Search

Objective: The aim of this study was to explore the potential values of Krebs von den Lungen-6 (KL-6), neutrophil to lymphocyte ratio (NLR), systemic immune inflammation (SII), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR) and red blood cell distribution width (RDW) in the diagnosis and evaluation of the severity of connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: A total of 140 connective tissue disease (CTD) patients and 85 CTD-ILD patients were recruited for this study at Shanxi Provincial People's Hospital from May 2022 to May 2023. Patients were divided into subgroups based on medication history and CTD subtypes to compare and analyze the clinical data and laboratory parameters of CTD-ILD patients and CTD patients. The receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of KL-6, NLR, SII, PLR, MLR, and RDW in identifying CTD-ILD patients from CTD patients. A Spearman correlation analysis was conducted to elucidate the correlations between these markers and the lung function parameters of forced vital capacity (FVC, %), forced expired volume in one second (FEV1, %), and diffusing capacity of carbon monoxide (DLCO, %). Finally, binary logistic regression analysis was applied to discern the independent risk factors for CTD-ILD. Results: NLR, SII, MLR, RDW, and KL-6 displayed significant statistical differences in the experimental groups. In both untreated and treated subgroups, KL-6 displayed higher values for CTD-ILD than CTD among all CTD subtypes. In untreated subgroups, there were significant differences in MLR levels between rheumatoid arthritis (RA) and RA-ILD patients and in NLR levels between Sjögren syndrome (SjS) and SjS-ILD patients. There were also significant differences in RDW-SD between the "other CTD" and "other CTD-ILD" groups. In treated subgroups, there were significant differences in both RDW-SD and RDW-CV between RA and RA-ILD patients and in NLR, SII, MLR, PLR, and RDW-SD between "other CTD" and "other CTD-ILD" groups. ROC revealed that KL-6 emerged as the most effective predictor for CTD-ILD in both treated and untreated groups. The multivariate logistic regression analysis results showed that both KL-6 and age were independent risk factors for CTD-ILD. NLR, SII, and PLR were negatively correlated with DLCO (%) in the untreated CTD-ILD group, and KL-6 was negatively correlated with various lung function parameters in both treated and untreated CTD-ILD groups. Conclusion: KL-6 emerged as the most promising biomarker for diagnosing CTD-ILD and assessing its severity. The diagnostic value of KL-6 was unaffected by medication interference and surpassed the value of other parameters, such as NLR, SII, MLR, and RDW. The diagnostic value of RDW-SD was higher than that of RDW-CV in CTD-ILD patients. NLR, SII, MLR, and PLR have potential value in diagnosing the different types of CTD-ILD. [ABSTRACT FROM AUTHOR]

Naotatsu Otsuji,1 Kumiya Sugiyama,1,2 Takayoshi Owada,1 Hajime Arifuku,1 Kenya Koyama,1 Hirokuni Hirata,1 Yasutsugu Fukushima1 1Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan; 2National Hospital Organization Utsunomiya Hospital, Utsunomiya, Tochigi, JapanCorrespondence: Kumiya Sugiyama, National Hospital Organization Utsunomiya Hospital, 2160, Shimo-Okamoto, Utsunomiya, Tochigi, 329-1193, Japan, Email sugiyama@dokkyomed.ac.jpPurpose: The prognosis of rheumatoid arthritis (RA) with interstitial lung disease (ILD) is particularly poor. Although drugs that do not contribute to the progression of ILD should be used in RA treatment, none have been established. This study evaluated the safety of tocilizumab in terms of ILD activity.Patients and Methods: This study prospectively enrolled all 55 patients with RA complicated by ILD who were treated with tocilizumab at Dokkyo Medical University Saitama Medical Center from April 2014 to June 2022. The outcome measures were MMP-3 and KL-6 as biomarkers of RA and ILD activity, respectively, and the relationship between them was analyzed.Results: Both MMP-3 and KL-6 were significantly improved at 6 months of treatment (P < 0.001 and P < 0.05, respectively), and a weak correlation between MMP-3 and KL-6 was observed (R2 = 0.086, P = 0.087). The group with increased MMP-3 due to RA progression had significantly higher KL-6 at 6 months compared with the group with RA improvement (P < 0.05). Also, the group with ILD progression on computed tomography had significantly higher MMP-3 compared with the groups with improvement or no change of ILD (P < 0.05 and P < 0.01, respectively). The mortality rate was 0% at 6 months, 2.0% at 1 year, 16.7% at 2 years, and 32.4% at 3 years, and mortality from acute exacerbation of ILD due to respiratory infection increased over time.Conclusion: RA activity and ILD activity were found to be related at 6 months of treatment. Tocilizumab does not seem to affect the mechanism of ILD progression, as most patients showed improvement in both MMP-3 and KL-6 with tocilizumab within 6 months, when this drug would be expected to affect the lungs directly. However, respiratory infection exacerbated ILD from 1 year after the start of treatment. As immunosuppressive drugs, including tocilizumab, have a risk of respiratory infection, it is important to identify early signs of infection.Keywords: interstitial lung disease, Krebs von den Lungen-6, KL-6, matrix metalloproteinase-3, MMP-3, rheumatoid arthritis, mortality, tocilizumab

Objective The aim of this study was to investigate the diagnostic potential of Krebs von den Lungen-6 (KL-6) in differentiating between malignant pleural effusion (MPE) induced by non–small cell lung cancer (NSCLC) and benign pleural effusion (BPE). Methods We collected 143 pleural effusion samples from August 2018 to March 2021. The samples included 91 cases of MPE and 52 cases of BPE. The KL-6 and other indicators in pleural effusion were detected. Results The level of pleural effusion KL-6 (pKL-6) in the MPE group was significantly higher than in the BPE group (Mann-Whitney U = 442.500, P =.000). The area under the curve (AUC) of pKL-6/pleural effusion adenosine deaminase (pADA) + pleural effusion carcinoembryonic antigen (pCEA)/pADA (AUC = 0.992) in diagnosing MPE was higher than that of pKL-6 alone (AUC = 0.903), with a sensitivity of 93.26% and specificity of 100%. Conclusion The measurement of pKL-6 can differentiate NSCLC-induced MPE from BPE. Furthermore, the combined detection of pKL-6/pADA and pCEA/pADA can significantly improve the diagnostic efficiency for distinguishing NSCLC-induced MPE. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to explore the potential values of Krebs von den Lungen-6 (KL-6), neutrophil to lymphocyte ratio (NLR), systemic immune inflammation (SII), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR) and red blood cell distribution width (RDW) in the diagnosis and evaluation of the severity of connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods A total of 140 connective tissue disease (CTD) patients and 85 CTD-ILD patients were recruited for this study at Shanxi Provincial People’s Hospital from May 2022 to May 2023. Patients were divided into subgroups based on medication history and CTD subtypes to compare and analyze the clinical data and laboratory parameters of CTD-ILD patients and CTD patients. The receiver operating characteristic curve (ROC) was used to evaluate the diagnostic efficacy of KL-6, NLR, SII, PLR, MLR, and RDW in identifying CTD-ILD patients from CTD patients. A Spearman correlation analysis was conducted to elucidate the correlations between these markers and the lung function parameters of forced vital capacity (FVC, %), forced expired volume in one second (FEV1, %), and diffusing capacity of carbon monoxide (DLCO, %). Finally, binary logistic regression analysis was applied to discern the independent risk factors for CTD-ILD. Results NLR, SII, MLR, RDW, and KL-6 displayed significant statistical differences in the experimental groups. In both untreated and treated subgroups, KL-6 displayed higher values for CTD-ILD than CTD among all CTD subtypes. In untreated subgroups, there were significant differences in MLR levels between rheumatoid arthritis (RA) and RA-ILD patients and in NLR levels between Sjögren syndrome (SjS) and SjS-ILD patients. There were also significant differences in RDW-SD between the “other CTD” and “other CTD-ILD” groups. In treated subgroups, there were significant differences in both RDW-SD and RDW-CV between RA and RA-ILD patients and in NLR, SII, MLR, PLR, and RDW-SD between “other CTD” and “other CTD-ILD” groups. ROC revealed that KL-6 emerged as the most effective predictor for CTD-ILD in both treated and untreated groups. The multivariate logistic regression analysis results showed that both KL-6 and age were independent risk factors for CTD-ILD. NLR, SII, and PLR were negatively correlated with DLCO (%) in the untreated CTD-ILD group, and KL-6 was negatively correlated with various lung function parameters in both treated and untreated CTD-ILD groups. Conclusion KL-6 emerged as the most promising biomarker for diagnosing CTD-ILD and assessing its severity. The diagnostic value of KL-6 was unaffected by medication interference and surpassed the value of other parameters, such as NLR, SII, MLR, and RDW. The diagnostic value of RDW-SD was higher than that of RDW-CV in CTD-ILD patients. NLR, SII, MLR, and PLR have potential value in diagnosing the different types of CTD-ILD.

Abstract Background Systemic sclerosis (SSc) is a well-known multi-system connective tissue disease, it has an unidentified aetiology that is characterised by abnormal immune system activation, vascular injury, which may progress to faulty neovascularization and inadequate vessel remodelling, and tissue scarring of the skin, lungs, and other internal viscera. Krebs von den Lungen-6 is a kind of transmembrane glycoprotein of type II alveolar epithelial cells and is specific for determining its damage. Regardless of the cause, serum Krebs von den Lungen-6 levels have been investigated in interstitial lung disease (ILD) of several etiologies and have been found to be a significant serum marker for ILD. The current research aims to look into the relationship between serum Krebs von den Lungen-6 levels and disease severity and clinical manifestations, specifically interstitial pulmonary fibrosis, in patients with SSc. In this study, 30 patients with systemic sclerosis and 30 control subjects—15 dermatomyositis patients and 15 healthy volunteers— were also incorporated to see if the change in serum Krebs von den Lungen-6 levels is specific for SSc as dermatomyositis is another connective tissue disorder with lung affection. Results A statistically significant difference (P < 0.001) in the median value of Krebs von den Lungen-6 when compared to the control groups was observed, which was 447.95 (145.68–817.98) in the SSc patients group, 158.80 (130.00–730.70) in the dermatomyositis group, and 48.10 (39.50–103.90) in the healthy control group. A significantly higher median value of Krebs von den Lungen-6 in ground glass, honeycombing, and nodular HRCT was established, with P-value (P < 0.001). There was a highly statistically significant discrepancy in the median Krebs von den Lungen-6 value between patients with ILD (717.7) and patients without ILD (145.7) with P-value (P < 0.001). A statistically significant positive correlation was found between Krebs von den Lungen-6 (U/ml) and Disease duration (years), Medsger severity scale, Digital ulceration, modified Rodnan skin score (MRSS), and P-value (P < 0.05). Conclusion Krebs von den Lungen-6 could be a scleroderma biomarker. It has been linked to the development and severity of interstitial lung disease in systemic sclerosis patients and may shed light on the pathophysiology of some fibrotic lung changes.

Background: Systemic sclerosis (SSc) is a well-known multi-system connective tissue disease, it has an unidentified aetiology that is characterised by abnormal immune system activation, vascular injury, which may progress to faulty neovascularization and inadequate vessel remodelling, and tissue scarring of the skin, lungs, and other internal viscera. Krebs von den Lungen-6 is a kind of transmembrane glycoprotein of type II alveolar epithelial cells and is specific for determining its damage. Regardless of the cause, serum Krebs von den Lungen-6 levels have been investigated in interstitial lung disease (ILD) of several etiologies and have been found to be a significant serum marker for ILD. The current research aims to look into the relationship between serum Krebs von den Lungen-6 levels and disease severity and clinical manifestations, specifically interstitial pulmonary fibrosis, in patients with SSc. In this study, 30 patients with systemic sclerosis and 30 control subjects—15 dermatomyositis patients and 15 healthy volunteers— were also incorporated to see if the change in serum Krebs von den Lungen-6 levels is specific for SSc as dermatomyositis is another connective tissue disorder with lung affection. Results: A statistically significant difference (P < 0.001) in the median value of Krebs von den Lungen-6 when compared to the control groups was observed, which was 447.95 (145.68–817.98) in the SSc patients group, 158.80 (130.00–730.70) in the dermatomyositis group, and 48.10 (39.50–103.90) in the healthy control group. A significantly higher median value of Krebs von den Lungen-6 in ground glass, honeycombing, and nodular HRCT was established, with P-value (P < 0.001). There was a highly statistically significant discrepancy in the median Krebs von den Lungen-6 value between patients with ILD (717.7) and patients without ILD (145.7) with P-value (P < 0.001). A statistically significant positive correlation was found between Krebs von den Lungen-6 (U/ml) and Disease duration (years), Medsger severity scale, Digital ulceration, modified Rodnan skin score (MRSS), and P-value (P < 0.05). Conclusion: Krebs von den Lungen-6 could be a scleroderma biomarker. It has been linked to the development and severity of interstitial lung disease in systemic sclerosis patients and may shed light on the pathophysiology of some fibrotic lung changes. [ABSTRACT FROM AUTHOR]

Purpose: Krebs von den Lungen-6 (KL-6) functions as a tumor marker, as well as a diagnostic tool for interstitial pneumonia (IP). However, the significance of KL-6 in the immune-checkpoint inhibitor (ICI) treatment of non-small cell lung cancer (NSCLC), especially in patients without IP, is unknown. Methods: This multicenter, retrospective study, which included patients with advanced NSCLC who received ICI therapy, analyzed the association between serum KL-6 values and ICI efficacy and the association between serum KL-6 values and ICI-induced interstitial lung disease (ILD) occurrence, focusing primarily on patients without IP. Results: In total, 322 patients had available KL-6 values before ICI therapy. Among 202 patients without IP who received ICI monotherapy, the high-KL-6 group (≥ 500 U/mL) showed significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-KL-6 group (< 500 U/mL) (median: 2.1 vs. 3.6 months, p = 0.048; median: 9.2 vs. 14.5 months, p = 0.035). There was no significant difference in response rate between the KL-6 high and low groups (19% vs. 29%, p = 0.14). In the multivariate analysis, high KL-6 was a significant predictor of poor PFS (hazard ratio [HR], 1.52; 95% confidence interval [CI] 1.10–2.11, p = 0.012) and OS (HR, 1.51; 95% CI 1.07 − 2.13, p = 0.019) for patients treated with ICI monotherapy. There was no significant difference in the occurrence rate of ILD between the high KL-6 and low KL-6 groups in patients with (20% vs. 15%, p = 1.00) or without IP (12% vs. 12%, p = 1.00). Conclusion: In ICI monotherapy for NSCLC without IP, elevated serum KL-6 levels were associated with poorer outcomes. [ABSTRACT FROM AUTHOR]

A 71-year-old male visited a hospital with a chief complaint of exertional dyspnea. A chest CT revealed multiple nodular lesions on the parietal pleura. Thoracoscopic pleural biopsy was performed resulting in a diagnosis of pleural mesothelioma with epithelioid type. When chemotherapy was initially initiated, his serum level of Krebs von den Lungen-6 (KL-6) was high. However, once chemotherapy was started, the serum KL-6 level gradually decreased with tumor shrinkage. Immunohistochemical staining revealed the expression of KL-6 from the tumor cells. This is the first report of KL-6 production directly from tumor cells in epithelial-type pleural mesothelioma.

Zhifei Hou,1,2 Xinran Zhang,3 Yong Gao,4 Jing Geng,2 Yu Jiang,5 Huaping Dai,1,2 Chen Wang1,2 1Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Department of Clinical Research and Data Management, Center of Respiratory Medicine, China-Japan Friendship Hospital; National Center for Respiratory Medicine; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Pulmonary and Critical Care Medicine, Sinopharm Tongmei General Hospital, Datong, Shanxi Province, People’s Republic of China; 5Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Huaping Dai; Chen Wang, Email daihuaping@ccmu.edu.cn; cyh-birm@263.netBackground: Coal worker’s pneumoconiosis (CWP) is a chronic occupational disease mainly caused by coal dust inhalation in miners. This study aimed to investigate the clinical value of Osteopontin (OPN), KL-6, Syndecan-4 and Gremlin-1 as serum biomarkers in CWP.Patients and Methods: We integrated reported lung tissues transcriptome data in pneumoconiosis patients with silica-exposed alveolar macrophage microarray data to identify four CWP-associated serum biomarkers. The serum concentrations of Osteopontin, Krebs von den Lungen-6 (KL-6), Syndecan-4 and Gremlin-1 were measured in 100 healthy controls (HCs), 100 dust-exposed workers (DEWs) and 200 patients of CWP. Receiver operating characteristic (ROC) curve analysis was used to determine the sensitivity, specificity, cut-off value and area under the curve (AUC) value of biomarkers.Results: The pulmonary function parameters decreased sequentially, and the serum OPN, KL-6, Syndecan-4 and Gremlin-1 concentrations were increased sequentially among the HC, DEW and CWP groups. Among all participants, multivariable analysis revealed that these four biomarkers were negatively correlated with the pulmonary function parameters (all p< 0.05). Compared with HCs, patients with higher OPN, KL-6, Syndecan-4 and Gremlin-1 had higher risk for CWP. The combination of OPN, KL-6, and Syndecan-4 can improve the diagnostic sensitivity and specificity of CWP patients differentiated from HCs or DEWs.Conclusion: OPN, KL-6 and Syndecan-4 are novel biomarkers that can be used for CWP auxiliary diagnosis. The combination of three biomarkers can improve the diagnostic values of CWP.Keywords: coal workers’ pneumoconiosis, biomarker, osteopontin, Krebs von den Lungen-6, Syndecan-4, Gremlin-1

Background: As fibrosing interstitial lung diseases (fILDs) are associated with high mortality, monitoring of disease activity under treatment is highly relevant. Krebs von den Lungen-6 (KL-6) is associated with the presence and severity of different fILDs, mainly in Asian patient populations. Objectives: Our aim was to evaluate KL-6 as a predictive biomarker in fILDs in Caucasian patients. Methods: Consecutive patients with fILDs were recruited prospectively and serum concentrations of KL-6 were measured at baseline (BL), after 6 and 12 months (6 Months, 12 Months). Clinical characteristics including pulmonary function tests were assessed at 6-monthly visits and correlated with KL-6 BL levels as well as with KL-6 level changes. Results: A total of 47 fILD patients were included (mean age: 65 years, 68% male). KL-6 levels at BL were significantly higher in fILD patients than in healthy controls (n = 44, mean age: 45, 23% male) (ILD: 1,757 ± 1960 U/mL vs. control: 265 ± 107 U/mL, p < 0.0001). However, no differences were noted between ILD subgroups. KL-6 decreased significantly under therapy (6M∆BL-KL6: −486 ± 1,505 mean U/mL, p = 0.032; 12M∆BL-KL6: −547 ± 1,782 mean U/mL, p = 0.041) and KL-6 level changes were negatively correlated with changes in pulmonary function parameters (forced vital capacity [FVC]: r = −0.562, p < 0.0001; DLCOSB: r = −0.405, p = 0.013). While neither absolute KL-6 levels at BL nor KL-6 level changes were associated with ILD progression (FVC decline ≥10%, DLCOSB decline ≥15% or death), patients with a stable FVC showed significantly decreasing KL-6 levels (p = 0.022). Conclusions: A decline of KL-6 under therapy correlated with a clinically relevant stabilization of lung function. Thus, KL-6 might serve as a predictive biomarker, which however must be determined by larger prospective cohorts. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This systematic review and meta-analysis aimed to find the association between serum Krebs von den Lungen-6 (KL-6) and the severity of Coronavirus disease 2019 (COVID-19) infection. DATA SOURCES: Databases of Embase, PubMed, Web of Science, Science Direct, and Google Scholar were searched for studies reporting KL- 6 levels in COVID-19 patients, published between January 2020 and September 30 2022. DATA SYNTHESIS: For comparison between the groups, standard mean difference (SMD) and 95% confidence intervals (CI) were computed as the effect sizes. Sensitivity, specificity, positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were measured to assess the diagnostic power of KL-6. In addition, the summary receiver operating characteristics curve (sROC) was constructed to summarize the true positive (TP), and false positive (FP) rates. To validate the findings of meta-analysis, Trial Sequential Analysis (TSA) was conducted. RESULTS: Altogether 497 severe COVID-19 patients and 934 non-severe (mild to moderate) COVID-19 patients were included. Pooling of 12 studies indicated that the serum KL-6 level had significant association with severity of COVID-19 infection: standard mean difference = 1.18 (95% CI: 0.93-1.43), p = 0.01; I²: 58.56%]. Pooled diagnostic parameters calculated from eight studies were: sensitivity 0.53 (95% CI: 0.47-0.59); specificity 0.90 (95% CI: 0.88-0.93); positive likelihood ratio 4.80 (95% CI: 3.53-6.53); negative likelihood ratio 0.46 (95% CI: 0.32-0.68); and area under curve: 0.8841. Additionally, TSA verified the adequacy of sample size and robustness of the meta-analysis. CONCLUSION: Serum KL-6 level has a moderate degree of correlation with the severity of COVID-19 infection but has low sensitivity. So, it is not recommended as a screening test for severe COVID-19 infection. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the expressions and significance of 25 hydroxyvitamin D [25(OH)D3], Krebs von den Lungen (KL)-6, and interleukin (IL)-32 in serum and alveolar lavage fluid (SALF) in patients with connective tissue disease-related interstitial lung disease (CTD-ILD). Methods: Forty CTD-ILD patients admitted to Affiliated Hospital of Jianghan University (The Sixth Hospital of Wuhan) were retrospectively categorized into a study group (SG), while 45 healthy individuals were categorized into a control group (CG). The SG was grouped based on the imaging performance of the high-resolution computed tomography (HRCT). If the lesions were ground-glass-like changes, featuring predominant exudative changes in spots and patchy shadows, the patients were placed in subgroup A of the study group, but if they were fibrous cord-like, grid-like, and honeycomb-like fibrotic lesions, the patients were placed in subgroup B of study group. Results: Serum 25(OH)D3 in the SG was lower than in the CG, while the serum levels of KL-6 and IL- 32 were higher than in CG. Furthermore, in the SG, KL-6 and IL-32 levels were lower in serum than in alveolar lavage fluid (p < 0.05). Sub-group A showed higher SALF levels in KL-6 and IL-32 than subgroup B. Forced vital capacity (FVC) and the diffusing capacity of the lungs for carbon monoxide (DLCO) in SG were lower than in CG (p < 0.05). Serum 25(OH)D3 had negative correlation with the SALF of KL-6 and IL-32 in CTD-ILD patients (p < 0.05), while KL-6 and IL-32 levels in serum were positively correlated with those in alveolar lavage fluid (p < 0.05). Conclusion: The results indicate the possible involvement of 25(OH)D3, KL-6, and IL-32 in the development of CTD-ILD. Thus, serum 25(OH)D3, SALF KL-6, and IL-32 levels may affect lung function and therefore, can serve as indicators of the patients' condition. [ABSTRACT FROM AUTHOR]

There is a need for biomarkers to predict outcomes, including mortality, in interstitial lung disease (ILD). Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are associated with lung damage and fibrosis in all ILDs and are related to important clinical outcomes. Though these two biomarkers have been associated with ILD outcomes, there are no studies that have evaluated their predictive potential in combination. This study aims to determine whether KL-6 and SP-D are linked to poor disease outcomes and mortality. Additionally, we plan to examine whether changes in KL-6 and SP-D concentrations correspond with changes in lung function and whether serial measurements improve their predictive potential to identify disease progression and mortality. Forty-four patients with ILD participated in a prospective 6-month longitudinal observational study. ILD patients who succumbed had the highest KL-6 levels (3990.4 U/mL (3490.0–4467.6)) and highest SP-D levels (256.1 ng/mL (217.9–260.0)), followed by those who deteriorated: KL-6 levels 1357.0 U/mL (822.6–1543.4) and SP-D levels 191.2 ng/mL (152.8–210.5). The generalized linear model (GLM) analysis demonstrated that changes in forced vital capacity (FVC), diffusing capacity of lungs for carbon monoxide (DLCO), forced expiratory volume in 1 s (FEV1), and partial pressure of arterial oxygen (PaO2) were correlated to changes in KL6 (p = 0.016, 0.014, 0.027, 0.047) and SP-D (p = 0.008, 0.012, 0.046, 0.020), respectively. KL-6 (odds ratio (OR): 2.87 (1.06–7.79)) and SPD (OR: 1.76 (1.05–2.97)) were independent predictors of disease progression, and KL-6 (hazard ratio (HR): 3.70 (1.46–9.41)) and SPD (HR: 2.58 (1.01–6.59)) were independent predictors of death by Cox regression analysis. Combined biomarkers (KL6 + SPD + CT + FVC) had the strongest ability to predict disease progression (AUC: 0.797) and death (AUC: 0.961), on ROC analysis. Elevated KL-6 and SPD levels are vital biomarkers for predicting the severity, progression, and outcomes of ILD. High baseline levels or an increase in levels over a six-month follow-up despite treatment indicate a poor prognosis. Combining KL6 and SPD with conventional measures yields a more potent prognostic indicator. Clinical studies are needed to test additional interventions, and future research will determine if this combined biomarker benefits different ethnicities globally. [ABSTRACT FROM AUTHOR]

• A total of 16 papers with approximately 2700 study subjects were included in our study for meta-analysis. • Serum KL-6 has a high diagnostic value with a sensitivity of 0.87%, specificity of 91%, and an area under SROC of 0.95 for pulmonary fibrosis. • KL-6 may serve as an important and good biomarker for the diagnosis of pulmonary fibrosis. Pulmonary fibrosis (PF) is a respiratory disease with end-stage pathological changes of interstitial lung disease that severely affects the survival of patients. Among the many biomarkers that have been identified, serum Krebs von den Lungen-6 (KL-6) is by far the most frequent marker for detecting pulmonary fibrosis. We searched Medline (Pubmed), Embase, Web of science, and Cochrane databases for articles published between inception and August 2022 in order to explore the association between KL-6 and pulmonary fibrosis. Characteristics of patients and studies included in the articles were extracted by two independent investigators according to the inclusion and exclusion criteria. We reflected the accuracy of KL-6 in distinguishing between PF and non-PF by calculating sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and area under the curve by SROC curves. The presence of heterogeneity was reflected by I2 in the forest plot, and then the source of heterogeneity was investigated by meta-regression. We searched for 939 research papers, of which 16 met the inclusion criteria. Meta-analysis showed a sensitivity of 0.87 (95 % CI: 0.78–0.92), specificity of 0.91 (95 % CI: 0.86–0.95), positive likelihood ratio of 10.2 (95 % CI: 6.1, 17.0) and negative likelihood ratio of 0.14 (95 % CI: 0.08, 0.25) for KL-6 in diagnosing pulmonary fibrosis. The area under the receiver operating characteristic curve was 0.95 (95 % CI: 0.93–0.97). The results showed significant heterogeneity in both sensitivity and specificity (I2 = 94.55 and 91.52, respectively). Meta-regression analysis identified race as the cause of sensitivity heterogeneity and assay methodology as the cause of specificity heterogeneity. The analysis of this study suggests that serum KL-6 is a better tool for the diagnosis of pulmonary fibrosis when factors such as disease cause and control group category are not specifically considered. [ABSTRACT FROM AUTHOR]

Abstract Background Antifibrotic therapy can slow disease progression (DP) in patients with idiopathic pulmonary fibrosis (IPF). However, the prognostic biomarkers for DP in patients with IPF receiving antifibrotic therapy have not been identified. Therefore, we aimed to evaluate the prognostic efficacy of serum Krebs von den Lungen-6 (KL-6) for DP in patients with IPF receiving antifibrotic therapy. Methods The clinical data of 188 patients with IPF who initiated antifibrotic therapy at three tertiary hospitals was retrospectively analyzed. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, diffusing capacity for carbon monoxide ≥ 15%, acute exacerbation, or deaths during 6 months after antifibrotic therapy. Results The mean age of patients was 68.9 years, 77.7% were male, and DP occurred in 43 patients (22.9%) during follow-up (median, 7.6 months; interquartile range, 6.2–9.8 months). There was no difference in baseline KL-6 levels between the DP and no-DP groups; however, among patients with high baseline KL-6 levels (≥ 500 U/mL), changes in KL-6 levels over 1 month were higher in the DP group than those in the non-DP group, and higher relative changes in KL-6 over 1 month were independently associated with DP (odds ratio, 1.043; 95% confidence interval 1.005–1.084) in the multivariable logistic analysis adjusted for age and FVC. In the receiver operating characteristic curve analysis, the 1-month change in KL-6 was also useful for predicting DP (area under the curve = 0.707; P

Waterproofing spray-associated lung injury (WALI) is an acute respiratory disorder characterized by bilateral diffuse lung injury on chest computed tomography (CT). In most cases, the symptoms and abnormal radiographic findings of WALI patients improve spontaneously over several days; however, some cases have persistent symptoms and abnormal shadows for >1 week. The distinctive features of each WALI are unknown. Herein, we present two new cases of WALI that we encountered in our hospital, and we previously reported two other cases of WALI. We examined the characteristics of WALI in our cases and 39 other cases of WALI definitively diagnosed and reported in PubMed and the Japan medical board with verifiable data during a 15-year period. We compared the clinical characteristics of the 22 cases in which the patients' symptoms were resolved within 1 week (early improvement) to those of the 21 cases in which the symptoms were resolved after >1 week (delayed improvement). The WALI cases with delayed improvement had significantly more shadowing that extended over the entire lung field and was not biased in intensity toward the upper or lower lung field. In addition, the serum white blood cell (WBC) counts and serum Krebs von den Lungen-6 (KL-6) levels differed significantly between the cases of early and delayed improvement of WALI. [ABSTRACT FROM AUTHOR]

Abstract Background This study aimed to search for blood biomarkers among the profiles of patients with RA-ILD by using machine learning classifiers and probe correlations between the markers and the characteristics of RA-ILD. Methods A total of 153 RA patients were enrolled, including 75 RA-ILD and 78 RA-non-ILD. Routine laboratory data, the levels of tumor markers and autoantibodies, and clinical manifestations were recorded. Univariate analysis, least absolute shrinkage and selection operator (LASSO), random forest (RF), and partial least square (PLS) were performed, and the receiver operating characteristic (ROC) curves were plotted. Results Univariate analysis showed that, compared to RA-non-ILD, patients with RA-ILD were older (p

Background: Antifibrotic therapy can slow disease progression (DP) in patients with idiopathic pulmonary fibrosis (IPF). However, the prognostic biomarkers for DP in patients with IPF receiving antifibrotic therapy have not been identified. Therefore, we aimed to evaluate the prognostic efficacy of serum Krebs von den Lungen-6 (KL-6) for DP in patients with IPF receiving antifibrotic therapy. Methods: The clinical data of 188 patients with IPF who initiated antifibrotic therapy at three tertiary hospitals was retrospectively analyzed. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, diffusing capacity for carbon monoxide ≥ 15%, acute exacerbation, or deaths during 6 months after antifibrotic therapy. Results: The mean age of patients was 68.9 years, 77.7% were male, and DP occurred in 43 patients (22.9%) during follow-up (median, 7.6 months; interquartile range, 6.2–9.8 months). There was no difference in baseline KL-6 levels between the DP and no-DP groups; however, among patients with high baseline KL-6 levels (≥ 500 U/mL), changes in KL-6 levels over 1 month were higher in the DP group than those in the non-DP group, and higher relative changes in KL-6 over 1 month were independently associated with DP (odds ratio, 1.043; 95% confidence interval 1.005–1.084) in the multivariable logistic analysis adjusted for age and FVC. In the receiver operating characteristic curve analysis, the 1-month change in KL-6 was also useful for predicting DP (area under the curve = 0.707; P < 0.012). Conclusions: Our data suggest that the relative change in KL-6 over 1 month might be useful for predicting DP in patients with IPF receiving antifibrotic therapy when baseline KL6 is high. [ABSTRACT FROM AUTHOR]

Aim: Hypersensitivity pneumonitis (HP), also referred to as exogenous allergic alveolitis, is one of the most common interstitial lung diseases (ILDs). A potential immune biomarker, Krebs von den lgen-6 (KL-6) characterizes the progression and severity of HP. The meta-analysis in this study was conducted to elucidate the variations in the concentrations of KL-6 in different types of HP. Methods: A systematic search of various databases such as EMBASE, Pubmed, CNKI, VIP, Web of Science, and WanFang was carried out to find relevant published articles between January 1980 and August 2022 that explored the relationship between KL-6 and allergic pneumonia. Standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect sizes for comparison among different groups. The GSE47460 and GSE150910 datasets were downloaded to extract and validate the differences in KL-6 mRNA expression between HP lung tissue and healthy controls. Furthermore, the single-cell sequencing dataset GSE135893 was downloaded to extract KL-6 mRNA expression in type II alveolar epithelial cells to validate the differences between HP and healthy controls. Two researchers evaluated the quality of the included studies by employing Newcastle-Ottawa Scale. All the qualified studies were subjected to statistical analyses carried out utilizing RevMan 5.2, Stata 11.0, and R software 4.1.3. Results: Twenty studies aligned perfectly with the inclusion criteria of the meta. The concentrations of KL-6 were substantially higher in the blood of HP patients as compared to the control group. Subgroup analyses were carried out in accordance with the allergen source and the results revealed that patients with different allergens had higher blood KL-6 concentrations than healthy controls. Additionally, different subgroups of subjects were created for meta-analysis as per the fibrosis status, race, measurement method, and sample type. The concentration of KL-6 in blood was much higher in all HP subgroups than in healthy control groups. Moreover, the bioinformatics analysis revealed that KL-6 mRNA expression was higher in HP lung tissue and type II alveolar epithelial cells as compared to healthy controls. Conclusion: The present meta-analysis and bioinformatics analysis suggested that the concentration levels of KL-6 varied between HP patients and healthy individuals, and the KL-6 concentrations may be higher in the blood samples of HP patients. [ABSTRACT FROM AUTHOR]

Background: Biomarkers of lung injury and interstitial fibrosis give insight about the extent of involvement and prognosis in well-known interstitial lung diseases (ILD). Serum Krebs von den Lungen-6 (KL-6) reflects direct alveolar injury and, transforming growth factor-beta1 (TGF-β1) and fibroblast growth factor-2 (FGF-2) are principal mediators of fibrosis in ILD and in almost all fibrotic diseases. In this sense, we aimed to assess associations of these biomarkers with traditional inflammatory markers and clinical course of COVID-19. Methods: Patients with COVID-19 who had confirmed diagnosis with SARS-CoV-2 nucleic acid RT-PCR were enrolled and followed up prospectively with a standardized approach one month after diagnosis. Patients were divided into severe and non-severe groups according to National Institutes of Health criteria. Outcome was assessed for the requirement of intensive care unit (ICU) admission, long term respiratory support and death. Blood samples were collected at enrollment and serum levels of KL-6, TGF-β1, FGF-2 were determined by ELISA. Association between these markers with other prognostic markers and prognosis were analyzed. Results: Overall 31 severe and 28 non-severe COVID-19 patients were enrolled and were compared with healthy control subjects (n = 30). Serum KL-6 levels in COVID-19 patients were significantly higher (median [IQR]; 11.54 [4.86] vs 8.54 [3.98] ng/mL, P =.001] and FGF-2 levels were lower (median [IQR]; 76.84 [98.2] vs 101.62 [210.6] pg/mL) compared to healthy control group. A significant correlation was found between KL-6 values and CRP, fibrinogen, d -dimer and lymphocyte counts. However, we did not find an association between these markers and subsequent severity of COVID-19, mortality and long-term prognosis. Conclusions: Serum KL-6 levels were significantly elevated at the diagnosis of COVID-19 and correlated well with the other traditional prognostic inflammatory markers. Serum levels of principal fibrosis mediators, TGF-β1, FGF-2, were not elevated at diagnosis of COVID-19, therefore did not help to anticipate long term prognosis. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 (COVID-19) pandemic is a major issue that necessitates the use of cutting-edge disease prediction models. The aim of the study was to assess the existing evidence regarding association between Krebs von den Lungen-6 levels and COVID-19 severity. A literature search was performed on Web of Science, PubMed, Scopus and Cochrane Central Register of Controlled Trials databases from 1 January 2020 up to 2 August 2022. The electronic database search was supplemented by searching Google Scholar. In addition, reference lists of relative articles were also reviewed. KL-6 levels among COVID-19 positive vs. negative patients varied and amounted to 443.37 ± 249.33 vs. 205.73 ± 86.8 U/mL (MD = 275.33; 95%CI: 144.57 to 406.09; p < 0.001). The KL-6 level was 402.82 ± 261.16 U/mL in the severe group and was statistically significantly higher than in the non-severe group (297.38 ± 90.46 U/mL; MD = 192.45; 95%CI: 118.19 to 266.72; p < 0.001). The KL-6 level in the mild group was 272.28 ± 95.42 U/mL, compared to 268.04 ± 55.04 U/mL in the moderate COVID-19 group (MD = −12.58; 95%CI: −21.59 to −3.57; p = 0.006). Our meta-analysis indicates a significant association between increased KL-6 levels and SARS-CoV-2 infection. Moreover, KL-6 levels are significantly higher in patients with a more severe course of COVID-19, indicating that KL-6 may be a useful predictor to identify patients at risk for severe COVID-19. [ABSTRACT FROM AUTHOR]

• The role of KL-6 and IL-6 for predicting mortality in critically ill COVID-19 patients was studied. • Peak KL-6 and IL-6 levels were elevated in deceased COVID-19 patients. • In multivariable analysis, peak KL-6 ≥ 1019.2 U/mL was associated with mortality. • Increase in KL-6 level 1 week after admission was significantly higher in the deceased group. • Serum KL-6 and IL-6 levels could predict mortality in critically ill COVID-19 patients. [ABSTRACT FROM AUTHOR]

Introduction: This study explored circulating pneumoproteins in the diagnosis, severity, and prognosis of COVID-19 by meta-analysis. Methods: We searched five databases and other sources until December 16, 2021. Standardized mean difference (SMD) and 95% confidence interval (CI) were the overall outcomes. RevMan 5.3, Stata 16, and Meta-DiSc 1.4 were utilized for pooled analysis. Results: A total of 2432 subjects from 26 studies were included. Patients with COVID-19 had higher circulating KL-6, SP-D, and SP-A levels (SMD 1.34, 95% CI [0.60, 2.08]; SMD 1.74, 95% CI [0.64, 2.84]; SMD 3.42, 95% CI [1.31, 5.53], respectively) than healthy individuals. Circulating SP-D levels were not significantly different in survivors and non-survivors (SMD − 0.19, 95% CI [− 0.78, 0.40]). Circulating KL-6, SP-D, and RAGE levels in patients with mild to moderate COVID-19 were significantly lower (SMD − 0.93, 95% CI [− 1.22, − 0.65]; SMD − 1.32, 95% CI [− 2.34, − 0.29]; SMD − 1.17, 95% CI [− 2.06, − 0.28], respectively) than in patients with severe COVID-19. Subgroup analysis suggested that country and total number may be related to the heterogeneity when analyzing SP-D in patients with mild to moderate vs. severe COVID-19. The meta-analysis of diagnostic accuracy including KL-6 for severity, KL-6 for mortality, and SP-D for severity demonstrated that they all had limited diagnostic value. Conclusion: Therefore, circulating pneumoproteins (KL-6, SP-D, and RAGEs) reflect the diagnosis, severity, and prognosis of COVID-19, and follow-up studies are still needed. [ABSTRACT FROM AUTHOR]

A 71-year-old male visited a hospital with a chief complaint of exertional dyspnea. A chest CT revealed multiple nodular lesions on the parietal pleura. Thoracoscopic pleural biopsy was performed resulting in a diagnosis of pleural mesothelioma with epithelioid type. When chemotherapy was initially initiated, his serum level of Krebs von den Lungen-6 (KL-6) was high. However, once chemotherapy was started, the serum KL-6 level gradually decreased with tumor shrinkage. Immunohistochemical staining revealed the expression of KL-6 from the tumor cells. This is the first report of KL-6 production directly from tumor cells in epithelial-type pleural mesothelioma. [ABSTRACT FROM AUTHOR]

COVID-19 encompasses a broad spectrum of clinical conditions caused by SARS-CoV-2 infection. More severe cases experience acute respiratory and/or multiorgan failure. KL-6 is a glycoprotein expressed mainly from type II alveolar cells with pro-fibrotic properties. Serum KL-6 concentrations have been found in patients with COVID-19. However, the relevance of KL-6 in patients with severe and critical COVID-19 has not been fully elucidated. Methods: Retrospective data from consecutive severe to critical COVID-19 patients were collected at UOC Clinica Pnuemologica "Vanvitelli", A.O. dei Colli, Naples, Italy. The study included patients with a positive rhinopharyngeal swab for SARS-CoV-2 RNA with severe or critical COVID-19. Results: Among 87 patients, 24 had poor outcomes. The median KL-6 value in survivors was significantly lower when compared with dead or intubated patients (530 U/mL versus 1069 U/mL p < 0.001). KL-6 was correlated with body mass index (BMI) (r: 0.279, p: 0.009), lung ultrasound score (LUS) (r: 0.429, p < 0.001), Chung Score (r: 0.390, p < 0.001). KL-6 was associated with the risk of death or oro-tracheal intubation (IOT) after adjusting for gender, BMI, Charlson Index, Chung Score, and PaO2/FIO2 (OR 1.003 95% CI 1.001–1.004, p < 0.001). Serum KL-6 value of 968 has a sensitivity of 79.2%, specificity of 87.1%, PPV 70.4%, NPV 91.5%, AUC: O.85 for risk of death or IOT. Conclusions: The presented research highlights the relevance of serum KL-6 in severe to critical COVID-19 patients in predicting the risk of death or IOT. [ABSTRACT FROM AUTHOR]

Abstract Background Clinical course of pleuroparenchymal fibroelastosis (PPFE) shows considerable variation among patients, but there is no established prognostic prediction model for PPFE. Methods The prediction model was developed using retrospective data from two cohorts: our single-center cohort and a nationwide multicenter cohort involving 21 institutions. Cox regression analyses were used to identify prognostic factors. The total score was defined as the weighted sum of values for the selected variables. The performance of the prediction models was evaluated by Harrell’s concordance index (C-index). We also examined the usefulness of the gender-age-physiology (GAP) model for predicting the prognosis of PPFE patients. Results We examined 104 patients with PPFE (52 cases from each cohort). In a multivariate Cox analysis, a lower forced vital capacity (FVC [defined as FVC 550 U/mL, HR, 2.56) were significantly associated with a poor prognosis. The total score was calculated as 1 × (FVC, 550 U/mL). PPFE patients were divided into three groups based on the prognostic score: stage I (0–1 points), stage II (2 points), and stage III (3–4 points). The survival rates were significantly different in each stage. The GAP stage was significantly associated with the prognosis of PPFE, but no difference was found between moderate (stage II) and severe (stage III) disease. Our new model for PPFE patients (PPFE Prognosis Score) showed better performance in the prediction of mortality in comparison to the GAP model (C-index of 0.713 vs. 0.649). Conclusions Our new model for PPFE patients could be useful for predicting their prognosis.

There is a need for biomarkers to predict outcomes, including mortality, in interstitial lung disease (ILD). Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are associated with lung damage and fibrosis in all ILDs and are related to important clinical outcomes. Though these two biomarkers have been associated with ILD outcomes, there are no studies that have evaluated their predictive potential in combination. This study aims to determine whether KL-6 and SP-D are linked to poor disease outcomes and mortality. Additionally, we plan to examine whether changes in KL-6 and SP-D concentrations correspond with changes in lung function and whether serial measurements improve their predictive potential to identify disease progression and mortality. Forty-four patients with ILD participated in a prospective 6-month longitudinal observational study. ILD patients who succumbed had the highest KL-6 levels (3990.4 U/mL (3490.0–4467.6)) and highest SP-D levels (256.1 ng/mL (217.9–260.0)), followed by those who deteriorated: KL-6 levels 1357.0 U/mL (822.6–1543.4) and SP-D levels 191.2 ng/mL (152.8–210.5). The generalized linear model (GLM) analysis demonstrated that changes in forced vital capacity (FVC), diffusing capacity of lungs for carbon monoxide (DLCO), forced expiratory volume in 1 s (FEV1), and partial pressure of arterial oxygen (PaO2) were correlated to changes in KL6 (p = 0.016, 0.014, 0.027, 0.047) and SP-D (p = 0.008, 0.012, 0.046, 0.020), respectively. KL-6 (odds ratio (OR): 2.87 (1.06–7.79)) and SPD (OR: 1.76 (1.05–2.97)) were independent predictors of disease progression, and KL-6 (hazard ratio (HR): 3.70 (1.46–9.41)) and SPD (HR: 2.58 (1.01–6.59)) were independent predictors of death by Cox regression analysis. Combined biomarkers (KL6 + SPD + CT + FVC) had the strongest ability to predict disease progression (AUC: 0.797) and death (AUC: 0.961), on ROC analysis. Elevated KL-6 and SPD levels are vital biomarkers for predicting the severity, progression, and outcomes of ILD. High baseline levels or an increase in levels over a six-month follow-up despite treatment indicate a poor prognosis. Combining KL6 and SPD with conventional measures yields a more potent prognostic indicator. Clinical studies are needed to test additional interventions, and future research will determine if this combined biomarker benefits different ethnicities globally.

Objective: To investigate the value of joint diagnosis of connective tissue disease combined with interstitial lung disease (ILD) with krebs von den lungen-6 (KL-6), matrix metalloproteinase-7 (MMP-7) and hyaluronic acid (HA). Methods: A total of 69 patients with connective tissue disease combined with ILD treated in our hospital from December 2017 to December 2019 were selected as the research object (combined ILD group), 67 patients with simple connective tissue disease and 60 healthy subjects who underwent physical examination in the same period were selected as the simple connective tissue disease group and the control group respectively. The serum KL-6, MMP-7 and HA of the three groups were compared, logistic regression analysis was used to determine the independent influencing factors of ILD in connective tissue disease, receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy. Results: There was statistical significant difference in the levels of serum KL-6, MMP-7 and HA among the three groups (P<0.05), the levels of serum KL-6, MMP-7 and HA in the combined ILD group were significantly higher than those in the simple connective tissue disease group and the control group (P<0.05), the levels of serum KL-6, MMP-7 and HA in the simple connective tissue disease group were significantly higher than those in the control group (P<0.05). Logistic regression analysis showed that serum KL-6, MMP-7, HA and dust exposure history were significant influencing factors of ILD in connective tissue disease (P<0.05). ROC curve analysis showed that the AUC（95%CI）of serum KL-6, MMP-7 and HA for ILD in connective tissue disease were 0.715(0.439~0.988), 0.702(0.440~0.959), 0.711 (0.500~0.919) respectively, the AUC (95%CI) of the joint detection of the above three indexes was 0.811 (0.705~0.913), which meant higher diagnostic efficiency. Conclusions: The levels of serum KL-6, MMP-7 and HA in patients with connective tissue disease combined with ILD increase, the joint diagnosis can improve the diagnostic efficiency of connective tissue disease combined with ILD, and provide some references for early diagnosis of ILD. [ABSTRACT FROM AUTHOR]

Abstract Background Drug-induced pneumonia (d-pneumonia) and bacterial pneumonia (b-pneumonia) are often difficult to differentiate; therefore, this study examined the possibility of differentiating them using serum biomarkers. Methods The study included 22 and 16 patients diagnosed with b- and d-pneumonia, respectively, at our institution or affiliated institutions. For d-pneumonia, the causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. White blood cell (WBC), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, and SP-A levels were measured in each patient and compared between the groups. Results Significant differences were noted in the WBC and SP-D levels between the two groups (P

Abstract Background Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes. Methods We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined. Results Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO)

Novel progressive fibrotic phenotype has recently been proposed characterized by progressive and inexorable worsening of the disease. Krebs von den Lungen-6 (KL-6) has been proposed as fibrotic-ILD biomarker. We aimed to assess the role of KL-6 in fibrotic-ILD and the progressive phenotype in accordance with serial serum KL-6. Methods: 107 patients were enrolled in the study (median age,IQR, 65(54−71)y/o) followed at respiratory diseases and rheumatology units of University of Siena. Thirty-five had diagnoses of IPF, 18 sarcoidosis, 10 PLCH, 5 LAM, 24 fibrotic HP(fHP), 13 RA (4/13 RA-ILD) and 22 SSc (18/22 SSc-ILD). Serial serum samples were collected before therapy (t0) and 24 months later (t1) from IPF, SSc- and RA-ILD patients. Twenty-two healthy controls (HC) were enrolled. Serum samples were assayed for KL-6 concentrations (Fujirebio Europe, Gent, Belgium). Results: Higher KL-6 concentrations were reported in IPF, fHP and SSc-ILD patients than HC (p<0.0001). KL-6 cut-off value of 885 U/mL identified fibrotic-ILD patients. Logistic regression analysis indicated KL-6 (p=0.004) and smoking-habit (p=0.005) affected the ILD diagnosis. The decision tree model showed KL-6>1145 U/mL, DLco≤60.15 %, FVC≤86 % to classify 86 % IPF patients. Inverse correlation between T0-KL-6 and T1-FVC%(r=-0.314, p=0.046) and T1-DLco%(r=-0.327, p=0.038) in the progressive group. Conclusion: KL-6 proved to be a reliable marker for diagnosis and prognosis of fibrotic ILD patients with predictive value in progressive fibrotic patients and a useful marker to identify the new and similar progressive phenotype of IPF and SSc-ILD patients assessing the functional progression in accordance with serial serum KL-6 measurements. • Progressive fibrotic phenotype encompasses all ILD patients generally show progressive deterioration of their condition. • No single validated marker can be routinely used in ILD clinical management. KL-6 has been proposed as prognostic marker. • Serial KL-6 values proved to be predictive marker for progressive fibrotic patients assessing the functional progression. [ABSTRACT FROM AUTHOR]

Waterproofing spray-associated lung injury (WALI) is an acute respiratory disorder characterized by bilateral diffuse lung injury on chest computed tomography (CT). In most cases, the symptoms and abnormal radiographic findings of WALI patients improve spontaneously over several days; however, some cases have persistent symptoms and abnormal shadows for >1 week. The distinctive features of each WALI are unknown. Herein, we present two new cases of WALI that we encountered in our hospital, and we previously reported two other cases of WALI. We examined the characteristics of WALI in our cases and 39 other cases of WALI definitively diagnosed and reported in PubMed and the Japan medical board with verifiable data during a 15-year period. We compared the clinical characteristics of the 22 cases in which the patients’ symptoms were resolved within 1 week (early improvement) to those of the 21 cases in which the symptoms were resolved after >1 week (delayed improvement). The WALI cases with delayed improvement had significantly more shadowing that extended over the entire lung field and was not biased in intensity toward the upper or lower lung field. In addition, the serum white blood cell (WBC) counts and serum Krebs von den Lungen-6 (KL-6) levels differed significantly between the cases of early and delayed improvement of WALI.

Abstract Background Some patients with interstitial pneumonia with autoimmune features (IPAF) showed a progressive course despite therapy. This study aimed to evaluate whether serial changes in the serum levels of surfactant protein-A (SP-A) and Krebs von den Lungen-6 (KL-6) can predict disease progression. Methods Sixty-four patients with IPAF and 41 patients with non-fibrotic lung disease (non-FLD) were examined. Based on long-term changes in lung function, 36 IPAF patients who were followed up for more than 3 months were divided into a progressive group (n = 9), an improvement group (n = 13), and a stable group (n = 14). Serum KL-6 and SP-A levels were measured. The sensitivity, specificity, cut-off value, and area under the curve (AUC) value for each of the indices were determined using receiver operating characteristic (ROC) curve analysis. The expression differences in these biomarkers and their correlation with disease severity were analyzed. Results Compared with non-FLD patients, serum SP-A and KL-6 levels in IPAF patients were increased significantly [SP-A: (p

Abstract Objectives The purpose of this study was to evaluate the value of serum krebs von den lungen-6 (KL-6) level as a diagnostic indicator for connective tissue disease associated with interstitial lung disease (CTD-ILD). Methods One hundred fifty five patients with newly diagnosed CTD in our hospital were enrolled and divided into two groups by their ILD manifestations, the CTD-ILD group and the CTD group. In parallel, 61 patients with pulmonary infection and 60 cases of healthy subjects were also enrolled into the study. The difference of serum KL-6 level among the four groups were compared. In CTD-ILD group, carbon monoxide diffusing capacity (DLCo) and high-resolution computed tomography (HRCT) of lung were also tested. The serum KL-6 level of 32 patients from the CTD-ILD group who received cyclophosphamide (CTX) pulse therapy were sampled and measured, by enzyme linked immunosorbent assay (ELISA), at three time points: before treatment, 3 months after treatment and 6 months after treatment. Results The serum KL-6 level in the CTD-ILD group (1004.9 (676.41738.1) IU/ml) is significantly higher than three other groups (χ 2 = 72.29, P

Background: Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified., Aim: We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI., Methods: Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured., Results: Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane., Conclusions: Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI., (© 2024 Wiley Periodicals LLC.)

The SARS-CoV-2 (COVID-19) pandemic is a major issue that necessitates the use of cutting-edge disease prediction models. The aim of the study was to assess the existing evidence regarding association between Krebs von den Lungen-6 levels and COVID-19 severity. A literature search was performed on Web of Science, PubMed, Scopus and Cochrane Central Register of Controlled Trials databases from 1 January 2020 up to 2 August 2022. The electronic database search was supplemented by searching Google Scholar. In addition, reference lists of relative articles were also reviewed. KL-6 levels among COVID-19 positive vs. negative patients varied and amounted to 443.37 ± 249.33 vs. 205.73 ± 86.8 U/mL (MD = 275.33; 95%CI: 144.57 to 406.09; p < 0.001). The KL-6 level was 402.82 ± 261.16 U/mL in the severe group and was statistically significantly higher than in the non-severe group (297.38 ± 90.46 U/mL; MD = 192.45; 95%CI: 118.19 to 266.72; p < 0.001). The KL-6 level in the mild group was 272.28 ± 95.42 U/mL, compared to 268.04 ± 55.04 U/mL in the moderate COVID-19 group (MD = −12.58; 95%CI: −21.59 to −3.57; p = 0.006). Our meta-analysis indicates a significant association between increased KL-6 levels and SARS-CoV-2 infection. Moreover, KL-6 levels are significantly higher in patients with a more severe course of COVID-19, indicating that KL-6 may be a useful predictor to identify patients at risk for severe COVID-19.

Background: Krebs von den Lungen‐6 (KL‐6) is a high‐molecular‐weight (200kDa) glycoprotein proposed as a diagnostic biomarker for differentiating interstitial lung disease (ILD). Systemic sclerosis (SSc) is a rare immune‐mediated disorder, and ILD is the leading cause of morbidity and mortality. Pleuroparenchymal fibroelastosis (PPFE) has been described to have a poor prognosis in SSc‐ILD patients. This study undertook to compare serial changes in KL‐6 in SSc‐ILD patients with and without PPFE, to verify its prognostic value as a disease biomarker. Materials and Methods: Twenty‐five SSc‐ILD patients (median IQR, 62 (56‐58); 20% males) were retrospectively enrolled. 12 SSc‐ILD patients (48%) had also a radiological diagnosis of PPFE. Serum KL‐6 concentrations were measured by KL‐6 reagent assay (Fujirebio Europe, Ghent, Belgium). Results: Serum KL‐6 measurements were increased in SSc‐ILD patients with and without PPFE compared with healthy controls (P <.0001). Comparative analysis of the rate of variation of KL‐6 over the 6 years of follow‐up was performed by serial two‐yearly KL‐6 measurements: Δ1(t1‐t0), Δ2(t2‐t1) and Δ3(t3‐t2). In SSc‐ILD patients with PPFE pattern, Δ3 was significantly different than those without PPFE pattern (P =.0020). Serum KL‐6 levels were significantly different (P =.0455) either at Δ2 and Δ3 in the PPFE group. In SSc‐ILD patients with PPFE, at t3 serum KL‐6 concentrations were inversely correlated with FEV1 (r = −.76; P =.037) and FVC percentages (r = −.79; P =.028). Conclusion: These results suggest that serial measurements of KL‐6 in the follow‐up of these patients may help to monitor disease progression. In real life, in SSc‐ILD patients PPFE should be always evaluated at CT and when present should suggest a tight follow‐up to monitor its evolution. [ABSTRACT FROM AUTHOR]

Background: Clinical course of pleuroparenchymal fibroelastosis (PPFE) shows considerable variation among patients, but there is no established prognostic prediction model for PPFE.Methods: The prediction model was developed using retrospective data from two cohorts: our single-center cohort and a nationwide multicenter cohort involving 21 institutions. Cox regression analyses were used to identify prognostic factors. The total score was defined as the weighted sum of values for the selected variables. The performance of the prediction models was evaluated by Harrell's concordance index (C-index). We also examined the usefulness of the gender-age-physiology (GAP) model for predicting the prognosis of PPFE patients.Results: We examined 104 patients with PPFE (52 cases from each cohort). In a multivariate Cox analysis, a lower forced vital capacity (FVC [defined as FVC < 65%]; hazard ratio [HR], 2.23), a history of pneumothorax (HR, 3.27), the presence of a lower lobe interstitial lung disease (ILD) (HR, 2.31), and higher serum Krebs von den Lungen-6 (KL-6) levels (> 550 U/mL, HR, 2.56) were significantly associated with a poor prognosis. The total score was calculated as 1 × (FVC, < 65%) + 1 × (history of pneumothorax) + 1 × (presence of lower lobe ILD) + 1 × (KL-6, > 550 U/mL). PPFE patients were divided into three groups based on the prognostic score: stage I (0-1 points), stage II (2 points), and stage III (3-4 points). The survival rates were significantly different in each stage. The GAP stage was significantly associated with the prognosis of PPFE, but no difference was found between moderate (stage II) and severe (stage III) disease. Our new model for PPFE patients (PPFE Prognosis Score) showed better performance in the prediction of mortality in comparison to the GAP model (C-index of 0.713 vs. 0.649).Conclusions: Our new model for PPFE patients could be useful for predicting their prognosis. [ABSTRACT FROM AUTHOR]

COVID-19 encompasses a broad spectrum of clinical conditions caused by SARS-CoV-2 infection. More severe cases experience acute respiratory and/or multiorgan failure. KL-6 is a glycoprotein expressed mainly from type II alveolar cells with pro-fibrotic properties. Serum KL-6 concentrations have been found in patients with COVID-19. However, the relevance of KL-6 in patients with severe and critical COVID-19 has not been fully elucidated. Methods: Retrospective data from consecutive severe to critical COVID-19 patients were collected at UOC Clinica Pnuemologica “Vanvitelli”, A.O. dei Colli, Naples, Italy. The study included patients with a positive rhinopharyngeal swab for SARS-CoV-2 RNA with severe or critical COVID-19. Results: Among 87 patients, 24 had poor outcomes. The median KL-6 value in survivors was significantly lower when compared with dead or intubated patients (530 U/mL versus 1069 U/mL p < 0.001). KL-6 was correlated with body mass index (BMI) (r: 0.279, p: 0.009), lung ultrasound score (LUS) (r: 0.429, p < 0.001), Chung Score (r: 0.390, p < 0.001). KL-6 was associated with the risk of death or oro-tracheal intubation (IOT) after adjusting for gender, BMI, Charlson Index, Chung Score, and PaO2/FIO2 (OR 1.003 95% CI 1.001–1.004, p < 0.001). Serum KL-6 value of 968 has a sensitivity of 79.2%, specificity of 87.1%, PPV 70.4%, NPV 91.5%, AUC: O.85 for risk of death or IOT. Conclusions: The presented research highlights the relevance of serum KL-6 in severe to critical COVID-19 patients in predicting the risk of death or IOT.

Background: Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes.Methods: We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined.Results: Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO) < 55% predicted, were associated with increased risk of hepatic injury (adjusted hazard ratio [aHR] was 3.46; 95% CI 1.13-10.60; p = 0.029 for KL-6, and 6.05; 95% CI 1.89-19.32; p = 0.002 for DLCO). Both factors also predicted severe and recurrent hepatic injury. Patients with baseline KL-6 ≥ 2.5 ng/mL also had a higher risk of AE-IPF (aHR 4.52; 95% CI 1.63-12.55; p = 0.004). For on-treatment mortality, baseline KL-6 ≥ 3.5 ng/mL and SPA ≥ 600 pg/mL were significant predictors (aHR 5.39; 95% CI 1.16-24.97; p = 0.031 for KL-6, and aHR 12.28; 95% CI 2.06-73.05; p = 0.006 for SPA). Results from subdistribution hazard regression and sensitivity analyses supported these findings. Patients with elevated baseline plasma KL-6 levels also exhibited a trend towards faster pulmonary function decline.Conclusions: For patients with IPF who are receiving nintedanib, we have identified baseline predictors, in particular plasma KL-6 levels, for the risk of adverse outcomes. Patients with these predictors may require close monitoring for unfavourable responses during treatment. Our findings also support the prognostic role of molecular markers like KL-6 and may contribute to future formulation of more individualized therapeutic strategies for IPF. [ABSTRACT FROM AUTHOR]

• SerumKL-6 level was significantly high in severe COVID-19 patients. • Serum KL-6 correlated positively with CRP and negatively with lymphocytes count. • No significant elevation in serum Fn was detected in COVID-19 patients. • Incident rate of pulmonary fibrosis at discharge was high in severe COVID-19 cases. • High level of serum KL-6 in early stage of COVID-19 should be paid close attention. Coronavirus Disease 2019 (COVID-19) caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still spreading worldwide, which may progress to pulmonary fibrosis (PF), leading to the worsen outcome. As the markers of lung injury, the correlation of Krebs von den Lungen-6 (KL-6) and fibronectin (Fn) with pulmonary fibrosis in COVID-19 was still unclear. 113 patients diagnosed as COVID-19 were enrolled in this retrospective study, and divided into three categories as mild, moderate and severe cases. The concentrations of serum KL-6 and Fn at hospital admission were tested using the method of latex agglutination assay and immunoturbidimetic assay, respectively. Compared with that in the non-severe COVID-19 cases and normal control subjects, serum KL-6 concentration on admission was significantly higher in the severe group, which was positively correlated with C-reactive protein, and negatively correlated with lymphocytes count. Whereas, no obvious elevation in serum Fn concentration was investigated in COVID-19 patients with the different phenotypes. The severe cases displayed the higher incident rate of pulmonary fibrosis at hospital discharge. Compared with non-PF patients, the COVID-19 cases with PF had the higher serum KL-6 values. Serum KL-6 concentration was significantly elevated in severe COVID-19 patients, which may be useful for evaluating the disease severity. For early prevention of the development of pulmonary fibrosis, high concentrations of serum KL-6 in the early stage of COVID-19 should be paid close attention. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐17 plays critical roles in the pathogenesis of both psoriasis and interstitial pneumonia (IP). We hypothesized that anti‐IL‐17 biologics might suppress both clinically relevant and latent IP activity and decrease Krebs von den Lungen‐6 (KL‐6) level in psoriasis patients. We aimed to elucidate the effects of anti‐IL‐17 biologics on KL‐6 levels. We retrospectively analyzed the clinical data of psoriasis patients treated with anti‐IL‐17 biologics. KL‐6 levels were measured before treatment (baseline) and at 3 and 6 months after the initiation of the treatment, and ratios of KL‐6 levels at each time point to the baseline levels were calculated. Chest computed tomography (CT) was performed on patients with coexisting IP. The clinical characteristics and radiographic findings were evaluated. A total of 294 psoriasis patients were treated with anti‐IL‐17 biologics. Baseline KL‐6 levels were higher than 401 U/mL in 34 patients (high baseline KL‐6 group). While anti‐IL‐17 biologics did not affect KL‐6 levels and ratios of KL‐6 to the baseline levels at any time point in the overall study population, they decreased both KL‐6 levels and ratios at 6 months after the initiation of the treatment in the high baseline KL‐6 group. A total of 10 patients with coexisting IP showed decreasing ratios of KL‐6 to the baseline levels at 6 months without affecting coexisting IP in CT performed at 3–12 months. Anti‐IL‐17 biologics decreased KL‐6 levels in the high baseline KL‐6 group regardless of recognizable IP. A decrease in KL‐6 levels was not associated with a radiographic improvement of IP, which should be examined in large numbers with long‐term observations in future studies. [ABSTRACT FROM AUTHOR]

The clinical course of systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is highly variable and easily measurable biomarkers are needed to predict disease progression. Serum epithelial biomarker KL‐6 is predictive of disease progression measured by a decline in DLCO, regardless of ILD severity, and could provide increased prognostic ability to inform risk stratification in SSc‐ILD. See relatedEditorial Background and objective: The course of systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is highly variable, and accurate prognostic markers are needed. KL‐6 is a mucin‐like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21‐1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. Methods: Serum KL‐6 and CYFRA 21‐1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed‐effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. Results: In both cohorts, KL‐6 and CYFRA 21‐1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL‐6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc‐ILD, serum KL‐6, but not CYFRA 21‐1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL‐6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. Conclusion: Our results suggest serum KL‐6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc‐ILD. [ABSTRACT FROM AUTHOR]

During biologic treatments, attention should be paid to adverse reactions, particularly infectious diseases. Furthermore, drug‐induced interstitial lung disease is also known to be associated with biologic therapies. We retrospectively reviewed serum Krebs von den Lungen‐6 (KL‐6) levels in psoriatic patients who underwent treatment with seven different biologics. A total of 67 patients who received 80 biologic treatments were evaluated. The 31 anti‐tumor necrosis factor (TNF)‐α treatments consisted of 17 infliximab (IFX) and 14 adalimumab. The 23 anti‐interleukin (IL)‐23 treatments consisted of 14 ustekinumab and nine guselkumab. The 26 anti‐IL‐17 treatments consisted of nine secukinumab, six ixekizumab and 11 brodalumab. The IFX showed significantly increased mean serum KL‐6 (170.9%), but none of the other treatments showed significant increases. Thirteen of the 17 (75.6%) patients in the IFX and 17 of the 31 (54.8%) patients in the total anti‐TNF‐α group demonstrated at least a 25% increase in serum KL‐6. Levels exceeding the cut‐off (500 U/mL) were detected in three patients before treatment and in seven patients after treatment. This study showed that anti‐IL‐17 and anti‐IL‐23 treatments have no significant impact on serum KL‐6 level. In addition to the influence of IFX, a significantly large number of patients in the IFX group had a history of methotrexate administration associated with psoriatic arthritis, which might have influenced the KL‐6 level. None of the patients with elevated serum KL‐6 showed pulmonary changes by computed tomography and/or X ray. [ABSTRACT FROM AUTHOR]

Certain biomarkers predict death due to acute respiratory distress syndrome in COVID-19 patients. We retrospectively analyzed biomarkers associated with time to mechanical ventilation for respiratory failure due to COVID-19 (time-to-mechanical ventilation) in 135 consecutive patients in our hospital. We analyzed biomarkers that were elevated immediately (at admission) and later (3 days after admission) using Cox proportional hazards regression analysis. Independent biomarkers of time-to-mechanical ventilation were high C-reactive protein (CRP), interleukin (IL)-6, and Krebs von den Lungen-6 (KL-6) concentrations at admission and elevated CRP, high-mobility group box-1 protein (HMGB-1), and d-dimer levels and low platelets 3 days after admission. Receiver operating characteristic analysis for detecting the association between independent biomarkers associated with time-to-event in multivariate analyses and the start of mechanical ventilation revealed that these biomarkers had area under the curve values higher than 0.700. The present study suggests that CRP was the only biomarker associated with time-to-mechanical ventilation both at admission and 3 days after admission. Moreover, IL-6 (an inflammatory cytokine), HMGB-1 (a late inflammatory mediator), and KL-6 (reflecting injury and/or remodeling of type II pneumocytes) were associated with outcomes in COVID-19 as reported previously. In conclusion, increased CRP, IL-6, KL-6, HMGB-1, and d-dimer levels and decreased platelet counts were associated with the start of mechanical ventilation due to COVID-19.

Background: Little is known about the annual change in Krebs von Lungen-6 (KL-6) and its correlation with forced vital capacity (FVC) in limited cutaneous systemic sclerosis-associated interstitial lung disease (lcSSc-ILD). We aimed to clarify the correlation during the clinical course., Methods: We retrospectively reviewed data from consecutive patients with lcSSc-ILD. We measured FVC and KL-6 annually and calculated their annual changes using the difference in absolute values. Decline in FVC was defined as annual decline in FVC ≥5 %., Results: Thirty-eight patients with SSc-ILD were included. The median age was 62 years and 58 % were female. The median FVC was 87.3 % and the median KL-6 was 1629 U/ml. The median observation period was 55.2 months and the annual changes in FVC and KL-6 were evaluated 151 times simultaneously. The annual change in KL-6 had a significant negative correlation with that in FVC in the first year from the initial evaluation (from the baseline to one-year follow-up) (r = -0.819, p < 0.01), but not after the first year. In the multivariable analysis adjusted by age, sex, and FVC at each year, the annual change of KL-6 (per 100 U/ml) was significantly associated with decline in FVC in the first year (odds ratio: 3.03, 95 % confidence interval: 1.21-7.59, p = 0.02), but not after the first year., Conclusions: Only in the first year from the initial evaluation, there was negative correlation between the annual change in FVC and that in KL-6 and the annual elevation in KL-6 was associated with decline in FVC in patients with lcSSc-ILD., Competing Interests: Conflict of interest Yasuhiro Kondoh received Honoraria from Boehringer Ingelheim, Co., Ltd. and SEKISUI MEDICAL Co., Ltd. Reoto Takei, Yasuhiko Yamano, Kensuke Kataoka, Jun Fukihara, Hajime Sasano, Toshiki Yokoyama, Toshiaki Matsuda and Tomoki Kimura have no conflict of interest., (© 2023 Published by Elsevier B.V. on behalf of The Japanese Respiratory Society.)

Background: Immunosuppressive therapy still is the standard treatment for patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). Objectives: This retrospective study aimed to provide data on the tolerability and efficacy of azathioprine in progressive CTD-ILDs. Methods: A total of 56 patients with CTD-ILD treated with azathioprine between 2003 and 2014 were included in the study. The patients were assessed every 3 months during follow-up. Results: The mean treatment duration was 34 months, with a range of 3–105 months. Fifteen patients (27%) discontinued treatment due to side effects, mostly due to elevated liver enzymes, within the first 3 months. Forty-one patients were treated for longer than 3 months, and 27 of those (66%) had stabilization or improvement of pulmonary function during treatment. In patients who remained stable or improved, the mean FVC was 62 ± 17% predicted (% pred) at initiation of treatment and 65 ± 17% pred at the last follow-up visit (p = 0.036), and the mean DLCO was 38 ± 16% pred at initiation of treatment and 39 ± 17% pred at the last follow-up visit (p = 0.06). Conclusions: Azathioprine can stabilize or improve CTD-ILD. While early drug intolerance is frequent, most patients who have tolerated the drug well achieve long-term stabilization or improvement of lung function. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the value of serum krebs von den lungen-6 (KL-6) level as a diagnostic indicator for connective tissue disease associated with interstitial lung disease (CTD-ILD).Methods: One hundred fifty five patients with newly diagnosed CTD in our hospital were enrolled and divided into two groups by their ILD manifestations, the CTD-ILD group and the CTD group. In parallel, 61 patients with pulmonary infection and 60 cases of healthy subjects were also enrolled into the study. The difference of serum KL-6 level among the four groups were compared. In CTD-ILD group, carbon monoxide diffusing capacity (DLCo) and high-resolution computed tomography (HRCT) of lung were also tested. The serum KL-6 level of 32 patients from the CTD-ILD group who received cyclophosphamide (CTX) pulse therapy were sampled and measured, by enzyme linked immunosorbent assay (ELISA), at three time points: before treatment, 3 months after treatment and 6 months after treatment.Results: The serum KL-6 level in the CTD-ILD group (1004.9 (676.41738.1) IU/ml) is significantly higher than three other groups (χ2 = 72.29, P < 0.001). In the CTD-ILD group the level of serum KL-6 was positively correlated with disease severity on HRCT (r = 0.75, P <  0.001), while was negatively correlated with DLCo (r = - 0.50, P <  0.001). In 32 patients who received CTX pulse therapy, the level of serum KL-6 was gradually decreased in 20 cases whose lesions were absorbed within 6 months (F = 13.67, P <  0.001), whereas it remained unchanged in the rest of 12 patients (Z = -1.328, P = 0.198).Conclusions: Serum KL-6 level can potentially serve as a diagnostic marker for CTD-ILD and be utilized to evaluate the effectiveness of CTX pulse therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Asbestosis and silicosis are progressive pneumoconioses characterized by interstitial fibrosis following exposure to asbestos or silica dust. We evaluated the potential diagnostic biomarkers for these diseases. Methods The serum concentrations of Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), and matrix metalloproteinase-2 (MMP-2), MMP-7, and MMP-9 were measured in 43 patients with asbestosis, 45 patients with silicosis, 40 dust-exposed workers (DEWs) without pneumoconiosis, and 45 healthy controls (HCs). Chest high-resolution computed tomography (HRCT) images were reviewed by experts blinded to the clinical data. According to the receiver operating characteristic (ROC) curve, the ideal level of each biomarker and its diagnostic sensitivity were obtained. Results The serum KL-6 and MMP-2 concentrations were highest in patients with asbestosis, particularly in comparison with those in DEWs and HCs (P