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OBJECTIVE: Interstitial lung disease (ILD) is a severe complication of connective tissue disease (CTD) that can significantly impact patients' prognosis and quality of life. However, the current diagnostic arena lacks reliable biomarkers for detecting and monitoring the progression and exacerbation of CTD-ILD. This study aimed to investigate the clinical value of 12 serum cytokines in the diagnosis of CTD-ILD and prediction of the risk of acute exacerbation (AE) in this disease. METHODS: This study was a cross-sectional investigation. Ninety-one hospitalized CTD patients were allocated into two groups: CTD-ILD group (n = 61) and CTD-non-ILD group (n = 30), and 30 sex-age matched healthy volunteers were enrolled as controls. The serum concentrations of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, and IL-1ß were measured by Luminex suspension arrays. Logistic regression was employed to determine the significance of variables in the occurrence of AE-CTD-ILD. A nomogram was constructed to visualize the independent variables. RESULTS: Elevated levels of IL-6, IL-8, and TNF-α were observed and compared in the CTD-ILD group with CTD-non-ILD (all P < 0.05). Similarly, the levels of IL-6, IL-8 and TNF-α were higher in the acute exacerbation (AE-CTD-ILD) group compared with stable CTD-ILD (S-CTD-ILD) (P < 0.001, P < 0.001, and P = 0.022). Significant correlations between serum IL-6 and PaO2/FiO2 ratio (r = - 0.463, P < 0.001), percent predicted forced vital capacity (FVC%; r = - 0.362, P < 0.05), and total ground-glass opacity (GGO) score (r = 0.439, P < 0.001) were observed in CTD-ILD patients. Multivariate logistic regression analysis revealed that elevated IL-6 levels, total bilirubin (TBil), and decreased CD3 + CD4 + T cells counts were independent risk factors for the occurrence of AE-CTD-ILD (OR = 1.121, P = 0.024; OR = 1.865, P = 0.047; OR = 0.983, P = 0.037, respectively). Furthermore, by employing these three variables in combination for the prediction of AE status, their collective impact surpasses the independent effects of any single biomarker. CONCLUSIONS: Elevated levels of serum IL-6, IL-8, and TNF-α were associated with the complication of ILD in CTD patients and the occurrence of AE in CTD-ILD patients. IL-6 could be a promising serum biomarker of severity and the occurrence of AE in CTD-ILD patients. The combination of the three variables (IL-6 level, TBil and CD3 + CD4 + T cells) predicted the AE-CTD-ILD better.

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Background: The high-resolution computed tomography (HRCT) score is an important component of the severity and prognosis score of pulmonary alveolar proteinosis (SPSP). However, the HRCT score in SPSP only considers the extent of opacity, which is insufficient. Methods: We retrospectively evaluated HRCT scores for 231 patients with autoimmune pulmonary alveolar proteinosis (APAP) from three centers of the China Alliance for Rare Diseases. The SPSPII was created based on the overall density and extent, incorporating the SPSP. The severity of APAP patients was assessed using disease severity scores (DSS), SPSP, and SPSPII to determine the strengths and weaknesses of the different assessment methods. We then prospectively applied the SPSPII to patients before treatment, and the curative effect was assessed after 3 months. Results: The HRCT overall density and extent scores in our retrospective analysis were higher than the extent scores in all patients and every original extent score severity group, as well as higher related to arterial partial oxygen pressure (PaO2) than extent scores. The mild patients accounted for 61.9% based on DSS 1-2, 20.3% based on SPSP 1-3, and 20.8% based on SPSPII 1-3. Based on SPSP or SPSPII, the number of severe patients deteriorating was higher in the mild and moderate groups. When applied prospectively, arterial PaO2 differed between any two SPSPII severity groups. The alveolar-arterial gradient in PaO2 (P[A-a]O2), % predicted carbon monoxide diffusing capacity of the lung (DLCO), and HRCT score were higher in the severe group than in the mild and moderate groups. After diagnosis, mild patients received symptomatic treatment, moderate patients received pure whole lung lavage (WLL) or granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy, and severe patients received WLL and GM-CSF therapy. Importantly, the SPSPII in mild and severe groups were lower than baseline after 3 months. Conclusion: The HRCT density and extent scores of patients with APAP were better than the extent score. The SPSPII score system based on smoking status, symptoms, PaO2, predicted DLCO, and overall HRCT score was better than DSS and SPSP for assessing the severity and efficacy and predicting the prognosis. Trial registration: ClinicalTrial.gov, identifier: NCT04516577.

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Background: High-resolution computed tomography (HRCT) plays an important role in accessing the severity of pulmonary alveolar proteinosis (PAP). Visual evaluation of changes between two HRCT scans is subjective. This study was conducted to quantitatively evaluate lung burden changes in patients with PAP using HRCT-based automated deep-learning method following 12 months of statin therapy. Methods: In this prospective real-world observational study, patients with PAP who underwent chest HRCT were evaluated from November 28, 2018, to April 12, 2021. Oral statin administration was initiated as therapy for these PAP patients with 12 months of follow-up. HRCT-derived lung ground-glass opacification percentage of the whole lung and 5 lobes and the percentage of different densities of ground glass were automatically quantified with deep-learning software. Longitudinal changes of the HRCT quantitative parameter were also compared. Results: The study enrolled 50 patients with PAP, including 25 mild-moderate PAP cases and 25 severe PAP cases. The percentage of lung ground-glass opacification of the whole lung and 5 lobes and the percentage of different densities of ground glass were significantly different among the 2 different clinical types at baseline (all P values <0.05). Overall, the percentage of whole-lung ground-glass opacification significantly decreased between the baseline HRCT and the HRCT results after 12 months of follow-up (P=0.023; 95% CI: 1.384-18.684). Changes in the total opacification of the whole lung were positively correlated with changes in partial pressure of arterial oxygen (PaO2; r=0.716; P<0.001) and percentage of predicted diffusion capacity for carbon monoxide (DLCO%pred; r=0.664; P<0.001). Conclusions: A quantitative image parameter automatically generated by a deep-learning tool from chest HRCT scans may be used to evaluate the severity of PAP and may help to evaluate and quantify the response to statin therapy.

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Background: Pulmonary alveolar proteinosis (PAP) is a rare disorder which is characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy has been reported to be a novel therapy for PAP with hypercholesterolemia. We aimed to evaluate the safety and efficacy of oral statin therapy for PAP without hypercholesterolemia. Methods: In a prospective real-world observational study, 47 PAP patients without hypercholesterolemia were screened. Oral statin was initiated as therapy for these PAP patients with 12 months of follow-up. Results: Forty PAP patients completed the study. 26 (65%) of 40 PAP patients responded to statin therapy according to the study criteria. Partial pressure of arterial oxygen (PaO2) and percentage of diffusion capacity predicted (DLCO%) significantly increased while disease severity score (DSS) and radiographic abnormalities decreased after 12 months of statin therapy (all p < 0.05). The factors associated with response were higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody and baseline total cholesterol/high-density lipoprotein cholesterol (TC/HDL) (p = 0.015 and p = 0.035, respectively). The area under the receiver operating characteristic curve (AUROC) of dose of atorvastatin for predicting the response to statin therapy for PAP was 0.859 (95% CI: 0.738-0.979, p < 0.001). The cutoff dose of atorvastatin was 67.5 mg daily with their corresponding specificity (64.3%) and sensitivity (96.2%). No severe side effects were observed during the study. Conclusions: In PAP patients without hypercholesterolemia, statin therapy resulted in improvements in arterial blood gas (ABG) measurement, pulmonary function, and radiographic assessment.

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Background: Anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (anti-MDA5 DM-ILD) is a disease with high mortality. We sought to develop an effective and convenient prediction tool to estimate mortality risk in patients with anti-MDA5 DM-ILD and inform clinical decision-making early. Methods: This prognostic study included Asian patients with anti-MDA5 DM-ILD hospitalized at the Nanjing Drum Hospital from December 2016 to December 2020. Candidate laboratory indicators were retrospectively collected. Patients hospitalized from 2016 to 2018 were used as the discovery cohort and applied to identify the optimal predictive features using a least absolute shrinkage and selection operator (LASSO) logistic regression model. A risk score was determined based on these features and used to construct the mortality risk prediction model in combination with clinical characteristics. Results were verified in a temporal validation comprising patients treated between 2019 and 2020. The primary outcome was mortality risk within one year. The secondary outcome was overall survival. The prediction model's performance was assessed in terms of discrimination, calibration, and clinical usefulness. Results: This study included 127 patients, (72 men [56.7%]; median age, 54 years [interquartile range, 48-63 years], split into discovery (n = 87, 70%) and temporal validation (n=37, 30%) cohorts. Five optimal features were selected by LASSO logistic regression in the discovery cohort (n = 87) and used to construct a risk score, including lymphocyte counts, CD3+CD4+ T-cell counts, cytokeratin 19 fragment (CYFRA21-1), oxygenation index, and anti-Ro52 antibody. The retained predictive variables in the final prediction model were age, Heliotrope, fever, and risk score, and the most predictive factor was the risk score. The prediction model showed good discrimination (AUC: 0.915, 95% CI: 0.846-0.957), good calibration (Hosmer-Lemeshow test, P = 0.506; Brier score, 0.12), and fair clinical usefulness in the discovery cohort. The results were verified among patients in the temporal validation cohort (n = 38). We successfully divided patients into three risk groups with very different mortality rates according to the predictive score in both the discovery and validation cohorts (Cochran-Armitage test for trend, P < 0.001). Conclusions: We developed and validated a mortality risk prediction tool with good discrimination and calibration for Asian patients with anti-MDA5 DM-ILD. This tool can offer individualized mortality risk estimation and inform clinical decision-making.

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Fibrosing interstitial lung disease (ILD) can cause high mortality and sensitive evaluation of fibrosing ILD could be critical. The aim of this study is to develop a scoring system to predict prognosis of fibrosing ILD. 339 patients with fibrosing ILD were enrolled as a derivation cohort. Cox multiple regression analysis indicated that smoking history (HR = 3.826, p = 0.001), age(HR = 1.043, p = 0.015), CEA(HR = 1.059, p = 0.049),CYFRA21-1(HR = 1.177, p = 0.004) and DLCO% predicted (HR = 0.979, p = 0.032) were independent prognostic factors for fibrosing ILD. The clinical scoring system for fibrosing ILD was established based on the clinical variables (age [A], CEA and CYFRA21-1 [C], DLCO% predicted [D], and smoking history [S]; ACDS). The area under the receiver operating characteristic curve (AUROC) of the scoring system for predicting prognosis of fibrosing ILD was 0.90 (95%CI: 0.87-0.94, p < 0.001). The cutoff value was 2.5 with their corresponding specificity (90.7%) and sensitivity (78.8%). To validate the value of ACDS score levels to predict the survival of patients with fibrosing ILD, 98 additional fibrosing ILD patients were included as a validation cohort. The log-rank test showed a significant difference in survival between the two groups(ACDS score < 2.5 and ACDS score ≥ 2.5) in validation cohort. The independent risk factors for mortality in patients with fibrosing ILD are higher CEA, higher CYFRA21-1, smoking history, lower DLCO%predicted at baseline and older age. ACDS is a simple and feasible clinical model for predicting survival of fibrosing ILD.

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BACKGROUND: Overexpression of human epididymis protein 4 (HE4) was previously described in idiopathic pulmonary fibrosis (IPF), but whether serum HE4 can be considered as a potential biomarker in connective tissue disease-associated interstitial lung disease (CTD-ILD) with usual interstitial pneumonia (UIP) pattern was still unknown. METHOD: A total of 55 CTD-ILD patients with UIP pattern (UIP-CTD) and 52 healthy controls were enrolled in this study. The serum levels of HE4 and Krebs von den Lungen-6 (KL-6) were evaluated in both cohorts. In addition, immunohistochemistry analysis for HE4 was performed on the lung sections of 6 patients with rheumatoid arthritis-associated UIP (UIP-RA) and 6 patients with early-stage lung cancer as normal control. RESULTS: The levels of serum HE4 and KL-6 were higher in patients with UIP-CTD than in healthy controls (292.3 pmol/L versus 79.5 pmol/L for HE4, p < 0.001; 1091.0 IU/mL versus 171.5 IU/mL for KL-6, p < 0.001). Significant correlations between serum HE4 levels and percentpredicted forced vital capacity (FVC%) (r = -0.425, p = 0.004), percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r = -0.447, p = 0.003), and Gender-Age-Physiology (GAP) index (r = 0.494, p < 0.001) were observed in UIP-CTD patients. In immunohistochemistry analysis, elevated expression of HE4 in bronchiolar epithelium and mesenchyme was observed in patients with UIP-RA compared with controls. The serum levels of HE4 (≥277.5 pmol/L) and GAP index were related to an increased risk of mortality (HR = 3.884, p = 0.034; HR = 1.480, p = 0.028, respectively). CONCLUSION: The expression of HE4 in serum and lung specimens was significantly elevated in UIP-CTD patients. Moreover, serum HE4 may be utilized as a biomarker to evaluate the severity of disease and predict the prognosis of UIP-CTD patients.

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Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous disorder which is less typical in adults than pediatric patients. In this study, we reported a rare case of adult-onset FHL3 with progressive lymphocytosis and lymphocytic interstitial pneumonia (LIP). A 20-year old female was admitted to our institution for persistent cough with fever. A chest high-resolution computed tomography (HRCT) scan showed diffuse bilateral ground glass opacities (GGO). A lung biopsy revealed infiltration of lymphocyte in the pulmonary interstitium. The patient was treated with corticosteroids and immunosuppressants, followed by significant clinical improvement although lymphocytosis still persisted. The definitive diagnosis of FHL was based on whole genome sequencing by which heterozygous mutations in UNC13D gene were identified. Lymphocytosis may be a remarkable feature of some patients with FHL. Performing gene sequencing is important to improve the recognition of FHL to avoid misdiagnosis.

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OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic value of red blood cell distribution width (RDW) in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). METHODS: We retrospectively reviewed 213 CTD-ILD patients and 97 CTD patients without ILD from February 2017 to February 2020. Hospital and office records were used as data sources. CTD-ILD patients were followed up. RESULTS: Patients with CTD-ILD had significantly higher RDW than those with CTD without ILD (p < 0.001). The area under the receiver operating characteristic curve (AUROC) of RDW for discriminating CTD-ILD from CTD without ILD was 0.64 (95% CI: 0.57-0.70, p < 0.001). The cutoff value of RDW for discriminating CTD-ILD from CTD without ILD was 13.95% with their corresponding specificity (55.9%) and sensitivity (70.1%). Correlation analyses showed that the increased RDW was significantly correlated with decreased DLCO%predicted (r = -0.211, p = 0.002). Cox multiple regression analysis indicated that RDW (HR = 1.495, p < 0.001) was an independent factor in the survival of CTD-ILD. The best cutoff value of RDW to predict the survival of patients with CTD-ILD was 14.05% (AUC = 0.78, 95% CI: 0.72-0.84, p < 0.001). The log-rank test showed a significant difference in survival between the two groups (RDW > 14.05% and RDW < 14.05%). CONCLUSION: RDW was higher in CTD-ILD patients and had a negative correlation with DLCO%predicted. RDW may be an important serum biomarker for severity and prognosis of patients with CTD-ILD.

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Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the accumulation of excessive surfactant lipids and proteins in alveolar macrophages and alveoli. Oral statin therapy is a novel treatment for PAP with hypercholesterolemia. However, this treatment has never been described in a patient without hypercholesterolemia. Here, we present a case of successful treatment with atorvastatin for a patient with possibly unclassified PAP without hypercholesterolemia who responded poorly to whole lung lavage therapy and inhaled granulocyte-macrophage colony-stimulating factor. After 18 months of atorvastatin treatment, the patient experienced improvements in dyspnea, radiographic abnormalities and pulmonary function. The present case study supports the feasibility of statin therapy for PAP regardless of the level of cholesterol.

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OBJECTIVES: In the present study, we aimed to assess the clinical significance of cytokeratin 19 fragment (CYFRA21-1) in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-interstitial lung disease (MDA5-DM-ILD). METHODS: A total of 73 MDA5-DM-ILD patients were retrospectively analysed in this work. Their clinical characteristics, including clinical manifestations, laboratory findings, peripheral blood lymphocyte subsets and lung function, were compared between patients with acute/subacute interstitial pneumonia (A/SIP) and chronic interstitial pneumonia (CIP). The level of serum CYFRA21-1 was also compared between the above-mentioned two groups of patients, and its association with the clinical features and mortality of MDA5-DM-ILD was also evaluated. RESULTS: Of the 73 MDA5-DM-ILD patients, 26 patients exhibited the A/SIP pattern. The level of serum CYFRA21-1 was higher in MDA5-DM patients with A/SIP compared with the CIP group (P = 0.009). Lower oxygenation index (OI), CD3+CD4+ T cell counts and percentage of CD3+CD4+ cells were also observed in MDA5-DM patients with A/SIP compared with the CIP group. Higher serum CYFRA21-1, lower OI, and lower zone consolidation were associated with a higher risk of A/SIP in MDA5-DM-ILD. In addition, 38 decedents with MDA5-DM-ILD exhibited a greater level of CYFRA21-1 compared with 35 survivors (P < 0.001). Furthermore, it was a prognostic factor and also associated with a higher mortality rate (log-rank test, P < 0.001). CONCLUSIONS: CYFRA21-1 could be a useful serum indicator associated with occurrence of A/SIP in MDA5-DM-ILD. Moreover, it was associated with a poor survival in MDA5-DM-ILD patients.

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Bilirubin exerts antioxidant activity that has been associated with respiratory diseases. However, the relationship between serum bilirubin levels and idiopathic pulmonary fibrosis (IPF) is not clear. Therefore, in this study, we evaluated the relationship between serum bilirubin levels and the severity as well as the prognosis of IPF. One hundred and forty-six patients with IPF and 69 healthy individuals as the control group were enrolled as a derivation cohort. Routine blood examination and pulmonary function tests were performed and serum bilirubin levels were measured. To validate the value of serum bilirubin levels to predict the survival of patients with IPF, 40 additional IPF patients were included as a validation cohort. IPF patients were followed-up. Patients with IPF had significantly lower levels of serum total bilirubin (TBIL) and direct bilirubin (DBIL) than those in the control group (P < 0.05). Patients with acute exacerbation of IPF (AE-IPF) had significantly lower levels of serum TBIL and IBIL than those in patients with stable IPF (P < 0.05). The area under the receiver operating characteristic curve (AUROC) of serum TBIL levels for the prediction of the incidence of AE-IPF was 0.72 (95% CI: 0.56-0.87, P = 0.0057). The best cutoff value of serum TBIL level to predict the survival of patients with IPF was 8.8 µmol/l (AUC = 0.75, 95% CI: 0.64-0.87, P = 0.022). The log-rank test showed a significant difference in survival between the two groups (TBIL ≤8.8 µmol/l and TBIL >8.8 µmol/l) in derivation and validation cohort. Cox multiple regression analysis indicated that serum TBIL levels were an independent prognostic factor for IPF prognosis (HR = 0.582, P = 0.026). Serum TBIL levels might be useful for reflecting the severity and predicting the survival of patients with IPF.

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OBJECTIVE: Several serum markers were reported to reflect the severity of pulmonary alveolar proteinosis (PAP). The aim of this study is to investigate a reliable and facile marker to access and monitor the clinical course of PAP in a large cohort. METHODS: PAP patients from January 2010 to June 2018 were enrolled. Hospital records were used as data sources. The levels of various serum indicators were detected. We evaluated the correlation between pulmonary function test results and clinical variables. RESULTS: Diffusion capacity for carbon monoxide (DLCO) level was positively correlated with the level of high-density lipoprotein cholesterol (HDL-C) (P < 0.05) in 122 patients of PAP at baseline. The levels of HDL-C and DLCO significantly increased while carcinoembryonic antigen (CEA), CYFRA21-1, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH) levels decreased six months after granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy between 14 patients with PAP. Nevertheless, the increased DLCO was significantly correlated with decreased CEA (r = -0.579, P = 0.031) and CYFRA 21-1 (r = -0.632, P = 0.015). In 10 PAP patients without GM-CSF inhalation therapy, HDL-C and DLCO significantly decreased while NSE and LDH levels increased after six months of follow-up. The decreased DLCO was significantly correlated with increased LDH (r = -0.694, P = 0.026). CONCLUSIONS: Serum CEA, CYFRA21-1, and LDH are valuable serum markers for the evaluation of disease activity of PAP and may predict the response to treatment of PAP.

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The study aimed to evaluate the clinical and imaging features of critically ill patients with interstitial lung disease (ILD) treated in respiratory intensive care unit (RICU) and assess the prognostic effects of these factors. A total of 160 severe ILD patients admitted to the RICU were finally enrolled in this study. The clinical, imaging and follow-up data of them were studied retrospectively. The in-hospital mortality and total mortality were 43.1% and 63.8% respectively. By multivariate cox regression analysis, shock (OR = 2.39, P = 0.004), pulmonary fibrosis on CT (OR = 2.85, P = 0.002) and non-invasive ventilation (OR = 1.86, P = 0.037) were harmful factors to survivals of critically ill patients with ILD. In contrast, oxygenation index (OR = 0.99, P = 0.028), conventional oxygen therapy (OR = 0.59, P = 0.048) and ß-lactam antibiotics use (OR = 0.51, P = 0.004) were protective factors. There is significant difference of survivals between patients with and without fibrosing ILD on CT (Log-rank, p = 0.001). The prognosis of critically ill patients with ILD was poor. Shock, respiratory failure and fibrosing signs on chest CT affected the prognosis. Chest CT was considered as a valuable tool to indicate the prognosis.

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