Serum KL-6 Levels Research Articles

Expression and significance of serum KL-6 in patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a common and serious complication that occurs in the ICU. the determination of early ARDS indicators, along with timely treatment, can potentially diminish medical costs and reduce ARDS-related mortality. In this report, we evaluated the clinical significance of circulating Krebs von den Lungen-6 (KL-6) content among patients with intra- and extrapulmonary ARDS to investigate the clinical significance of serum KL-6. Patients who met the ARDS Berlin criteria and were hospitalized in the intensive care unit of the China-Japan Union Hospital of Jilin University between September 2021 and September 2022 were recruited for analysis. ARDS patients were divided into an intrapulmonary ARDS group (n=23) and an extrapulmonary ARDS group (n=27) based on their primary diagnosis. Baseline demographic data, including age and sex, and clinical data, including underlying diseases and mortality, of the two groups were collected and analyzed. Peripheral venous blood was collected on Day 0 (baseline), Day 1, Day 3, and Day 7. The kinetic levels of serum KL-6 were compared between patients who survived and those who died within one week of ARDS diagnosis. The prognosis, survival times, and status of patients within 28 days after diagnosis were evaluated. In the intrapulmonary ARDS group, patients who died had significantly higher serum KL-6 levels in the seven days following diagnosis than those who survived. In contrast, in the extrapulmonary group, the difference in KL-6 values between patients who survived and died was only significant on the first day after diagnosis. The peak levels of serum KL-6 in the death group were significantly higher than those in the survival group for both intra- and extrapulmonary ARDS (P=0.0253). The optimal cutoff value of the serum KL-6 level was 1,452.3 U/mL in intrapulmonary ARDS patients and 828.2 U/mL in extrapulmonary patients. Serum KL-6 levels higher than the cutoff levels were confirmed to be a significant prognostic predictor of poor survival within 28 days of diagnosis in patients with intra- and extrapulmonary ARDS. The serum KL-6 level is potentially a good indicator for predicting the prognosis of patients with ARDS.

Identifying the link between serum VEGF and KL-6 concentrations: a correlation analysis for idiopathic pulmonary fibrosis interstitial lung disease progression.

Idiopathic pulmonary fibrosis interstitial lung disease (IPF-ILD) is a progressive lung disease characterized by excessive collagen deposition and fibrotic changes in the lungs. Identifying reliable serum markers that correlate with disease progression is crucial for diagnosis and prognosis. This study aimed to explore the association between serum markers KL-6 and VEGF and IPF-ILD. Specifically, it assessed their correlation with PaO2, a measure of pulmonary gas function, to provide diagnostic and prognostic indicators. Patients with IPF-ILD were included, and their serum levels of KL-6 and VEGF were measured. Correlations with fibrotic damage and PaO2 were analyzed using statistical methods. The analysis confirmed a positive correlation between the serum marker KL-6 and the degree of fibrotic damage in IPF-ILD. On the other hand, the serum marker VEGF was found to promote disease progression. In terms of correlation with PaO2, both KL-6 and VEGF demonstrated high sensitivity and specificity. Specifically, the correlation between KL-6 and PaO2 suggests that it can be used as a reliable indicator to assess the status of pulmonary oxygenation function in patients with ILD. The correlation between VEGF and PaO2 helps to understand its role in the progression of IPF-ILD and provides an important basis for predicting patient prognosis. This study confirmed the correlation between KL-6 and VEGF with IPF-ILD and their association with PaO2. KL-6 and VEGF demonstrated high specificity and sensitivity in diagnosing, monitoring, and predicting prognosis in IPF-ILD. These findings contribute to our understanding of the disease and have clinical implications for diagnosis and prognostication.

Serum KL-6 as a Candidate Predictor of Outcome in Patients with SARS-CoV-2 Pneumonia.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-infection is associated with an extremely variable disease course. When interstitial pneumonia (IP) occurs, it can lead to acute respiratory distress syndrome and death. Serum Krebs von den Lungen-6 (KL-6) is an established marker of IP, but its role as a marker of SARS-CoV-2 pneumonia is debated. This bicentric study included 157 patients with SARS-CoV-2 pneumonia. The WHO Ordinal Scale for Clinical Improvement (0-10 points) was used to classify the clinical course. Serum samples were collected at admission, and on days 3 and 7 of hospitalization. KL-6 was measured by using automated chemiluminescence immunoassay. A total of 68 patients developed a severe SARS-CoV-2 pneumonia, 135 of them required oxygen, and 15 died during hospitalization. The patients requiring non-invasive ventilation, invasive ventilation, or extracorporeal membrane oxygenation had significantly higher serum KL-6 levels at admission. The serum KL-6 levels were tendentially higher in patients who died than in those who survived. Logistic regression identified serum KL-6 at a cut-off of 335 U/mL at admission as a significant predictor of severe SARS-CoV-2 pneumonia outcome. Serum KL-6 seems to be a candidate biomarker for the clinical routine to stratify patients with SARS-CoV-2 pneumonia for the risk of a severe disease outcome or death.

Serum KL-6 levels predict the occurrence and severity of treatment-related interstitial lung disease in lung cancer

In this study, we aimed to investigate the feasibility of serum Krebs von den Lungen-6 (KL-6) as a potential biomarker for treatment-related ILD (TR-ILD) in lung cancer. We recruited patients with lung cancer in whom KL-6 was measured to differentiate between pneumonia and ILD (category 1), diagnose and assess the severity of suspicious ILD (category 2), or evaluate baseline levels before cancer treatment (category 3). Among 1,297 patients who underwent KL-6 testing, 422 had lung cancer, and TR-ILD was detected in 195 patients. In categories 1–2, median KL-6 level was higher in drug-induced ILD or acute exacerbation of underlying ILD than in no ILD or radiation-induced pneumonitis, and it was correlated with the severity of TR-ILD. High KL-6 level (cut-off: > 436U/mL) was an independent risk factor for severe TR-ILD, and low KL-6 level with high procalcitonin level (> 0.5 ng/mL) could exclude severe TR-ILD. Patients with severe TR-ILD had worse overall survival than those without, whereas high baseline KL-6 level was associated with worse survival, especially in patients without severe TR-ILD. Therefore, serum KL-6 may be a surrogate marker for predicting the occurrence and assessing the severity of TR-ILD at the time of suspected ILD and before lung cancer treatment.

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.

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.

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)...

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.

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.

Increased KL-6 levels in moderate to severe COVID-19 infection.

The global coronavirus disease 2019 (COVID-19) has presented significant challenges and created concerns worldwide. Besides, patients who have experienced a SARS-CoV-2 infection could present post-viral complications that can ultimately lead to pulmonary fibrosis. Serum levels of Krebs von den Lungen 6 (KL-6), high molecular weight human MUC1 mucin, are increased in the most patients with various interstitial lung damage. Since its production is raised during epithelial damages, KL-6 could be a helpful non-invasive marker to monitor COVID-19 infection and predict post-infection sequelae. We retrospectively evaluated KL-6 levels of 222 COVID-19 infected patients and 70 healthy control. Serum KL-6, fibrinogen, lactate dehydrogenase (LDH), platelet-lymphocytes ratio (PLR) levels and other biological parameters were analyzed. This retrospective study also characterized the relationships between serum KL-6 levels and pulmonary function variables. Our results showed that serum KL-6 levels in COVID-19 patients were increased compared to healthy subjects (470 U/ml vs 254 U/ml, P <0.00001). ROC curve analysis enabled us to identify that KL-6 > 453.5 U/ml was associated with COVID-19 (AUC = 0.8415, P < 0.0001). KL-6 level was positively correlated with other indicators of disease severity such as fibrinogen level (r = 0.1475, P = 0.0287), LDH level (r = 0,31, P = 0,004) and PLR level (r = 0.23, P = 0.0005). However, KL-6 levels were not correlated with pulmonary function tests (r = 0.04, P = 0.69). KL-6 expression was correlated with several disease severity indicators. However, the association between mortality and long-term follow-up outcomes needs further investigation. More extensive trials are required to prove that KL-6 could be a marker of disease severity in COVID-19 infection.

Clinical clustering with prognostic implications in Japanese COVID-19 patients: report from Japan COVID-19 Task Force, a nation-wide consortium to investigate COVID-19 host genetics

BackgroundThe clinical course of coronavirus disease (COVID-19) is diverse, and the usefulness of phenotyping in predicting the severity or prognosis of the disease has been demonstrated overseas. This study aimed to investigate clinically meaningful phenotypes in Japanese COVID-19 patients using cluster analysis.MethodsFrom April 2020 to May 2021, data from inpatients aged ≥ 18 years diagnosed with COVID-19 and who agreed to participate in the study were collected. A total of 1322 Japanese patients were included. Hierarchical cluster analysis was performed using variables reported to be associated with COVID-19 severity or prognosis, namely, age, sex, obesity, smoking history, hypertension, diabetes mellitus, malignancy, chronic obstructive pulmonary disease, hyperuricemia, cardiovascular disease, chronic liver disease, and chronic kidney disease.ResultsParticipants were divided into four clusters: Cluster 1, young healthy (n = 266, 20.1%); Cluster 2, middle-aged (n = 245, 18.5%); Cluster 3, middle-aged obese (n = 435, 32.9%); and Cluster 4, elderly (n = 376, 28.4%). In Clusters 3 and 4, sore throat, dysosmia, and dysgeusia tended to be less frequent, while shortness of breath was more frequent. Serum lactate dehydrogenase, ferritin, KL-6, d-dimer, and C-reactive protein levels tended to be higher in Clusters 3 and 4. Although Cluster 3 had a similar age as Cluster 2, it tended to have poorer outcomes. Both Clusters 3 and 4 tended to exhibit higher rates of oxygen supplementation, intensive care unit admission, and mechanical ventilation, but the mortality rate tended to be lower in Cluster 3.ConclusionsWe have successfully performed the first phenotyping of COVID-19 patients in Japan, which is clinically useful in predicting important outcomes, despite the simplicity of the cluster analysis method that does not use complex variables.

Exploring the Association Between Air Pollutant Exposure and Krebs von den Lungen-6 (KL 6) Serum Levels in Outdoor and Indoor Workers in Banyumas District, Central Java

Introduction: Indonesia ranks 8th globally in the air pollution index, with poor air quality causing premature deaths from lung ailments such as interstitial lung diseases. Krebs von den Lungen-6 (KL 6) can be used to detect lung disease caused by air pollution. However, the number of studies investigating the link between air pollutant exposure and KL-6 levels is inadequate. The present study explores the association between air pollutant exposure and KL-6 levels in workers in different settings. Methods: This cross-sectional study recruited 70 individuals who were divided into two groups. Dust levels were measured using a particle counter as a proxy for air pollutant levels. KL-6 levels were measured with ELISA. The Spearman correlation test, Mann-Whitney test, and generalized linear model were used in statistical analyses. Results and Discussion: Air pollutant exposure differed significantly between outdoor and indoor settings (p = 0.000). A significant difference was found in KL-6 serum levels between outdoor and indoor workers (p = 0.000). Air pollutant levels were inversely associated with KL-6 serum levels in outdoor (r = -0.557, p &lt; 0.05) and indoor workers (r = -0.360, p &lt; 0.05). Working duration did not significantly correlate with KL-6 serum levels in either group. A tendency of linear association among air pollutant exposure, overall working duration, and KL-6 serum levels was found in the multivariable model. Conclusion: Work settings were associated with varying exposures to air pollutants and KL-6 serum levels. Higher exposure to pollutants may be associated with an increase in KL-6 serum levels.

YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis

YKL-40 (chitinase 3-like-1) and Krebs von den Lungen-6 (KL-6) are 2 promising biomarkers that may have an important role in the management of interstitial lung diseases (ILD). The aim of this study was to investigate the values of KL-6 and YKL-40 as biomarkers in the diagnosis and prognosis of patients with hypersensitivity pneumonitis (HP). A cross-sectional study conducted in 49 patients diagnosed with HP due to exposure to birds (n= 32) or fungi (n= 17), 48 patients with other ILD, and 67 healthy volunteers. Patients with HP were divided into fibrotic and nonfibrotic. Serum and sputum YKL-40 and KL-6 levels were determined using commercial enzyme-linked immunosorbent assay kits. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of both biomarkers for the diagnosis of HP. Pulmonary function tests were performed in patients during follow-up. KL-6 and YKL-40 levels were significantly higher in serum of patients with HP exposed to birds with a fibrotic pattern than in controls (P < .0001 and .0055, respectively). Serum KL-6 levels were also significantly higher in patients with fibrotic HP exposed to fungi compared with the control group (P= .0001). In patients with HP exposed to fungi, sputum KL-6 and YKL-40 levels were higher in those with a fibrotic pattern (P= .0289 and .016, respectively). ROC analysis showed that the range between 55-121 ng/mL for serum YKL-40 levels and 346-1441 U/mL for serum KL-6 levels had the best sensitivity and specificity for discriminating between patients with HP, healthy controls, and patients with idiopathic pulmonary fibrosis (IPF). In patients with HP, serum KL-6 levels correlated negatively with total lung capacity (r=-0.485; P= .0103) and diffusing capacity of the lungs for carbon monoxide (r=-0.534; P= .0002) at 12 months. Both KL-6 and YKL-40 proteins seem to be capable of distinguishing patients with HP from healthy individuals and from patients with IPF. Their sensitivity and specificity confirm their potential role as biomarkers. KL-6 may also be a predictor of disease progression.

Association of serum Krebs von den Lungen-6 and chest CT as potential prognostic factors in severe acute respiratory syndrome SARS-CoV-2: a preliminary experience

PurposeTo correlate in COVID-19 pneumonia CT-based semi-quantitative score of pulmonary involvement with high serum levels of KL-6, a biomarker of disease severity.MethodsBetween March 28 to May 21, 2020, 196 patients with strong suspicion of SARS-CoV-2 were evaluated with RT-PCR for SARS-CoV-2, chest CT scan and blood test, including KL-6 serum protein, in our Emergency Unit. The final population included only patients who underwent blood sampling for KL-6 within 5 days from CT scan (n = 63), including n = 37 COVID-19-positive patients and n = 26 with negative RT-PCR testing for SARS-CoV-2 (control group). A semi-quantitative CT score was calculated based on the extent of lobar involvement (0:0%; 1, < 5%; 2:5–25%; 3:26–50%; 4:51–75%; 5, > 75%; range 0–5; global score 0–25).ResultsCT score was significantly correlated with serum value of KL-6 (r = 27, p = 0.035). This correlation was also present in COVID-19 positive patients (r = 0.423, p = 0.009) and CT score median value was significantly higher in patients with high KL-6 value (> 400 U/mL; 12.00, IQR 5.00-18.00, p-value 0.027). In control group, no statistically significant correlation was found between CT score and KL-6 value and CT score was higher in patients with high KL-6, although this difference was not statistically significant (5.00, IQR:1.75–8.00 versus 3.50, IQR:2.00–6.50). "Crazy paving" at the right upper (n = 8; 61.5%) and middle lobe (n = 4; 30.8%) and "consolidation" at the middle lobe (n=5; 38.5%) were observed in COVID-19 group with a significant difference between patients with high KL-6 value.ConclusionCT score is highly correlated with KL-6 value in COVID-19 patients and might be beneficial to speed-up diagnostic workflow in symptomatic cases.

Pirfenidone inhibits cell fibrosis in connective tissue disease-associated interstitial lung disease by targeting the TNF-α/STAT3/KL6 pathway.

BackgroundTo explore the effect and mechanism of pirfenidone in inhibiting pulmonary fibrosis in connective tissue disease-associated interstitial lung disease (CTD-ILD).MethodsFrom 2018 to 2020, 50 CTD-ILD patients were enrolled in the clinical study. Based on whether pirfenidone was used during treatment, patients were enrolled into the pirfenidone group and the control group. Pulmonary function tests were compared before and after treatment. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression of tumor necrosis factor-α (TNF-α), signal transducer and activator of transcription 3 (STAT3), and Krebs Von den Lungen-6 (KL-6) in venous blood before and after treatment. Rat type II (RLE-6TN) lung epithelial cells were cultivated for in vitro experiments, and they were sorted into the control group, bleomycin group, pirfenidone group, TNF-α group, Stattic group, and TNF-α/Stattic combined treatment group. For the in vitro experiments, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to evaluate cell proliferation, Reverse Transcription-Polymerase Chain Reaction(RT–PCR) was performed to detect STAT3 and KL-6 mRNA expression levels, ELISA was utilized to detect TNF-α and E-cadherin expression levels, and Western blotting (WB) was performed to determine α-smooth muscle actin (α-SMA), vimentin, TNF-α, STAT3, phosphorylated signal transducer and activator of transcription 3 (PSTAT3) and KL-6 expression.ResultsIn the clinical study, the pulmonary function indices including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF) and partial pressure (PaO2) of the patients in the study group were superior to those in the control group (P<0.05). The serum TNF-α, STAT3 and KL-6 levels in the study group were significantly lower than those in the control group (P<0.05). In the in vitro experiments, the α-SMA, vimentin, STAT3 and KL-6 levels in the treatment group were significantly lower than those in the bleomycin group (P<0.05). Compared with those in the pirfenidone group, the α-SMA, vimentin, STAT3 and KL-6 levels in the TNF-α-treated group were significantly upregulated (P<0.05). Meanwhile, cell viability was further upregulated (P<0.05), and the expression of STAT3 and KL-6 was further decreased in the Stattic-treated group (P<0.05). In the group treated with infliximab combined with Stattic, TNF-α expression was significantly increased (P<0.05), cell activity was significantly restored (P<0.05), and the STAT3, KL-6 and E-cadherin expression levels were inhibited (P<0.05).ConclusionsPirfenidone improved pulmonary function 1 and decreased TNF-α, STAT3, and KL-6 expression in CTD-ILD patients. Moreover, pirfenidone inhibits cell fibrosis through the TNF-α/STAT3/Mucin 1(MUC1) pathway.

Krebs von den Lungen-6 (KL-6), soluble programmed cell death-1 (sPD-1) and its ligand-1(sPDL-1) in systemic sclerosis patients: Relation to disease parameters

Aim of the workThis study aimed to assess the levels of Krebs von den Lungen-6 (KL-6), soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1(sPDL-1) in systemic sclerosis (SSc) patients, and to evaluate their relation with disease parameters. Patients and methodsForty-six SSc patients (31 limited, 15 diffuse) and 43 matched controls were included. Serum levels of KL-6, sPD-1, and sPDL-1 were assessed by enzyme-linked immune-sorbent assay (ELISA). ResultsPatients mean age was 40.2 ± 12.2 years, disease duration 8.04 ± 6.02 years and females: male was 10.5:1. Levels of KL-6, sPD-1, and sPDL-1 were significantly higher in SSc patients compared to the controls 22.4(14.1–637.6) vs. 14.8(8.9–182.3) (p < 0.001), 3.1(1.8–64.2) vs. 1.2(0.68–14.4) (p < 0.001), and 2.8(1.5–84.4) vs. 1.4(0.92–36.4) (p < 0.001) respectively. KL-6 and sPD-1 levels were significantly lower in diffuse SSc subtype than the limited subtype 20.7(14.1–637.6) vs. 24.5(16.2–328.8) (p = 0.01), and 2.5(1.8–64.2) vs. 3.2(2.1–63.4) (p = 0.03) respectively. KL-6 was significantly decreased in SSc patients who developed pulmonary hypertension compared to those without 20.9(14.1–36.3) vs. 27.5(16.5–637.6) (p = 0.02), and in those who received cyclophosphamide 21(14.1–310.9 vs. 31.6(16.2–637.6) (p = 0.019). The three markers were significantly correlated. KL-6 levels with sPD-1 (r = 0.79, p < 0.001) and sPDL-1 (r = 0.79, p < 0.001) and between sPD-1 and sPDL-1 (r = 0.82, p < 0.001) respectively. Both sPD-1 and sPDL-1 significantly correlated with age (r = 0.29, p = 0.048 and r = 0.34, p = 0.021 respectively). ConclusionsKL-6, sPD-1, and sPDL-1 may be considered as potential biomarkers in the diagnosis and assessment of SSc patients. Significantly lower levels of KL-6 were detected in diffuse SSc patients, those with pulmonary hypertension, and patients who received cyclophosphamide.