KL-6 Levels Research Articles

Exogenous Apelin-13 Administration Ameliorates Cyclophosphamide- Induced Oxidative Stress, Inflammation, and Apoptosis in Rat Lungs.

Apelin-13 is an endogenous adipocytokine known for its antioxidant, antiinflammatory, and antiapoptotic properties. We aimed to investigate the possible protective effects of exogenous Apelin-13 administration on oxidative stress, inflammation, and apoptosis induced by the cytotoxic agent cyclophosphamide (CP) in the lungs. Twenty-four male Wistar albino rats were divided into four groups: Control (saline), CP (200 mg/kg), Apelin-13 (10 μg/kg/day), and CP+Apelin-13. CP was administered as a single dose on the fifth day, and apelin-13 was administered intraperitoneally for five days. Total oxidant status (TOS), total antioxidant status (TAS), and lipid peroxidation were determined with spectrophotometry, TNFα and IL1β were determined with ELISA, APJ, Sirt1, NF-κB, and p53 mRNA expressions were determined with qRT-PCR, cytochrome (Cyt) C and caspase-3 protein expressions were studied with western blotting in lung tissues. The oxidative stress index (OSI) was also calculated. Furthermore, serum surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6) levels were measured with ELISA. Compared to the control group, TOS, OSI, lipid peroxidation, TNFα, IL1β, cyt C, caspase-3, APJ, NF-κB, and p53 were higher, and Sirt1 was lower in the lung tissue of rats in the CP group. Serum KL-6 and SP-D levels were higher in the CP group. Co-administration of CP with Apelin-13 completely reversed the changes induced by CP administration. Exogenous Apelin-13 treatment protected lung tissue against injury by inhibiting cyclophosphamide-induced oxidative stress, inflammation, and apoptosis. This protective effect of apelin-13 was accompanied by upregulation of the Sirt1 and downregulation of NF-κB/p53 in the lungs.

Prognostic Value of Serum Biomarkers in Patients with Idiopathic Pulmonary Fibrosis in Relation to Disease Progression.

The aim of this present study was to determine serum biomarker levels and their correlation with respiratory function and the clinical course of patients with idiopathic pulmonary fibrosis (IPF). This study included 72 IPF patients, according to the ATS/ERS criteria, in whom antifibrotic treatment was initiated. Blood samples were taken, and serum biomarkers, such as KL-6, SP-D, CCL18, CXCL13, VEGF-A, IL-8, IGFBP-1, IGFBP-2, IGFBP-7 and ICAM-1 were measured using ELISA methodology. Pulmonary function tests (FVC, TLC, DLCO-% pred) were determined at baseline and after 12 and 24 months and analyzed in correlation with the biomarkers. The majority of patients (mean age 72 ± 6 years) were men (83%). The FVC and DLCO values at the 12-month follow-up were found to be statistically decreased in deceased patients (p < 0.05). The SP-D (p < 0.001) and the IGFBP-1 (p = 0.021) levels were found to be increased at the 1-year follow-up in deceased patients, and similarly, the SP-D (p = 0.005) and ICAM-1 (p = 0.043) levels at the 2-year follow-up. A chi-square test revealed that 70% of the category IV GAP index was found with cut-off elevated levels of a biomarker combination (KL-6, SP-D, VEGF-A) from the ROC curve analysis (p < 0.05). This study provides evidence, for the first time in a Greek population, of the possibility of using a combination of KL-6, SP-D, and VEGF-A serum levels along with the GAP index.

Krebs von den Lungen-6 as a Potential Predictive Biomarker in Fibrosing Interstitial Lung Diseases

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.

Diagnostic value of pleural effusion Krebs von den Lungen-6 in malignant pleural effusion of patients with non-small cell lung cancer.

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). 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. 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%. 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.

Anti-parietal cell antibodies as a potential biomarker for interstitial lung disease associated with primary Sjögren's syndrome

BackgroundILD is a common manifestation in pSS and is associated with an increased risk of death. APCA are strongly expressed by hyperplastic alveolar epithelial cells in the fibrotic lung and are associated with an accelerated decline in lung function in IPF. In the present study, we aimed to evaluate the clinical utility of APCA in ILD patients with pSS. MethodsClinical, laboratory, PFTs and imaging data from pSS patients were reviewed, and the ESSDAI was utilized to evaluate disease activity. HRCT semiquantitative scoring was conducted. We compared the clinical characteristics of pSS patients with and without ILD and carried out logistic regression analysis of risk factors for ILD in pSS. ResultsA total of 74 patients with pSS and 40 HCs were included in the study. ILD was more commonly observed in the APCA-positive group than in the APCA-negative group. The quantitative levels of APCA were positively correlated with the imaging score. Multivariate analysis found that the long disease duration, elevated APCA and elevated KL-6 level were independent risk factors for ILD in pSS patients. The area under ROC curve for APCA was 0.6618, and the threshold concentration was 153.82ng/ml (sensitivity 45.24%, specificity 87.50%). ConclusionAPCA level is an independent risk factor and might be a potential biomarker for ILD in patients with pSS.

Evaluation of the Clinical Value of KL-6 and Tumor Markers in Primary Sjögren's Syndrome Complicated with Interstitial Lung Disease.

primary Sjögren's syndrome (pSS) is an autoimmune disease, of which the most common complication is interstitial lung disease (ILD). This study aimed to analyze the clinical value of Krebs von den Lungen-6 (KL-6), carcinoembryonic antigen (CEA), and carbohydrate antigen 153(CA153) in patients with pSS complicated with ILD (pSS-ILD), given that only few studies have evaluated this. This is a cross-sectional study. Serum KL-6 levels (U/mL) were measured using chemiluminescence immunoassay, and concentrations of serum tumor markers were determined using the immunofluorescence method in 64 cases of pSS-ILD (pSS-ILD group), 23 cases without ILD (non-ILD group), and 45 healthy controls. The correlation between KL-6 and tumor markers as well as lung function was analyzed, and the factors that were associated with pSS-ILD were screened. The serum KL-6 was more abnormally increased in patients with pSS-ILD, and the serum KL-6, CEA, carbohydrate antigen 125 (CA125), and CA153 levels were significantly higher in the pSS-ILD group than in the non-ILD and healthy control groups (p < 0.05). KL-6, CEA, and CA153 were negatively correlated with forced vital capacity (FVC%), forced expiratory volume in 1 s (FEV1%), total lung capacity (TLC%), and diffusing capacity for carbon monoxide (DLCO%) (all p < 0.05). Multivariate logistic analysis showed that KL-6 was an independent factor associated with pSS-ILD. In conclusion, we evaluated the association between clinical values of KL-6, tumor markers, and pSS-ILD, and found that KL-6 and tumor markers such as CEA, CA153, and CA125 in patients with pSS-ILD were higher than in patients with non-ILD, and KL-6 was more abnormally increased and significantly associated with ILD development in patients with pSS.

Performance of serum biomarkers reflective of different pathogenic processes in systemic sclerosis-associated interstitial lung disease.

Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. Serum levels of KL-6 [MD 35.67 (95% CI 22.44-48.89, P < 0.01)], SP-D [81.13 (28.46-133.79, P < 0.01)], CCL18 [17.07 (6.36-27.77, P < 0.01)], YKL-40 [22.81 (7.19-38.44, P < 0.01)] and MMP-7 [2.84 (0.88-4.80, P < 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53-1.00, P'<0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01-1.61, P'=0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52-9.03, P < 0.01)] or SP-D [OR 2.00 (1.06-3.78, P = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665-1.554, P < 0.01)] showed improved performance compared with KL-6 and SP-D alone. All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression.

Usefulness and performance evaluation of serum KL-6 and SP-A assays in healthy individuals and patients with interstitial lung disease

BackgroundInterstitial lung abnormalities (ILAs) are associated with the risk of progression to interstitial lung diseases (ILDs). Krebs von den Lungen 6 (KL-6) and surfactant protein (SP)-A have been used as biomarkers of ILDs. In this study, we evaluated the levels of these biomarkers and identified their clinical correlations in healthy individuals to assess their usefulness in the diagnosis of ILAs. MethodsThe patient samples were categorized into three groups: healthy, disease, and ILD groups. We used the automated immunoassay HISCL KL-6 and SP-A assay kits. The analytical performance evaluation involved precision, linearity, comparison, establishment of reference intervals, and determination of the cutoff points. We also analyzed the correlations between presence of abnormalities on chest radiography and computed tomography (CT) or pulmonary function test (PFT) and serum levels in the healthy group. ResultsKL-6 and SP-A assays showed good analytical performance. The KL-6 and SP-A cutoff values were 304 U/mL and 43.5 ng/mL between the ILD and healthy groups, respectively, which were lower than the values recommended by the manufacturer. In the clinical correlations with radiological findings, SP-A values in subjects with lung abnormalities on CT scans were significantly higher than those in normal scans. There was no significant difference in KL-6 and SP-A levels among PFT patterns; however, both serum levels in the mixed pattern showed higher values than those in the other patterns. ConclusionsThe results revealed a positive association between increased serum levels of SP-A and KL-6 and clinical characteristics as incidental findings on chest imaging and reduced lung function.

KL-6 levels in the connective tissue disease population: typical values and potential confounders-a retrospective, real-world study.

Krebs von den Lungen 6 (KL-6) is a potential biomarker for determining the severity of interstitial lung disease (ILD) in patients with connective tissue disease (CTD). Whether KL-6 levels can be affected by potential confounders such as underlying CTD patterns, patient-associated demographics, and comorbidities needs further investigation. From the database created by Xiangya Hospital, 524 patients with CTD, with or without ILD, were recruited for this retrospective analysis. Recorded data included demographic information, comorbidities, inflammatory biomarkers, autoimmune antibodies, and the KL-6 level at admission. Results of CT and pulmonary function tests were collected one week before or after KL-6 measurements. The percent of predicted diffusing capacity of the lung for carbon monoxide (DLCO%) and computed tomography (CT) scans were used to determine the severity of ILD. Univariate linear regression analysis showed that BMI, lung cancer, TB, lung infections, underlying CTD type, white blood cell (WBC) counts, neutrophil (Neu) counts, and hemoglobin (Hb) were related to KL-6 levels. Multiple linear regression confirmed that Hb and lung infections could affect KL-6 levels independently; the β were 9.64 and 315.93, and the P values were 0.015 and 0.039, respectively. CTD-ILD patients had higher levels of KL-6 (864.9 vs 463.9, P < 0.001) than those without ILD. KL-6 levels were closely correlated to the severity of ILD assessed both by CT and DLCO%. Additionally, we found that KL-6 level was an independent predictive factor for the presence of ILD and further constructed a decision tree model to rapidly determine the risk of developing ILD among CTD patients. KL-6 is a potential biomarker for gauging the incidence and severity of ILD in CTD patients. To use this typical value of KL-6, however, doctors should take Hb and the presence of lung infections into account.

Serum KL-6 levels predict clinical outcomes and are associated with MUC1 polymorphism in Japanese patients with COVID-19

BackgroundKrebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037)...

Correlation between CT Score and KL-6: A Severity Assessing in Juvenile Dermatomyositis Associated Interstitial Lung Disease.

There is no radiological measurement to estimate the severity of pediatrics juvenile dermatomyositis (JDM) with interstitial lung disease (ILD). We validated the effectiveness of CT scoring assessment in JDM patients with ILD. To establish a CT scoring system and calculate CT scores in JDM patients with ILD and to determine its reliability and the correlation with Krebs von den Lungen-6 (KL-6). The study totally enrolled 46 JDM-ILD patients and 16 JDM without ILD (non-ILD, NILD) patients. The chest CT images (7.0 ± 3.6 years; 32 male and 30 female) were all analyzed. CT scores of six lung zones were retrospectively calculated, included image pattern score and distribution range score. Image pattern score was defined as follows: increased broncho-vascular bundle (1 point); ground glass opacity (GGO) (2 points); consolidation (3 points); GGO with bronchiectasis (4 points); consolidation with bronchiectasis (5 points); and honeycomb lung (6 points). Distribution range score was defined as no infiltrate (0 point); <30% (1 point); 30%-60% (2 points); and ≥60% (3 points). Two pediatric radiologists reviewed all CT images independently. The ROC curve was established, and the optimal cutoff score for severity discrimination was set. The agreement between two observers was excellent, and the ICC was 0.930 (95% CI 0.882-0.959, p < 0.01). CT score and KL-6 level had a positive linear correlation (r = 0.784, p < 0.01). However, the correlation between CT scores of different lung zone and KL-6 level was different. The KL-6 cut off level suggested for JDM with ILD was 209.0 U/ml, with 73.9% sensitivity and 87.5% specificity, and the area under curve was (AUC) 0.864 (p < 0.01). The CT scoring system we established, as a semiquantitative method, can effectively evaluate ILD in JDM-PM patients and provide reliable evidence for treatment.

Inflammation Related to Association of Low Uric Acid and Progression to Severe Disease in Patients Hospitalized for Non-Severe Coronavirus Disease 2019

Uric acid has antioxidant properties. To examine whether a low uric acid level is associated with severe coronavirus disease 2019 (COVID-19) progression via inflammation, alveolar damage, and/or coagulation abnormality, a retrospective observational study of 488 patients with non-severe COVID-19 and serum uric acid level ≤7 mg/dL at admission was conducted. Serum C-reactive protein (CRP), serum Krebs von den Lungen 6 (KL-6), and plasma D-dimer levels were also measured as markers of inflammation, alveolar damage, and coagulation abnormality, respectively. Median values for uric acid, CRP, KL-6, and D-dimer at admission were 4.4 mg/dL, 3.33 mg/dL, 252.0 U/mL, and 0.8 µg/mL, respectively. Among the total cohort, 95 (19.5%) progressed to severe COVID-19 with a median (interquartile range) time of 7 (4-14) days. Multivariable Cox proportional hazards regression analysis showed that low uric acid level was associated with a higher rate of severe COVID-19 progression. However, uric acid level was inversely associated with CRP level, and the association between the level of uric acid and severe COVID-19 progression was significantly different with and without CRP level inclusion. In contrast, no such association was found for KL-6 or D-dimer level. Low uric acid may contribute to severe COVID-19 progression via increased inflammation in subjects without hyperuricemia.

Biomarker Profiles Associated with COVID-19 Severity and Mortality.

The aim of this study was to analyze biomarkers that might predict the severity and progression of the SARS-CoV-2 infection, both in the acute phase and after recovery. Unvaccinated patients infected with the original strain of COVID-19 requiring ward (Group 1, n = 48) or ICU (Group 2, n = 41) admission were included. At the time of admission (visit 1), a clinical history was acquired, and blood samples were obtained. One and six months after discharge from the hospital (visits 2 and 3, respectively), a clinical history, lung function tests, and blood samples were carried out. At visit 2, patients also underwent a chest CT scan. Different cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, G-CSF, GM-CSF, IFN-ɣ, MCP-1, MIP-1β, and TNF-α) and lung fibrosis biomarkers (YKL-40 and KL-6) were measured in blood samples obtained at visits 1, 2, and 3. At visit 1, IL-4, IL-5, and IL-6 levels were higher in Group 2 (p = 0.039, 0.011, and 0.045, respectively), and IL-17 and IL-8 levels were higher in Group 1 (p = 0.026 and 0.001, respectively). The number of patients in Groups 1 and 2 who died during hospitalization was 8 and 11, respectively. YKL-40 and KL-6 levels were higher in patients who died. Serum YKL-40 and KL-6 levels determined at visit 2 correlated negatively with FVC (p = 0.022 and p = 0.024, respectively) and FEV1 (p = 0.012 and p = 0.032, respectively) measured at visit 3. KL-6 levels also correlated negatively with the diffusing capacity of the lungs for carbon monoxide (DLCO, p = 0.001). Patients who required ICU admission had higher levels of Th2 cytokines, while patients admitted to the ward showed an innate immune response activation, with IL-8 release and Th1/Th17 lymphocyte contribution. Increased levels of YKL-40 and KL-6 were associated with mortality in COVID-19 patients.

Change in Serum KL-6 Level during Biologic Treatment for Psoriasis.

We previously analyzed data from blood examination screenings, including serum Krebs von den Lungen (KL) -6 level, before starting biologic treatment for psoriasis in a real-world setting. However, we did not follow change in KL-6 level after the initiation of biologics. Furthermore, there has been no follow-up study of certolizumab pegol, risankizumab, or tildrakizumab. This study evaluated change in serum KL-6 levels in patients during treatment with biologics, including certolizumab pegol, risankizumab, and tildrakizumab. We analyzed data from 111 patients. Change in KL-6 level was regarded as significant if it increased to greater than 500 U/mL at least once and if the maximum level after treatment with biologics was at least 1.5 times that of the baseline level. KL-6 level significantly changed during treatment with TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors in 9 (20.9%), 2 (6.3%), and 2 (5.6%) patients, respectively. Mean age, mean baseline KL-6 level, and frequency of TNF inhibitor use were higher in patients with a significant change in KL-6 level than those in patients without a significant change. Ten patients had minor interstitial changes on chest CT scans but no clinical signs suggesting interstitial pneumonia. Older patients with psoriasis and high baseline KL-6 levels must be carefully monitored during treatment with biologics, especially TNF inhibitors. Monitoring of KL-6 level and chest CT scans is necessary to exclude the possibility of drug-induced interstitial pneumonia.

Understanding the Utilization of the Krebs von den Lungen 6 Test in a Clinical Laboratory.

We aimed to investigate Krebs von den Lungen 6 (KL-6) assay results in a clinical laboratory to better understand patient population and test utilization. We investigated serum KL-6 test results in Korean adults by the type of medical institution visited between October 2019 and December 2021. Overall, 7,677 KL-6 tests were performed in 5,527 Korean adults (3,627 men and 1,900 women) with a median age of 68.3 years (interquartile range 59.6 - 75.8). The median KL-6 level in 507 patients who visited health promotion centers was lower than the other 5,020 patients who visited other types of medical institutions (196 U/mL vs. 588.0 U/mL, respectively, p < 0.05). Increased KL-6 levels (≥ 500 U/mL) were observed in 0.8% of patients who visited health promotion centers and in 57.1% of patients who visited other types of medical institutions. This study will help to understand patient populations and test utilization for KL-6 in clinical laboratories in Korea.

Serum Krebs von den Lungen-6 for Predicting the Severity of COVID-19: A Systematic Review, Meta-Analysis, and Trial Sequence Analysis.

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. 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. 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. 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. 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.

Serum Krebs von den Lungen-6: promising biomarker to differentiate CPFE from IPF.

Background Combined pulmonary fibrosis and emphysema (CPFE) has been recognised as a phenotype of pulmonary fibrosis. We aimed to compare serum surfactant protein-A (SP-A), surfactant protein-D (SP-D) and Krebs von den Lungen-6 (KL-6) levels, functional parameters, in CPFE and IPF (idiopathic pulmonary fibrosis) patients. Methods Patients diagnosed with 'CPFE' and 'IPF' were consecutively included in 6 months as two groups. The patients with connective tissue diseases are excluded. Results In this study, 47 patients (41 males, 6 females) with CPFE (n = 21) and IPF (n = 26) with a mean age of 70.12 ± 8.75 were evaluated. CPFE patients were older, had more intense smoking history, had lower DLCO/VA, lower FVC, and worse six-minute walking distance than the IPF group (p=0.005, p=0.027, p=0.02, p<0.001, p=0.001, respectively). Serum KL-6 levels were higher in CPFE group compared to IPF group [264.70 U/ml (228.90-786) vs 233.60 (101.8-425.4), p<0.001]. Serum KL-6 levels of 245.4 U/ml and higher have 81% sensitivity and 73% specificity for the discrimination of CPFE from IPF. Conclusions Our study has shown that serum KL-6 level is a promising biomarker to differentiate CPFE from IPF. In CPFE cases respiratory and functional parameters are worse than those of pure fibrosis cases.

Serum B-cell activating factor and lung ultrasound B-lines in connective tissue disease related interstitial lung disease.

To investigate the role of serum B-cell activating factor (BAFF) and lung ultrasound (LUS) B-lines in connective tissue disease related interstitial lung disease (CTD-ILD), and their association with different ILD patterns on high resolution computed tomography (HRCT) of chest. We measured the levels of BAFF and KL-6 by ELISA in the sera of 63 CTD-ILD patients [26 with fibrotic ILD (F-ILD), 37 with non-fibrotic ILD (NF-ILD)], 30 CTD patients without ILD, and 26 healthy controls. All patients underwent chest HRCT and LUS examination. Serum BAFF levels were significantly higher in CTD patients compared to healthy subjects (617.6 ± 288.1 pg/ml vs. 269.0 ± 60.4 pg/ml, p < 0.01). BAFF concentrations were significantly different between ILD group and non-ILD group (698.3 ± 627.4 pg/ml vs. 448.3 ± 188.6 pg/ml, p < 0.01). In patients with ILD, BAFF concentrations were significantly correlated with B-lines number (r = 0.37, 95% CI 0.13-0.56, p < 0.01), KL-6 level (r = 0.26, 95% CI 0.01-0.48, p < 0.05), and Warrick score (r = 0.33, 95% CI 0.09-0.53, p < 0.01), although all correlations were only low to moderate. B-lines number correlated with Warrick score (r = 0.65, 95% CI 0.48-0.78, p < 0.01), and KL-6 levels (r = 0.43, 95% CI 0.21-0.61, p < 0.01). Patients with F-ILD had higher serum BAFF concentrations (957.5 ± 811.0 pg/ml vs. 516.1 ± 357.5 pg/ml, p < 0.05), KL-6 levels (750.7 ± 759.0 U/ml vs. 432.5 ± 277.5 U/ml, p < 0.05), B-lines numbers (174.1 ± 82 vs. 52.3 ± 57.5, p < 0.01), and Warrick score (19.9 ± 4.6 vs. 13.6 ± 3.4, p < 0.01) vs. NF-ILD patients. The best cut-off values to separate F-ILD from NF-ILD using ROC curves were 408 pg/ml for BAFF (AUC = 0.73, p < 0.01), 367 U/ml for KL-6 (AUC = 0.72, p < 0.05), 122 for B-lines number (AUC = 0.89, p < 0.01), and 14 for Warrick score (AUC = 0.87, p < 0.01) respectively. Serum BAFF levels and LUS B-lines number could be useful supportive biomarkers for detecting and evaluating the severity and/or subsets of CTD-ILD. If corroborated, combining imaging, serological, and sonographic biomarkers might be beneficial and comprehensive in management of CTD-ILD.

Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis

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. 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. 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). 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.

Krebs von den lungen-6 as a clinical marker for hypersensitivity pneumonitis: A meta-analysis and bioinformatics analysis.

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. 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. 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. 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. https://www.crd.york.ac.uk/prospero/, CRD42022355334.