In patients without histological evidence, the diagnosis was based on the findings of high-resolution computed tomography (HRCT) scans of the chest, medical history taking and physical examinations. IPA was diagnosed according to the European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria [ 7 , 8 ]. Diagnostic criteria for IPA included the following items: (a) host factors such as solid-organ transplant, hereditary immunodeficiencies, connective tissue disorders (CTD) and use of immunosuppressive agents. Critically, acute respiratory distress syndrome, COPD, influenza, pneumonia, burns, severe bacterial infection, surgery, diabetes and malnutrition were included; (b) Clinical manifestations, including fever, cough, sputum, hemoptysis, dyspnea or other symptoms of lower respiratory tract infection that were not relieved with broad-spectrum antibacterial treatment; (c) radiological data such as nodule(s) > 1 cm, which may be surrounded by a halo of ground-glass attenuation, pleural based wedge-shaped areas of consolidation, alveolar consolidations, masses, internal low attenuation, reverse halo sign, cavity or air-crescent sign and ground-glass opacities and pleural effusion; (d) mycological evidence, such as a positive aspergillus culture from qualified specimens (sputum and BALF) or a positive serum galactomannan (GM) result; and (e) histological evidence of aspergillus hyphae in lung biopsy specimens or a positive aspergillus culture from lung biopsy specimens. A proven diagnosis was made with histological evidence, and a probable diagnosis was made on the basis of host risk factors, clinical and radiological manifestations and microbiological evidence. Finally, we extracted 58 patients who had IPA with ILD and then collected data from these patients’ medical records that included characteristics, laboratory data, pulmonary function results, and chest HRCT findings at the time of the IPA diagnosis. Each subject’s radiological findings were reviewed by 2 independent radiologists. HRCT patterns were classified as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP). Honeycombing pattern was defined as clustered cystic air spaces with well-defined walls and typically comparable diameters of 3 to 10 mm in subpleural and lower lobes. Survival was defined as the time from the date of either the IPA diagnosis or ILD diagnosis to the date of death or date of censoring. Statistical analysis Categorical variables were compared using the chi-square test and continuous variables were compared using Student’s t -test or the Mann-Whitney test based on the distribution of the data. Fisher’s exact test was used to compare qualitative variables. Survival curves were generated using the Kaplan-Meier method. Differences in survival were compared using the log-rank test. The Cox proportional hazards model was used to assess the associations between clinical variables and survival. Variables with a P value < 0.1 in univariate analysis were included into the multivariate model. Finally, only variables with P value < 0.05 were retained in the multivariate model. Statistical analysis was performed using SPSS Statistics 23.0 (SPSS Inc., Chicago, IL, USA), and statistical significance was defined as a two-tailed P value < 0.05. Results Patient characteristics The patient characteristics are summarized in Table 1 . Among the patients with ILD, we identified a total of 58 patients suffered from IPA, with a median age of 68.4 ± 8.6 years. 35 patients (60.3%) were male. History of smoking was present in 17 cases (29.3%). There were no significant differences in sex, underlying disease and its smoke status between the two groups. The subtypes of ILD were as follows: 21 patients had idiopathic pulmonary fibrosis (IPF), 13 patients had interstitial pneumonia with autoimmune features, 11 patients had rheumatoid arthritis (RA) associated interstitial lung disease, 4 patients had Sjögren′s syndrome, 5 patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, 3 patients with idiopathic inflammatory myopathy and 1 patient with systemic sclerosis. Of the 58 patients, 32 patients (55.2%) received corticosteroid over the last 3 weeks, 16 patients (27.6%) received immunosuppressive agents (i.e., cyclosporin, tacrolimus, methotrexate, and abatacept), and 27 patients (46.6%) received antifibrotic agents (i.e., pirfenidone or nintedanib). Table 1 Characteristics of ILD patients in the IPA and non-IPA groups Characteristic IPA group ( n = 58) Non-IPA group ( n = 295) P value Sex; n (%) male 35 (60.3) 152 (51.5) 0.219 Age; mean (SD) 68.4 (8.6) 64.7 (11.4) 0.019 Current/ex-smoker 17 (29.3) 64 (21.7) 0.207 Clinical symptoms; n (%) Cough 58 (100.0) 292 (99.0) 1.000 Dyspnea 54 (93.1) 289 (98.0) 0.064 Fever 32 (55.2) 87 (29.5) < 0.001 Hemoptysis 5 (8.6) 9 (2.9) 0.043 Chest pain 1 (1.7) 2 (0.6) 0.350 Forms of interstitial pneumonia; n (%) IPF 21 (36.2) 97 (32.9) 0.624 CTD-ILD IPAF 13 (22.4) 67 (22.7) 0.960 RA-ILD 11 (19.0) 15 (5.1) < 0.001 pSS-ILD 4 (6.9) 57 (19.3) 0.022 ANCA-ILD 5 (8.6) 6 (2.0) 0.021 IIM-ILD 3 (5.2) 42 (14.2) 0.082 SSc-ILD 1 (1.7) 3 (9.8) 0.118 COP 0 7 (2.4) 0.605 Complication in disease; n (%) Diabetes 19 (32.8) 82 (27.8) 0.617 Hypertension 22 (37.9) 84 (28.5) 0.151 Cardiovascular disease 7 (12.1) 34 (11.5) 0.906 Case classification; n (%) Proven IPA 2 (3.4) - Probable IPA 56 (96.6) - Glucocorticoid exposure 32 (55.2) 110 (37.3) 0.011 High-dose corticosteroid use 16 (27.6) 60 (20.3) 0.220 Low-dose corticosteroid use 16 (27.6) 50 (16.9) 0.058 Immunosuppressive agents 16 (27.6) 85 (28.8) 0.850 Antifibrotic agents 27 (46.6) 101 (32.9) 0.075 pirfenidone 7 (12.1) 36 (12.2) 0.977 nintedanib 21 (36.2) 65 (22.0) 0.022 High-dose corticosteroid use: a therapeutic dose of ≥ 0.3 mg/kg corticosteroids for ≥ 3 weeks in the past 60 days Low-dose corticosteroid use: a therapeutic dose of < 0.3 mg/kg corticosteroids for ≥ 3 weeks in the past 60 days The clinical features of IPA in ILD were cough (100.0% vs. 99.0%, p = 1.000), dyspnea (93.1% vs. 98.0%, p = 0.064), fever (55.2% vs. 29.5%, P < 0.001) and hemoptysis (9.3% vs. 2.9%, P = 0.043). In terms of clinical symptoms, the IPA group displayed significantly greater proportions of fever (55.2% vs. 29.5%, p < 0.001). No significant differences were observed in cough, dyspnea or hemoptysis between the two groups. White blood cell count (median 11.1 x 10 9 vs. 8.3 x10 9 , p < 0.001), neutrophil count (median 9.6 x 10 9 vs. 6.2 x10 9 , p < 0.001) and NLR (median 16.3 vs. 6.4, p < 0.001) were significantly greater in the IPA group, while lymphocyte count (median 1.0 x 10 9 vs. 1.5 x 10 9 , p < 0.001) and eosinophils count (median 0.06 x 10 9 vs. 0.12 x 10 9 , p = 0.004) were significantly lower. Blood gas analysis indicated significantly greater oxygenation index in the IPA group (median 238.6 vs. 307.4 mmol/L, p = 0.005). Significant differences were observed between the IPA and non-IPA groups for CRP (median 84.8 mg/L vs. 28.1 mg/L, p < 0.001), PCT (median 1.06 ng/mL vs. 0.14 ng/mL, p = 0.001), LDH (median 379.2 U/L vs. 290.4 U/L, p < 0.001), ESR (median 45.7 mm/h vs. 37.1 mm/h, p = 0.038) and IL-6 (median 76.2 g/L vs. 24.8 g/L, p < 0.001). Compared with ILD patients without IPA, CD4+/CD8 + double positive cells were less abundant in ILD patients with IPA. Table 2 The microbiological, laboratory, and CT thorax findings of ILD patients in the IPA and non-IPA groups Factors IPA group (n = 58) Non-IPA group (n = 295) P value LABORATORY FINDINGS WBC count (×10 9 ) 11.1 ± 6.8 8.3 ± 3.3 < 0.001 Neutrophils 9.6 ± 6.8 6.2 ± 3.2 < 0.001 Lymphocyte 1.0 ± 0.6 1.5 ± 0.9 < 0.001 NLR 16.3 ± 17.3 6.4 ± 6.8 < 0.001 Eos 0.06 ± 0.10 0.12 ± 0.16 0.004 Hb 116.8 ± 18.4 124.2 ± 18.6 0.006 Alb 32.3 ± 4.3 35.3 ± 3.9 < 0.001 LDH (U/L) 379.2 ± 188.5 290.4 ± 116.1 < 0.001 CRP (mg/L) 84.8 ± 87.6 28.1 ± 38.5 < 0.001 ESR (mm/h) 45.7 ± 24.5 37.1 ± 25.1 0.038 PCT (ng/mL) 1.06 ± 4.10 0.14 ± 0.49 0.001 IL-6 (ng/L) 76.2 ± 169.1 24.8 ± 58.6 < 0.001 CD4+(×10 9 ) 312.7 ± 257.1 552.9 ± 386.0 < 0.001 CD4+ (%) 30.4 ± 12.6 35.6 ± 12.5 0.005 CD8+(×10 9 ) 365.3 ± 334.8 433.7 ± 290.7 0.130 CD8+ (%) 35.0 ± 16.3 29.9 ± 12.1 0.010 CD4+/CD8+ 1.2 ± 1.0 1.5 ± 1.0 0.048 T3 2.3 ± 1.0 3.4 ± 1.8 < 0.001 T4 14.0 ± 4.0 15.4 ± 4.3 0.058 TSH 1.5 ± 2.8 2.7 ± 4.9 0.165 Oxygenation index 238.6 ± 111.9 307.4 ± 110.8 0.005 HRCT patterns UIP 36 (62.1) 137 (46.4) 0.030 NSIP 16 (27.6) 110 (37.3) 0.159 OP 3 (5.2) 20 (6.8) 1.000 NSIP + OP 3 (5.2) 28 (9.5) 0.445 CT thorax findings Honeycombing 40 (69.0) 144 (48.8) 0.005 Consolidation 26 (44.8) 89 (30.2) 0.029 GGO 45 (77.6) 190 (64.4) 0.052 Traction bronchiectasis 49 (84.5) 224 (75.9) 0.155 Pleural effusion 14 (24.1) 39 (13.2) 0.033 Air crescent sign 1 (1.7) 0 0.164 ROC curves were generated to evaluate the diagnostic performance of each biomarker for IPA in ILD patients. The area under the curve (AUC), cutoff values, sensitivity and specificity for each biomarker are summarized in Table 3 . The AUC values for CRP, IL-6, PCT, ESR, and NLR were 0.731, 0.624, 0.707, 0.608, and 0.738, respectively. The corresponding cutoff values were 45.4, 11.1, 0.06, 31.5, and 7.33 g/L, respectively. The sensitivity and specificity were as follows: CRP (56.9%, 80.0%), IL-6 (61.5%, 64.8%), PCT (70.0%, 66.7%), ESR (65.9%, 48.9%), and NLR (65.5%, 72.9%). Table 3 Area under the curve (AUC), cutoff value, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the diagnosis of ILD combined with IPA by each biomarker. AUC Cutoff Sensitivity Specificity CRP (mg/L) 0.731 45.4 56.9% 80.0% IL-6 (ng/mL) 0.624 11.1 61.5% 64.8% PCT (ng/mL) 0.707 0.06 70.0% 66.7% ESR (mm/h) 0.608 31.5 65.9% 48.9% NLR 0.738 7.33 65.5% 72.9% Chest CT findings The CT findings are summarized in Table 2 . The HRCT patterns at the time of ILD diagnosis were UIP in 36 patients (62.1%), NSIP in 16 patients (27.6%), OP in 3 patients (5.2%), and NSIP-OP in 3 patients (5.2%). The most frequent abnormal finding was traction bronchiectasis (n = 49, 84.5%), GGO (n = 45, 77.6%), honeycombing (n = 40, 69.0%), consolidation (n = 26, 44.8%) and pleural effusion (n = 14, 24.1%). Radiographic findings revealed significantly more honeycombing (69.0% vs. 48.8%, p = 0.005) in the IPA group. Notably, typical IPA signs were rare in the IPA group, with only 1.7% each for the halo sign and air crescent sign. Microbiological analysis During the study period, respiratory cultures were collected from 257 patients with ILD and Aspergillus was detected in 30 patients (30/56, 53.6%). The most common species were A. fumigatus with 23 strains, A. flavus with 12 strains, A. niger with 3 strains and A. terreus with 2 strains were isolated. Moreover, GM was positive in 19 patients (33.9%). BAL fluid analyses were performed in 96 episodes (29 in the IPA group and 69 in the non-IPA group). In the 29 episodes in the IPA group, there were 20 (66.7%) cases of positive BAL fluid GMI and only 11 (36.7%) episode of positive BAL fluid culture for Aspergillus spp. Table 4 Species and Treatments IPA group (n = 58) Positive cultures Sputum 30/56 (53.6) Bronchoalveolar lavage 11/30 (36.7) Positive NGS in BALF 18/24 (75.0) Positive NGS in sputum 1/1 (100.0) Positive Aspergillus antibodies 4/8 (50.0) Positive GM in serum 19/56 (33.9) Positive GM in BALF 20/30 (66.7) Positive PCR 2/2 (100.0) Species A. fumigatus 23 (39.7) A. flavus 12 (20.7) A. niger 3 (5.2) A. terreus 2 (3.4) A. fumigatus + A. terreus 1 (1.7) A. fumigatus + A. flavus 4 (6.9) A. flavus + A. niger 1 (1.7) A. fumigatus + A. niger 1 (1.7) NA 11 (17.0) Treatment Voriconazole 50 (86.2) Isavuconazole 7 (12.1) Amphotericin B 1 (1.7) Treatments and outcomes The treatments and outcomes are summarized in Table 4 . Of the 58 patients with IPA associated with ILD, all patients received antifungal treatment regardless of the duration of treatment. The basic treatment was voriconazole as monotherapy or in combination with other antifungals in 86.2% of patients. Isavuconazole was used in 12.1% of patients; amphotericin B (1.7%) was rarely used. Kaplan-Meier survival curves and log-rank test showed a significant difference in overall survival rate after 90 days between the IPA patients (70.2%) and non-IPA patients (84.0%) from the viewpoints of the follow-up period from the ILD diagnosis. Multivariate analysis To further analyze the independent risk factors affecting the occurrence of IPA, a positive diagnosis was set as the dependent variable. Based on the ILD-IPA susceptibility factor analysis and univariate analysis results, we included CRP and NLR in the logistic regression model. The multivariate analysis summarized in Table 5 indicates that lymphopenia (OR = 2.745, 95% CI 1.344–5.607) and honeycombing (OR = 2.915, 95% CI 1.429–5.949) were independent risk factors for ILD-IPA. (P < 0.05) Table 5 Logistic regression analysis of risk factors for the occurrence of ILD-IPA Influencing factor β SE Wald value P value OR value 95% CI Age -0.052 0.378 0.019 0.890 0.949 0.453–1.990 Steroid before admission -0.592 0.360 2.695 0.101 0.553 0.273–1.122 Lymphopenia 1.010 0.364 7.676 0.006 2.745 1.344–5.607 IL-6 0.514 0.362 2.102 0.156 1.671 0.822–3.398 Honeycombing 1.070 0.364 8.645 0.003 2.915 1.429–5.949 Discussion IPA is a common opportunistic infection. Aspergillus infection is usually seen in those with underlying respiratory disease. However, the report of its association with ILD is rare. Therefore, we focused on the correlations between IPA and ILD in the present study and then investigated both the patient characteristics and the prognosis or mortality risk of IPA in patients with ILD. In this retrospective study, we included 58 patients with proven (3.4%) and probable (96.6%) IPA. Neutrophils play a key role of the first line defense against aspergillus infection. To eliminate aspergillus germinating spores, neutrophils produce extracellular traps, release antimicrobial proteases by degranulation, and activate the toll-like receptor pathway [ 9 ]. Our study presents the results of neutrophil-to-lymphocyte ratio (NLR) comparison between surviving and deceased ILD patients suffering from IPA infections. The increased risk for opportunistic infection in ILD is predominantly related to lymphocyte deficiency [ 10 ]. Immunosuppressive regimens have a lymphocyte reducing effect with a secondary increase in the NLR, a marker of poor prognosis for the patients [ 11 ]. The study indicates that a simple parameter such as NLR may predict mortality risk for mold infection following ILD. The combination of leukocyte reducing effects with secondarily increased neutrophils in peripheral blood presented as NLR in immunocompromised patients has already been postulated. Patients with high NLR on antifungal therapy had a poorer prognosis of IPA survival. On immunosuppressive therapy, the lymphocytes are depressed, which is evidenced by high NLR values, leading to suppression of the natural defense system, including inflammatory response. Notably, commonly available serum biomarkers NLR has several advantages, including ease of detection, affordability, and noninvasiveness [ 12 , 13 ]. Our experience also suggests that radiologic signs of IPA are non-specific. In the previous study, UIP pattern with honeycombing (40.6%) and smoking-related ILD (28.1%) accounted for the majority of cases of Aspergillus infection [ 14 ]. Wide-spread cystic lesions and emphysema as destructive changes in lung tissue can be colonized by Aspergillus [ 15 ]. The extensive honeycomb-like changes in the lungs caused structural damage to the lungs. Thus this UIP patient lacked the essential resistance to aspergillus, and aspergillus was much likely to colonize the lungs. According to the published reports, UIP that is diagnosed upon radiologic examination accounts for 80.4% of all patients with ILD plus IPA [ 16 ]. Moreover, a Japanese study has shown that UIP patients are inclined to have aspergillosis, indicating, from another perspective, the potential role of structural lesions of the lungs in the development or pathogenesis of aspergillosis [ 17 ]. Unfortunately, the clinical presentation and imaging features of such patients lack specificity, posing a great challenge for the early diagnosis of ILD-IPA. In studies carried out on patients with hematologic malignancy from our country, GM antigen test sensitivity was found as 56–61% and its specificity as 21–84% [ 18 ]. In addition, it has been indicated that GM positivity in COPD patients with IPA development in intensive care and the isolation of Aspergillus species in respiratory samples may be significant in terms of mortality [ 19 ]. As for our study, the GM value was found to be positive in 14 (25.9%) cases, and 11 of them (20.7%) died. This gives further support to the belief that GM positivity in ILD cases with the development of IPA is a significant parameter to be considered in terms of mortality. Glucocorticoids and immunosuppressants are the main medications for ILD, though they may increase the risk of aspergillosis [ 20 ]. Prolonged immunosuppressive therapy is a risk factor for IPA. Corticosteroid have often been used in non-IPF patients, and in fact, it was used in 51.9% of the patients in the present study. Patients treated with steroid therapy require special attention regarding the potential for Aspergillus infection. In recent years, it has been shown that corticosteroid use plays a significant role in terms of increasing the rate of IPA incidence in ILD cases. It was determined that IPA leads to increased mortality of ILD patients. Early antifungal therapy is mandatory for the successful treatment of IPA [ 21 , 22 ]. All our patients received antifungal therapy. Voriconazole was mainly used for IPA treatment in 89.6% patients. There are some limitations to the present study. First, it is a single-center retrospective study, which can introduce referral bias and limit the ability to generalize our findings. Moreover, the rate of positivity of mycological proof was low, although the diagnosis of IPA was made according to commonly used criteria. Randomized controlled trials are needed to evaluate the efficacy and safety of primary antifungal prophylaxis in these patients. Conclusions IPA with atypical manifestations can occur in patients with ILD. Constantly considering the potential presence of IPA can aid in the prompt diagnosis of such atypical IPA. As the complication of IPA may lead to a poor prognosis for any ILD, clinicians should be aware of the importance of a prompt. The presents study shows that NLR, IL-6 and chest imaging can be useful for the early differential diagnosis of IPA.NLR and IL-6, as a simple parameter of very basic blood analysis, may be of predictive value in the estimation of mortality risk or response to treatment among patients with IPA following ILD. Declarations Ethics approval and consent to participate The study protocol was approved by the Ethics Committee of Nanjing Drum Tower Hospital, with the ethics application number 2021–390-01. Due to the retrospective nature of the study using anonymous claims data, the requirement for informed consent was waived. Consent for publication Not Applicable. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. 2 Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. 3 Department of Medical Imaging, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. Funding This study was funded by National Natural Science Foundation of China (82270019), Fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2023-LCYJ-MS-18). The funder played no role in the study design, data collection, analysis and interpretation of data, or the writing of this manuscript. Author Contribution LY, and SX conceived and designed the analysis. LY, JHY, ZTT, and CM collected the data. NYL, LY, YX, and ZTT contributed to the analysis. XYL, QRF, ZTT, and HJ performed the analysis. LY and SX wrote the paper. All authors read and approved the final manuscript. Acknowledgements Not applicable Availability of data and materials The datasets used and/or analysed during this study are available from the corresponding author upon reasonable request. References El-Baba F, Gao Y, Soubani AO. Pulmonary Aspergillosis: What the Generalist Needs to Know. Am J Med. 2020;133(6):668–74. https://doi.org/10.1016/j.amjmed.2020.02.025 . Guinea J, Torres-Narbona M, Gijón P, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect. 2010;16(7):870–7. https://doi.org/10.1111/j.1469-0691.2009.03015.x . Yamakawa H, Nishizawa T, Ohta H, et al. Patient background and prognosis of chronic pulmonary aspergillosis in fibrosing interstitial lung disease. 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Tamura A, Suzuki J, Fukami T, et al. Chronic pulmonary aspergillosis as a sequel to lobectomy for lung cancer. Interact Cardiovasc Thorac Surg. 2015;21(5):650–6. https://doi.org/10.1093/icvts/ivv239 . Liu C, Yang J, Lu Z. Idiopathic pulmonary fibrosis with chronic necrotizing pulmonary aspergillosis: a case report. Int J Clin Exp Pathol. 2019;12(7):2653–6. Kurosaki F, Bando M, Nakayama M, et al. Clinical features of pulmonary aspergillosis associated with interstitial pneumonia. Intern Med. 2014;53(12):1299–306. https://doi.org/10.2169/internalmedicine.53.1578 . Yu W, Xiao Y, Luo Y, et al. Risk factors for short-term prognosis of end-stage liver disease complicated by invasive pulmonary aspergillosis. Eur J Clin Microbiol Infect Dis. 2024;43(4):713–21. https://doi.org/10.1007/s10096-024-04775-1 . Long Z, Li X, Li Z, et al. Improved diagnostic markers for invasive pulmonary aspergillosis in COPD patients. Front Cell Infect Microbiol. 2024;14:1294971. https://doi.org/10.3389/fcimb.2024.1294971 . Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet. 2003;362(9398):1828–38. https://doi.org/10.1016/S0140-6736(03)14904-5 . Dai Z, Zhao H, Cai S, et al. Invasive pulmonary aspergillosis in non-neutropenic patients with and without underlying disease: a single-centre retrospective analysis of 52 subjects. Respirology. 2013;18(2):323–31. https://doi.org/10.1111/j.1440-1843.2012.02283.x . Glampedakis E, Cassaing S, Fekkar A, et al. Invasive Aspergillosis Due to Aspergillus Section Usti: A Multicenter Retrospective Study. Clin Infect Dis. 2021;72(8):1379–85. https://doi.org/10.1093/cid/ciaa230 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2024 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 20 Sep, 2024 Editor assigned by journal 19 Sep, 2024 Submission checks completed at journal 19 Sep, 2024 First submitted to journal 11 Sep, 2024 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5069345","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":356749045,"identity":"9ddf3a7a-d3f1-49c0-a64c-1e02055855db","order_by":0,"name":"Yin Liu","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yin","middleName":"","lastName":"Liu","suffix":""},{"id":356749046,"identity":"93d7385d-d5d1-4f38-8f30-a6f6d1159523","order_by":1,"name":"Xin Su","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtElEQVRIiWNgGAWjYJCCAww8DHJs7O0HSNNizMdzJoE0mxLnSTgYEKdUfkaO4eECmbr0NgmGBIYfFdsIazG4kZZweAbP4dw26cYDjD1nbhOhRSL5wGEengO5bTIHEpgZ24jQIj8jsQGopS6dTSLBgDgtDDfAtjAnEK/F4MyzBKCWw4ZtwEA+SJRf5NtzjD/z9tTJy7e3H3zwo4IYh4EAYw+EPkCkehD4QYLaUTAKRsEoGHkAAImtOhLAydCnAAAAAElFTkSuQmCC","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Su","suffix":""},{"id":356749047,"identity":"eb0e3d22-79ef-4f13-a0a2-ca3b167a9b10","order_by":2,"name":"Min Cao","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Cao","suffix":""},{"id":356749048,"identity":"7bdd9347-9fbf-4610-9799-a0b15c43462d","order_by":3,"name":"Hanyi Jiang","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hanyi","middleName":"","lastName":"Jiang","suffix":""},{"id":356749049,"identity":"c4767cc7-c0c2-425f-af2d-01c0ee45cf2c","order_by":4,"name":"Tingting Zhao","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Zhao","suffix":""},{"id":356749050,"identity":"f643002b-d4d3-4414-8a1d-94b1adb1f735","order_by":5,"name":"Jian He","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jian","middleName":"","lastName":"He","suffix":""},{"id":356749051,"identity":"9f622090-6d5e-41bc-b375-b7f83042b7a4","order_by":6,"name":"Rongfeng Qi","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rongfeng","middleName":"","lastName":"Qi","suffix":""},{"id":356749052,"identity":"672b5668-bed7-4d3b-81e9-fb44c5628a70","order_by":7,"name":"Yonglong Xiao","email":"","orcid":"","institution":"Nanjing Drum Tower Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yonglong","middleName":"","lastName":"Xiao","suffix":""}],"badges":[],"createdAt":"2024-09-11 08:14:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5069345/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5069345/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-024-03430-x","type":"published","date":"2024-12-04T15:56:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69350493,"identity":"fb31412e-2d4e-42be-89ba-f0449fba9edd","added_by":"auto","created_at":"2024-11-19 13:02:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":140650,"visible":true,"origin":"","legend":"\u003cp\u003eRecruitment flowchart.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-5069345/v1/7e571c27e1821d60def24218.png"},{"id":69350491,"identity":"0602b979-f881-45d0-a3cb-b2b52dec7df3","added_by":"auto","created_at":"2024-11-19 13:02:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103569,"visible":true,"origin":"","legend":"\u003cp\u003eReceiver operating characteristic (ROC) curve for each biomarker in the IPA and non-IPA groups (A-E).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-5069345/v1/a032821a63c7169fb4f4ebbf.png"},{"id":69352288,"identity":"7088bd37-dd1f-45d0-8bfd-b79b2e2e72c6","added_by":"auto","created_at":"2024-11-19 13:10:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30703,"visible":true,"origin":"","legend":"\u003cp\u003eThe overall 90-days survival of IPA patients.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-5069345/v1/6a57a470c4c007c4e39c430e.png"},{"id":69350494,"identity":"f3fc6c73-44f3-48b5-9ff8-0fa21335b0b5","added_by":"auto","created_at":"2024-11-19 13:02:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":57816,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of Logistic regression analysis of risk factors for the occurrence of ILD-IPA\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-5069345/v1/a73b1744131695be47b57ac3.png"},{"id":70964583,"identity":"c84962e2-23de-4918-b62e-e8e4b2f3aa10","added_by":"auto","created_at":"2024-12-09 16:09:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1050746,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5069345/v1/047ba9db-d1b8-422d-b5a4-0d0df48d6ec5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical features and risk factors of invasive pulmonary aspergillosis in interstitial lung disease patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInvasive pulmonary aspergillosis (IPA) primarily occurs in severely immunocompromised patients, including those with neutropenia, a history of hematopoietic stem-cell transplantation, solid-organ transplantation or prolonged and/or high dose corticosteroid treatment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. IPA progresses rapidly, and the mortality rate is high. Underlying lung disease like chronic obstructive pulmonary disease (COPD) is a well-known risk factor of IPA [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]; however, interstitial lung disease (ILD) has not been recognized as a risk factor of IPA.\u003c/p\u003e \u003cp\u003eSeveral case reports on ILD with aspergillosis have been published recently [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The comorbid occurrence of IPA in patients with ILD severely impacts their short-term outcomes. Unfortunately, reports of these cases are few, the clinical presentation and imaging features of such patients are relatively rare. Therefore, we conducted a retrospective study of patients diagnosed with IPA associated with ILD in order to investigate the clinical features and risk factors of this condition.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects and study design\u003c/h2\u003e \u003cp\u003e Medical records of all patients treated for ILD with or without IPA, who were admitted to Nanjing Drum Tower Hospital between March 2023 and April 2024 were retrospectively reviewed. This study was approved from the institutional review board of Nanjing Drum Tower Hospital, which waived the need for patient approval or informed consent because the study involved a retrospective review of clinical records.\u003c/p\u003e \u003cp\u003eTo diagnose ILD, we used the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus classification [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In patients with histological evidence, the diagnosis of ILD was dependent on pathological findings. In patients without histological evidence, the diagnosis was based on the findings of high-resolution computed tomography (HRCT) scans of the chest, medical history taking and physical examinations.\u003c/p\u003e \u003cp\u003eIPA was diagnosed according to the European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Diagnostic criteria for IPA included the following items: (a) host factors such as solid-organ transplant, hereditary immunodeficiencies, connective tissue disorders (CTD) and use of immunosuppressive agents. Critically, acute respiratory distress syndrome, COPD, influenza, pneumonia, burns, severe bacterial infection, surgery, diabetes and malnutrition were included; (b) Clinical manifestations, including fever, cough, sputum, hemoptysis, dyspnea or other symptoms of lower respiratory tract infection that were not relieved with broad-spectrum antibacterial treatment; (c) radiological data such as nodule(s)\u0026thinsp;\u0026gt;\u0026thinsp;1 cm, which may be surrounded by a halo of ground-glass attenuation, pleural based wedge-shaped areas of consolidation, alveolar consolidations, masses, internal low attenuation, reverse halo sign, cavity or air-crescent sign and ground-glass opacities and pleural effusion; (d) mycological evidence, such as a positive aspergillus culture from qualified specimens (sputum and BALF) or a positive serum galactomannan (GM) result; and (e) histological evidence of aspergillus hyphae in lung biopsy specimens or a positive aspergillus culture from lung biopsy specimens. A proven diagnosis was made with histological evidence, and a probable diagnosis was made on the basis of host risk factors, clinical and radiological manifestations and microbiological evidence.\u003c/p\u003e \u003cp\u003eFinally, we extracted 58 patients who had IPA with ILD and then collected data from these patients\u0026rsquo; medical records that included characteristics, laboratory data, pulmonary function results, and chest HRCT findings at the time of the IPA diagnosis. Each subject\u0026rsquo;s radiological findings were reviewed by 2 independent radiologists. HRCT patterns were classified as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP). Honeycombing pattern was defined as clustered cystic air spaces with well-defined walls and typically comparable diameters of 3 to 10 mm in subpleural and lower lobes. Survival was defined as the time from the date of either the IPA diagnosis or ILD diagnosis to the date of death or date of censoring.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were compared using the chi-square test and continuous variables were compared using Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test or the Mann-Whitney test based on the distribution of the data. Fisher\u0026rsquo;s exact test was used to compare qualitative variables. Survival curves were generated using the Kaplan-Meier method. Differences in survival were compared using the log-rank test. The Cox proportional hazards model was used to assess the associations between clinical variables and survival. Variables with a \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in univariate analysis were included into the multivariate model. Finally, only variables with \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were retained in the multivariate model. Statistical analysis was performed using SPSS Statistics 23.0 (SPSS Inc., Chicago, IL, USA), and statistical significance was defined as a two-tailed \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eThe patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among the patients with ILD, we identified a total of 58 patients suffered from IPA, with a median age of 68.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6 years. 35 patients (60.3%) were male. History of smoking was present in 17 cases (29.3%). There were no significant differences in sex, underlying disease and its smoke status between the two groups. The subtypes of ILD were as follows: 21 patients had idiopathic pulmonary fibrosis (IPF), 13 patients had interstitial pneumonia with autoimmune features, 11 patients had rheumatoid arthritis (RA) associated interstitial lung disease, 4 patients had Sj\u0026ouml;gren\u0026prime;s syndrome, 5 patients with antineutrophil cytoplasmic antibody (ANCA)\u0026ndash;associated vasculitis, 3 patients with idiopathic inflammatory myopathy and 1 patient with systemic sclerosis. Of the 58 patients, 32 patients (55.2%) received corticosteroid over the last 3 weeks, 16 patients (27.6%) received immunosuppressive agents (i.e., cyclosporin, tacrolimus, methotrexate, and abatacept), and 27 patients (46.6%) received antifibrotic agents (i.e., pirfenidone or nintedanib).\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\u003eCharacteristics of ILD patients in the IPA and non-IPA groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIPA group\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-IPA group\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;295)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex; \u003cem\u003en\u003c/em\u003e (%) male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (60.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e152 (51.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.219\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge; mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.4 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.7 (11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent/ex-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (29.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.207\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical symptoms; \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e292 (99.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspnea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (93.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e289 (98.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (55.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87 (29.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eHemoptysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.043\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChest pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.350\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eForms of interstitial pneumonia; \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIPF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (36.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97 (32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.624\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTD-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIPAF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (22.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (22.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRA-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (5.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003epSS-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (19.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANCA-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIIM-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSc-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.605\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplication in disease; \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (32.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 (27.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.617\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (37.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (28.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (11.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.906\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase classification; \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProven IPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProbable IPA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (96.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoid exposure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (55.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e110 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-dose corticosteroid use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (20.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.220\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-dose corticosteroid use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (16.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunosuppressive agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85 (28.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.850\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntifibrotic agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (46.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e101 (32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epirfenidone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.977\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enintedanib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (36.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (22.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHigh-dose corticosteroid use: a therapeutic dose of \u0026ge;\u0026thinsp;0.3 mg/kg corticosteroids for \u0026ge;\u0026thinsp;3 weeks in the past 60 days\u003c/p\u003e \u003cp\u003eLow-dose corticosteroid use: a therapeutic dose of \u0026lt;\u0026thinsp;0.3 mg/kg corticosteroids for \u0026ge;\u0026thinsp;3 weeks in the past 60 days\u003c/p\u003e \u003cp\u003eThe clinical features of IPA in ILD were cough (100.0% vs. 99.0%, p\u0026thinsp;=\u0026thinsp;1.000), dyspnea (93.1% vs. 98.0%, p\u0026thinsp;=\u0026thinsp;0.064), fever (55.2% vs. 29.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and hemoptysis (9.3% vs. 2.9%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043). In terms of clinical symptoms, the IPA group displayed significantly greater proportions of fever (55.2% vs. 29.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). No significant differences were observed in cough, dyspnea or hemoptysis between the two groups. White blood cell count (median 11.1 x 10\u003csup\u003e9\u003c/sup\u003e vs. 8.3 x10\u003csup\u003e9\u003c/sup\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), neutrophil count (median 9.6 x 10\u003csup\u003e9\u003c/sup\u003e vs. 6.2 x10\u003csup\u003e9\u003c/sup\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and NLR (median 16.3 vs. 6.4, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were significantly greater in the IPA group, while lymphocyte count (median 1.0 x 10\u003csup\u003e9\u003c/sup\u003e vs. 1.5 x 10\u003csup\u003e9\u003c/sup\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and eosinophils count (median 0.06 x 10\u003csup\u003e9\u003c/sup\u003e vs. 0.12 x 10\u003csup\u003e9\u003c/sup\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) were significantly lower. Blood gas analysis indicated significantly greater oxygenation index in the IPA group (median 238.6 vs. 307.4 mmol/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005). Significant differences were observed between the IPA and non-IPA groups for CRP (median 84.8 mg/L vs. 28.1 mg/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), PCT (median 1.06 ng/mL vs. 0.14 ng/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), LDH (median 379.2 U/L vs. 290.4 U/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), ESR (median 45.7 mm/h vs. 37.1 mm/h, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.038) and IL-6 (median 76.2 g/L vs. 24.8 g/L, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Compared with ILD patients without IPA, CD4+/CD8\u0026thinsp;+\u0026thinsp;double positive cells were less abundant in ILD patients with IPA.\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\u003eThe microbiological, laboratory, and CT thorax findings of ILD patients in the IPA and non-IPA groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIPA group (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-IPA group (n\u0026thinsp;=\u0026thinsp;295)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLABORATORY FINDINGS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC count (\u0026times;10\u003csup\u003e9\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eLymphocyte\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eNLR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.3\u0026thinsp;\u0026plusmn;\u0026thinsp;17.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eEos\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e116.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.2\u0026thinsp;\u0026plusmn;\u0026thinsp;18.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eLDH (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e379.2\u0026thinsp;\u0026plusmn;\u0026thinsp;188.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e290.4\u0026thinsp;\u0026plusmn;\u0026thinsp;116.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eCRP (mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.8\u0026thinsp;\u0026plusmn;\u0026thinsp;87.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.1\u0026thinsp;\u0026plusmn;\u0026thinsp;38.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eESR (mm/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.7\u0026thinsp;\u0026plusmn;\u0026thinsp;24.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.1\u0026thinsp;\u0026plusmn;\u0026thinsp;25.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.038\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCT (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;4.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.2\u0026thinsp;\u0026plusmn;\u0026thinsp;169.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.8\u0026thinsp;\u0026plusmn;\u0026thinsp;58.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eCD4+(\u0026times;10\u003csup\u003e9\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e312.7\u0026thinsp;\u0026plusmn;\u0026thinsp;257.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e552.9\u0026thinsp;\u0026plusmn;\u0026thinsp;386.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eCD4+ (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.4\u0026thinsp;\u0026plusmn;\u0026thinsp;12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.6\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD8+(\u0026times;10\u003csup\u003e9\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e365.3\u0026thinsp;\u0026plusmn;\u0026thinsp;334.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e433.7\u0026thinsp;\u0026plusmn;\u0026thinsp;290.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD8+ (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.0\u0026thinsp;\u0026plusmn;\u0026thinsp;16.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4+/CD8+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\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\u003eT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.0\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygenation index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e238.6\u0026thinsp;\u0026plusmn;\u0026thinsp;111.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e307.4\u0026thinsp;\u0026plusmn;\u0026thinsp;110.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHRCT patterns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (62.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137 (46.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSIP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e110 (37.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.159\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (6.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNSIP\u0026thinsp;+\u0026thinsp;OP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCT thorax findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoneycombing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (69.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e144 (48.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsolidation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89 (30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGGO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (77.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e190 (64.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTraction bronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (84.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e224 (75.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleural effusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (24.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (13.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAir crescent sign\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.164\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eROC curves were generated to evaluate the diagnostic performance of each biomarker for IPA in ILD patients. The area under the curve (AUC), cutoff values, sensitivity and specificity for each biomarker are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The AUC values for CRP, IL-6, PCT, ESR, and NLR were 0.731, 0.624, 0.707, 0.608, and 0.738, respectively. The corresponding cutoff values were 45.4, 11.1, 0.06, 31.5, and 7.33 g/L, respectively. The sensitivity and specificity were as follows: CRP (56.9%, 80.0%), IL-6 (61.5%, 64.8%), PCT (70.0%, 66.7%), ESR (65.9%, 48.9%), and NLR (65.5%, 72.9%).\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\u003eArea under the curve (AUC), cutoff value, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the diagnosis of ILD combined with IPA by each biomarker.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\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\u003eAUC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCutoff\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSensitivity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSpecificity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.731\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e80.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.624\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e61.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e64.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCT (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e70.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e66.7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR (mm/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e65.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e48.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNLR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e65.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e72.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eChest CT findings\u003c/h2\u003e \u003cp\u003eThe CT findings are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The HRCT patterns at the time of ILD diagnosis were UIP in 36 patients (62.1%), NSIP in 16 patients (27.6%), OP in 3 patients (5.2%), and NSIP-OP in 3 patients (5.2%). The most frequent abnormal finding was traction bronchiectasis (n\u0026thinsp;=\u0026thinsp;49, 84.5%), GGO (n\u0026thinsp;=\u0026thinsp;45, 77.6%), honeycombing (n\u0026thinsp;=\u0026thinsp;40, 69.0%), consolidation (n\u0026thinsp;=\u0026thinsp;26, 44.8%) and pleural effusion (n\u0026thinsp;=\u0026thinsp;14, 24.1%). Radiographic findings revealed significantly more honeycombing (69.0% vs. 48.8%, p\u0026thinsp;=\u0026thinsp;0.005) in the IPA group. Notably, typical IPA signs were rare in the IPA group, with only 1.7% each for the halo sign and air crescent sign.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMicrobiological analysis\u003c/h2\u003e \u003cp\u003eDuring the study period, respiratory cultures were collected from 257 patients with ILD and Aspergillus was detected in 30 patients (30/56, 53.6%). The most common species were \u003cem\u003eA. fumigatus\u003c/em\u003e with 23 strains, \u003cem\u003eA. flavus\u003c/em\u003e with 12 strains, \u003cem\u003eA. niger\u003c/em\u003e with 3 strains and \u003cem\u003eA. terreus\u003c/em\u003e with 2 strains were isolated. Moreover, GM was positive in 19 patients (33.9%). BAL fluid analyses were performed in 96 episodes (29 in the IPA group and 69 in the non-IPA group). In the 29 episodes in the IPA group, there were 20 (66.7%) cases of positive BAL fluid GMI and only 11 (36.7%) episode of positive BAL fluid culture for Aspergillus spp.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpecies and Treatments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIPA group (n\u0026thinsp;=\u0026thinsp;58)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive cultures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSputum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30/56 (53.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBronchoalveolar lavage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11/30 (36.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive NGS in BALF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18/24 (75.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive NGS in sputum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1/1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive Aspergillus antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4/8 (50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive GM in serum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19/56 (33.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive GM in BALF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20/30 (66.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive PCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/2 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpecies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. fumigatus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (39.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. flavus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12 (20.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. niger\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (5.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. terreus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. fumigatus\u003c/em\u003e\u0026thinsp;+\u0026thinsp;\u003cem\u003eA. terreus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. fumigatus\u003c/em\u003e\u0026thinsp;+\u0026thinsp;\u003cem\u003eA. flavus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (6.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. flavus\u003c/em\u003e\u0026thinsp;+\u0026thinsp;\u003cem\u003eA. niger\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eA. fumigatus\u003c/em\u003e\u0026thinsp;+\u0026thinsp;\u003cem\u003eA. niger\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11 (17.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVoriconazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50 (86.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsavuconazole\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (12.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmphotericin B\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTreatments and outcomes\u003c/h2\u003e \u003cp\u003eThe treatments and outcomes are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Of the 58 patients with IPA associated with ILD, all patients received antifungal treatment regardless of the duration of treatment. The basic treatment was voriconazole as monotherapy or in combination with other antifungals in 86.2% of patients. Isavuconazole was used in 12.1% of patients; amphotericin B (1.7%) was rarely used. Kaplan-Meier survival curves and log-rank test showed a significant difference in overall survival rate after 90 days between the IPA patients (70.2%) and non-IPA patients (84.0%) from the viewpoints of the follow-up period from the ILD diagnosis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate analysis\u003c/h2\u003e \u003cp\u003eTo further analyze the independent risk factors affecting the occurrence of IPA, a positive diagnosis was set as the dependent variable. Based on the ILD-IPA susceptibility factor analysis and univariate analysis results, we included CRP and NLR in the logistic regression model. The multivariate analysis summarized in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e indicates that lymphopenia (OR\u0026thinsp;=\u0026thinsp;2.745, 95% CI 1.344\u0026ndash;5.607) and honeycombing (OR\u0026thinsp;=\u0026thinsp;2.915, 95% CI 1.429\u0026ndash;5.949) were independent risk factors for ILD-IPA. (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLogistic regression analysis of risk factors for the occurrence of ILD-IPA\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInfluencing factor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eWald value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e-0.052\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.378\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.949\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.453\u0026ndash;1.990\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroid before admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e-0.592\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.360\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.695\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.273\u0026ndash;1.122\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.676\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.344\u0026ndash;5.607\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e0.514\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.671\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.822\u0026ndash;3.398\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoneycombing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1.070\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.364\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.645\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.429\u0026ndash;5.949\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIPA is a common opportunistic infection. Aspergillus infection is usually seen in those with underlying respiratory disease. However, the report of its association with ILD is rare. Therefore, we focused on the correlations between IPA and ILD in the present study and then investigated both the patient characteristics and the prognosis or mortality risk of IPA in patients with ILD. In this retrospective study, we included 58 patients with proven (3.4%) and probable (96.6%) IPA.\u003c/p\u003e \u003cp\u003eNeutrophils play a key role of the first line defense against aspergillus infection. To eliminate aspergillus germinating spores, neutrophils produce extracellular traps, release antimicrobial proteases by degranulation, and activate the toll-like receptor pathway [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Our study presents the results of neutrophil-to-lymphocyte ratio (NLR) comparison between surviving and deceased ILD patients suffering from IPA infections. The increased risk for opportunistic infection in ILD is predominantly related to lymphocyte deficiency [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Immunosuppressive regimens have a lymphocyte reducing effect with a secondary increase in the NLR, a marker of poor prognosis for the patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The study indicates that a simple parameter such as NLR may predict mortality risk for mold infection following ILD. The combination of leukocyte reducing effects with secondarily increased neutrophils in peripheral blood presented as NLR in immunocompromised patients has already been postulated. Patients with high NLR on antifungal therapy had a poorer prognosis of IPA survival. On immunosuppressive therapy, the lymphocytes are depressed, which is evidenced by high NLR values, leading to suppression of the natural defense system, including inflammatory response. Notably, commonly available serum biomarkers NLR has several advantages, including ease of detection, affordability, and noninvasiveness [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur experience also suggests that radiologic signs of IPA are non-specific. In the previous study, UIP pattern with honeycombing (40.6%) and smoking-related ILD (28.1%) accounted for the majority of cases of Aspergillus infection [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Wide-spread cystic lesions and emphysema as destructive changes in lung tissue can be colonized by Aspergillus [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The extensive honeycomb-like changes in the lungs caused structural damage to the lungs. Thus this UIP patient lacked the essential resistance to aspergillus, and aspergillus was much likely to colonize the lungs. According to the published reports, UIP that is diagnosed upon radiologic examination accounts for 80.4% of all patients with ILD plus IPA [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Moreover, a Japanese study has shown that UIP patients are inclined to have aspergillosis, indicating, from another perspective, the potential role of structural lesions of the lungs in the development or pathogenesis of aspergillosis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUnfortunately, the clinical presentation and imaging features of such patients lack specificity, posing a great challenge for the early diagnosis of ILD-IPA. In studies carried out on patients with hematologic malignancy from our country, GM antigen test sensitivity was found as 56\u0026ndash;61% and its specificity as 21\u0026ndash;84% [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In addition, it has been indicated that GM positivity in COPD patients with IPA development in intensive care and the isolation of Aspergillus species in respiratory samples may be significant in terms of mortality [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. As for our study, the GM value was found to be positive in 14 (25.9%) cases, and 11 of them (20.7%) died. This gives further support to the belief that GM positivity in ILD cases with the development of IPA is a significant parameter to be considered in terms of mortality.\u003c/p\u003e \u003cp\u003eGlucocorticoids and immunosuppressants are the main medications for ILD, though they may increase the risk of aspergillosis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Prolonged immunosuppressive therapy is a risk factor for IPA. Corticosteroid have often been used in non-IPF patients, and in fact, it was used in 51.9% of the patients in the present study. Patients treated with steroid therapy require special attention regarding the potential for Aspergillus infection. In recent years, it has been shown that corticosteroid use plays a significant role in terms of increasing the rate of IPA incidence in ILD cases.\u003c/p\u003e \u003cp\u003eIt was determined that IPA leads to increased mortality of ILD patients. Early antifungal therapy is mandatory for the successful treatment of IPA [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. All our patients received antifungal therapy. Voriconazole was mainly used for IPA treatment in 89.6% patients.\u003c/p\u003e \u003cp\u003eThere are some limitations to the present study. First, it is a single-center retrospective study, which can introduce referral bias and limit the ability to generalize our findings. Moreover, the rate of positivity of mycological proof was low, although the diagnosis of IPA was made according to commonly used criteria. Randomized controlled trials are needed to evaluate the efficacy and safety of primary antifungal prophylaxis in these patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIPA with atypical manifestations can occur in patients with ILD. Constantly considering the potential presence of IPA can aid in the prompt diagnosis of such atypical IPA. As the complication of IPA may lead to a poor prognosis for any ILD, clinicians should be aware of the importance of a prompt. The presents study shows that NLR, IL-6 and chest imaging can be useful for the early differential diagnosis of IPA.NLR and IL-6, as a simple parameter of very basic blood analysis, may be of predictive value in the estimation of mortality risk or response to treatment among patients with IPA following ILD.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e The study protocol was approved by the Ethics Committee of Nanjing Drum Tower Hospital, with the ethics application number 2021\u0026ndash;390-01. Due to the retrospective nature of the study using anonymous claims data, the requirement for informed consent was waived.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot Applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eAuthor details\u003c/h2\u003e \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.\u003c/p\u003e \u003cp\u003e \u003csup\u003e2\u003c/sup\u003eDepartment of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.\u003c/p\u003e \u003cp\u003e \u003csup\u003e3\u003c/sup\u003eDepartment of Medical Imaging, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was funded by National Natural Science Foundation of China (82270019), Fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2023-LCYJ-MS-18). The funder played no role in the study design, data collection, analysis and interpretation of data, or the writing of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLY, and SX conceived and designed the analysis. LY, JHY, ZTT, and CM collected the data. NYL, LY, YX, and ZTT contributed to the analysis. XYL, QRF, ZTT, and HJ performed the analysis. LY and SX wrote the paper. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eThe datasets used and/or analysed during this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEl-Baba F, Gao Y, Soubani AO. Pulmonary Aspergillosis: What the Generalist Needs to Know. 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Invasive Aspergillosis Due to Aspergillus Section Usti: A Multicenter Retrospective Study. Clin Infect Dis. 2021;72(8):1379\u0026ndash;85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/cid/ciaa230\u003c/span\u003e\u003cspan address=\"10.1093/cid/ciaa230\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\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":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"interstitial lung disease, invasive pulmonary aspergillosis, risk factor, honeycombing","lastPublishedDoi":"10.21203/rs.3.rs-5069345/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5069345/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe prevalence of invasive pulmonary aspergillosis (IPA) among patients with interstitial lung disease (ILD) is steadily increasing, leading to high mortality. The purpose of this study is to analyze the clinical features and risk factors of IPA in patients with ILD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e353 hospitalized ILD patients admitted in Nanjing Drum Tower Hospital from March 2023 and April 2024 were enrolled. The enrolled patients were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 353 patients with ILD, 58 who suffered from IPA were identified. Among them, 2 (3.4%) episodes of proven IPA and 56 (96.6%) of probable IPA were diagnosed. The median age was 68.4\u0026thinsp;\u0026plusmn;\u0026thinsp;8.6 years, and 35 patients were men. The forms of ILD included idiopathic pulmonary fibrosis (n\u0026thinsp;=\u0026thinsp;21), interstitial pneumonia with autoimmune features (n\u0026thinsp;=\u0026thinsp;13), rheumatoid arthritis related interstitial pneumonia (n\u0026thinsp;=\u0026thinsp;11) and Sj\u0026ouml;gren\u0026prime;s syndrome (n\u0026thinsp;=\u0026thinsp;4). The clinical features of IPA in ILD were cough (100.0%), dyspnea (93.1%) and fever (55.2%). Chest CT images showed traction bronchiectasis (84.5%), GGO (77.6%), honeycombing (69.0%), consolidation (44.8%) and pleural effusion (24.1%). The incidence of honeycombing and consolidation were higher in ILD patients with IPA compared to control group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The main pathogens were A. fumigatus (50.0%) and A. flavus (29.3%). Following the diagnosis of IPA, all patients were treated with antifungal drugs. The overall survival rate after 90 days was 74.1%. Multivariate conditional Logistic regression analysis showed that lymphopenia (OR\u0026thinsp;=\u0026thinsp;2.745, 95% CI 1.344\u0026ndash;5.607) and honeycombing (OR\u0026thinsp;=\u0026thinsp;2.915, 95% CI 1.429\u0026ndash;5.949) were the risk factors of ILD with IPA (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIPA is one of the major complications of ILD and its prognosis is poor. Lymphopenia and honeycombing increased the risk of IPA in ILD patients.\u003c/p\u003e","manuscriptTitle":"Clinical features and risk factors of invasive pulmonary aspergillosis in interstitial lung disease patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-19 13:02:37","doi":"10.21203/rs.3.rs-5069345/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-20T09:39:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-19T10:48:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-19T10:43:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2024-09-11T08:12:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"72cc72a8-53fd-402e-ab23-91608aecbb1a","owner":[],"postedDate":"November 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-09T15:58:55+00:00","versionOfRecord":{"articleIdentity":"rs-5069345","link":"https://doi.org/10.1186/s12890-024-03430-x","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2024-12-04 15:56:54","publishedOnDateReadable":"December 4th, 2024"},"versionCreatedAt":"2024-11-19 13:02:37","video":"","vorDoi":"10.1186/s12890-024-03430-x","vorDoiUrl":"https://doi.org/10.1186/s12890-024-03430-x","workflowStages":[]},"version":"v1","identity":"rs-5069345","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5069345","identity":"rs-5069345","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}