Search

This article comprehensively elucidates the discovery of Krebs von den Lungen-6 (KL-6), its structural features, functional mechanisms, and the current research status in various respiratory system diseases. Discovered in 1985, KL-6 was initially considered a tumor marker, but its elevated levels in interstitial lung disease (ILD) led to its recognition as a relevant serum marker for ILD. KL-6 is primarily produced by type 2 alveolar epithelial cell regeneration. Over the past 30 years since the discovery of KL-6, the number of related research papers has steadily increased annually. Following the coronavirus disease 2019 (COVID-19) pandemic, there has been a sudden surge in relevant literature. Despite KL-6's potential as a biomarker, its value in the diagnosis, treatment, and prognosis varies across different respiratory diseases, including ILD, idiopathic pulmonary fibrosis (IPF), COVID-19, and lung cancer. Therefore, as an important serum biomarker in respiratory system diseases, the value of KL-6 still requires further investigation. [ABSTRACT FROM AUTHOR]

Li Zuo,1,* Wenhui Zhang,2,* Ying Wang,3 Xin Qi1 1Department of Pulmonary and Critical Care Medicine, China Aerospace Science & Industry Corporation 731 Hospital, Beijing, 100074, People’s Republic of China; 2General Practice Clinic, Sijiqing Town Community Health Service Center of Haidian District, Beijing, 100097, People’s Republic of China; 3Department of Pharmacy, Wangtai Branch of Jincheng General Hospital, Jincheng, 048006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin Qi, Department of pulmonary and critical care medicine, China Aerospace Science & Industry Corporation 731 Hospital, No. 3, Zhen Gang Nan Li, Feng Tai District, Beijing, 100074, People’s Republic of China, Email xinqixq015@163.comObjective: To explore serum KL-6 level and investigate its diagnostic value in interstitial lung diseases (ILDs).Methods: Serum KL-6 level was measured using the chemiluminescent enzyme immunoassay. Statistical analysis was performed for determining the KL-6 concentration of each group.Results: KL-6 level (U/mL) in the ILD group was 1388.321 ± 1943.116, which was higher than that in the control group, showing a significant statistical difference. ROC curve analysis based on the receiver operating characteristic curve showed the optimal cut-off value of 402.5U/mL, sensitivity of 77.4%, specificity of 93.4%, and accuracy of 89.4%; through Chi-square test with the two groups, the positive rate of KL-6 in patients with ILD was proved to be significantly higher than that in the control group. KL-6 level was 1063.00± 504.757 in the idiopathic pulmonary fibrosis (IPF) group, 1346.892 ± 1827.252 in the connective tissue disease-associated interstitial lung disease (CTD-ILD) group, 467.889± 288.859 in the organizing pneumonia (OP) group, 8252.333± 6050.625 in the pulmonary alveolar proteinosis (PAP) group, and 359.200± 392.707 in the sarcoidosis group. The rank sum test showed that the differences were statistically significant. KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group.Conclusion: Serum KL-6 level was confirmed to be highly sensitive, specific, and accurate in the diagnosis of ILD. Subgroup analysis showed that the KL-6 level was the lowest in the sarcoidosis group, followed by that in the OP group.Keywords: ILD, KL-6, diagnostic value, subgroup analysis

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

Objectives: Quantitatively assess the severity and predict the mortality of interstitial lung disease (ILD) associated with Rheumatoid arthritis (RA) was a challenge for clinicians. This study aimed to construct a radiomics nomogram based on chest computed tomography (CT) imaging by using the ILD-GAP (gender, age, and pulmonary physiology) index system for clinical management. Methods: Chest CT images of patients with RA- ILD were retrospectively analyzed and staged using the ILD-GAP index system. The balanced dataset was then divided into training and testing cohorts at a 7:3 ratio. A clinical factor model was created using demographic and serum analysis data, and a radiomics signature was developed from radiomics features extracted from the CT images. Combined with the radiomics signature and independent clinical factors, a nomogram model was established based on the Rad-score and clinical factors. The model capabilities were measured by operating characteristic curves, calibration curves and decision curves analyses. Results: A total of 177 patients were divided into two groups (Group I, n = 107; Group II, n = 63). Krebs von den Lungen-6, and nineteen radiomics features were used to build the nomogram, which showed favorable calibration and discrimination in the training cohort [AUC, 0.948 (95% CI: 0.910-0.986)] and the testing validation cohort [AUC, 0.923 (95% CI: 0.853-0.993)]. Decision curve analysis demonstrated that the nomogram performed well in terms of clinical usefulness. Conclusion: The CT-based radiomics nomogram model achieved favorable efficacy in predicting low-risk RA-ILD patients. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis (RA) and is associated with a poor prognosis. However, the role of blood biomarkers in RA-associated interstitial lung disease (RA-ILD) is ill-defined. We aim to evaluate the role of YKL-40 and Krebs von den Lungen-6 (KL-6) in the diagnosis and severity evaluation of RA-ILD. Methods: 45 RA-non-ILD patients and 38 RA-ILD patients were included. The clinical data and the levels of YKL-40 and KL-6 were measured and collected for all patients. The risk factors for RA-ILD were analyzed and their correlation with relevant indicators and predictive value for RA-ILD was explored. Results: The levels of YKL-40 and KL-6 in RA-ILD patients were higher than RA-non-ILD patients (p <.001). Both YKL-40 and KL-6 were correlated with the incidence of RA-ILD. The predictive power of combined KL-6 and YKL-40 for the presence of ILD was 0.789, with a sensitivity and specificity at 73.7% and 73.3%, respectively. In RA-ILD patients, both YKL-40 and KL-6 were positively correlated with the Scleroderma Lung Study (SLS) I score and negatively correlated with pulmonary function. Conclusions: KL-6 and YKL-40 might be a useful biomarker in the diagnosis and severity evaluation of RA-ILD. [ABSTRACT FROM AUTHOR]

In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant–associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD. [ABSTRACT FROM AUTHOR]

Aim: To evaluate whether seasonal changes influence fluctuations in serum Krebs von den Lungen‐6 (KL‐6) levels in systemic sclerosis‐related interstitial lung disease (SSc‐ILD). Methods: Summer was defined as the period between July and September, and winter as between December and February. The study was conducted between 2015 and 2016, with a focus on these two seasons. A diagnosis of ILD and ILD progression overtime were evaluated using chest computed tomography. Among patients with SSc‐ILD, those with data on serum KL‐6 and lactate dehydrogenase (LDH) levels in the 2015 winter, 2015 summer, and 2016 winter seasons were included. Patients with comorbidities that could affect serum KL‐6 levels were excluded. Results: Of 60 patients with SSc‐ILD, 52 (86.7%) had stable ILD, 5 (8.3%) had worsened ILD, and 3 (5.0%) had improved ILD. Serum KL‐6 levels were significantly higher during the winter than those during the summer (2015 winter vs. 2015 summer: 649 U/mL vs. 585 U/mL, p <.0001; 2016 winter vs. 2015 summer: 690 U/mL vs. 585 U/mL, p <.0001). No significant differences were observed between the winters of 2015 and 2016 (649 U/mL vs. 690 U/mL, p =.78). However, serum LDH levels did not exhibit seasonal fluctuations (2015 winter vs. 2015 summer: 203 U/L vs. 199 U/L, p =.3; 2016 winter vs. 2015 summer: 201 U/L vs. 199 U/L, p =.6; 2015 winter vs. 2016 winter: 203 U/L vs. 201 U/L, p =.24). Conclusion: Seasonal fluctuations in serum KL‐6 levels were observed in patients with SSc‐ILD. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia is a common cause of acute hospitalisation. Identifying patients with community-acquired pneumonia among patients suspected of having the disease can be a challenge, which causes unnecessary antibiotic treatment. We investigated whether the circulatory pulmonary injury markers surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and Club cell protein 16 (CC16) could help identify patients with community-acquired pneumonia upon acute admission. In this multi-centre diagnostic accuracy study, SP-D, KL-6, and CC16 were quantified in plasma samples from acutely hospitalised patients with provisional diagnoses of community-acquired pneumonia. The area under the receiver operator characteristics curve (AUC) was calculated for each marker against the following outcomes: patients' final diagnoses regarding community-acquired pneumonia assigned by an expert panel, and pneumonic findings on chest CTs. Plasma samples from 339 patients were analysed. The prevalence of community-acquired pneumonia was 63%. AUCs for each marker against both final diagnoses and chest CT diagnoses ranged between 0.50 and 0.56. Thus, SP-D, KL-6, and CC16 demonstrated poor diagnostic performance for community-acquired pneumonia in acutely hospitalised patients. Our findings indicate that the markers cannot readily assist physicians in confirming or ruling out community-acquired pneumonia. [ABSTRACT FROM AUTHOR]

Background: As a biomarker of alveolar-capillary basement membrane injury, Krebs von den Lungen-6 (KL-6) is involved in the occurrence and development of pulmonary diseases. However, the role of the KL-6 in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has yet to be elucidated. This prospective study was designed to clarify the associations of the serum KL-6 with the severity and prognosis in patients with AECOPD. Methods: This study enrolled 199 eligible AECOPD patients. Demographic data and clinical characteristics were recorded. Follow-up was tracked to evaluate acute exacerbation and death. The serum KL-6 concentration was measured via an enzyme-linked immunosorbent assay. Results: Serum KL-6 level at admission was higher in AECOPD patients than in control subjects. The serum KL-6 concentration gradually elevated with increasing severity of AECOPD. Pearson and Spearman analyses revealed that the serum KL-6 concentration was positively correlated with the severity score, monocyte count and concentrations of C-reactive protein, interleukin-6, uric acid, and lactate dehydrogenase in AECOPD patients during hospitalization. A statistical analysis of long-term follow-up data showed that elevated KL-6 level at admission was associated with longer hospital stays, an increased risk of future frequent acute exacerbations, and increased severity of exacerbation in COPD patients. Conclusion: Serum KL-6 level at admission is positively correlated with increased disease severity, prolonged hospital stay and increased risk of future acute exacerbations in COPD patients. There are positive dose–response associations of elevated serum KL-6 with severity and poor prognosis in COPD patients. The serum KL-6 concentration could be a novel diagnostic and prognostic biomarker in AECOPD patients. [ABSTRACT FROM AUTHOR]

Abstract Background Coronavirus disease 2019 (COVID-19) has had a global social and economic impact. An easy assessment procedure to handily identify the mortality risk of inpatients is urgently needed in clinical practice. Therefore, the aim of this study was to develop a simple nomogram model to categorize patients who might have a poor short-term outcome. Methods A retrospective cohort study of 189 COVID-19 patients was performed at Shanghai Ren Ji Hospital from December 12, 2022 to February 28, 2023. Chest radiography and biomarkers, including KL-6 were assessed. Risk factors of 28-day mortality were selected by a Cox regression model. A nomogram was developed based on selected variables by SMOTE strategy. The predictive performance of the derived nomogram was evaluated by calibration curve. Results In total, 173 patients were enrolled in this study. The 28-day mortality event occurred in 41 inpatients (23.7%). Serum KL-6 and radiological severity grade (RSG) were selected as the final risk factors. A nomogram model was developed based on KL-6 and RSG. The calibration curve suggested that the nomogram model might have potential clinical value. The AUCs for serum KL-6, RSG, and the combined score in the development group and validation group were 0.885 (95% CI: 0.804–0.952), 0.818 (95% CI: 0.711–0.899), 0.868 (95% CI: 0.776–0.942) and 0.932 (95% CI: 0.862–0.997), respectively. Conclusions Our results suggested that the nomogram based on KL-6 and RSG might be a potential method for evaluating 28-day mortality in COVID-19 patients. A high combined score might indicate a poor outcome in COVID-19 patients with pneumonia.

Abstract Background Lung cancer (LC) is an important comorbidity of interstitial lung disease (ILD) and has a poor prognosis. The clinical characteristics and outcome of each ILD subtype in LC patients have not been sufficiently investigated. Therefore, this study aimed to evaluate the difference between idiopathic pulmonary fibrosis (IPF) and non-IPF ILD as well as prognostic factors in patients with ILD-LC. Methods The medical records of 163 patients diagnosed with ILD-LC at Asan Medical Center from January 2018 to May 2023 were retrospectively reviewed. Baseline characteristics and clinical outcomes were compared between the IPF-LC and non-IPF ILD-LC groups, and prognostic factors were analyzed using the Cox proportional-hazard model. Results The median follow-up period was 11 months after the cancer diagnosis. No statistically significant differences were observed in clinical characteristics and mortality rates (median survival: 26 vs. 20 months, p = 0.530) between the groups. The independent prognostic factors in patients with ILD-LC were higher level of Krebs von den Lungen-6 (≥ 1000 U/mL, hazard ratio [HR] 1.970, 95% confidence interval [CI] 1.026-3.783, p = 0.025) and advanced clinical stage of LC (compared with stage I, HR 3.876 for stage II, p = 0.025, HR 5.092 for stage III, p = 0.002, and HR 5.626 for stage IV, p = 0.002). In terms of treatment, surgery was the significant factor for survival (HR 0.235; 95% CI 0.106-0.520; p

Objective: To investigate the prognostic relationship between serum KL-6 level and rheumatoid arthritis (RA) combined with interstitial lung disease (RA-ILD). Methods: In Affiliated Hospital of Inner Mongolia Medical University from January 2018 to January 2021, seventy patients with RA were selected and divided into RA-ILD group (34 cases) and RA (36 cases) according to whether they were complicated with ILD, clinicopathological characteristics of the two groups of patients were analyzed by univariate analysis, focusing on the comparison of the expression level of KL-6 in the serum of the two groups and the correlation analysis with laboratory indexes, lung function and imaging, multivariate Logistic regression analysis risk factors affecting RA-ILD. Results: There were significant differences in gender, smoking history, age, age of onset, course of disease, DAS28, KL-6, WBC, UA, RF, anti-CCP antibody, TLC%Pred and DLCO%Pred between the two groups (P<0.05). In RA-ILD group, the proportion of clinical symptoms was more prominent, joint pain was more prominent, and the thickening of pleural adhesion was more prominent on HRCT; Spearson correlation analysis showed that the level of serum KL-6 in RA-ILD group was significantly negatively correlated with TLC% Pred, VC%Pred and DLCO%Pred (P<0.05); there was a significant positive correlation with RF and anti-CCP antibody levels (P< 0.05); there was no significant correlation with FEV1% Pred and FEV1/FVC (P>0.05) ; expression level of KL-6 in RA-ILD group was significantly higher than that in RA group before treatment, and there was no significant difference after treatment (P>0.05) ;Fol- lowed up for one year, six patients died in RA-ILD group. The expression level of KL-6 in death group was significantly higher than that in non death group (P<0.05) ; multivariate Logistic regression analysis showed that old age, male, smoking, increased anti CCP antibody and KL-6 were independent risk factors for RA-ILD (P<0.05) ; the maximum area under the ROC curve predicted by serum KL-6 was 0.802, the 95%C/ was 0.743~0.866, the sensitivity was 0.853, the specificity was 0.827, and the maximum area under the ROC curve detected jointly was 0.854, indicating that the prediction ability of the model was strong. Conclusion: Serum KL-6 levels in RA-ILD patients are significantly increased. KL-6 can be used as a serological index for early detection of ILD, and combined with lung function detection can detect ILD earlier. Early diagnosis is of great significance for treatment and prognosis. [ABSTRACT FROM AUTHOR]

Background: Dermatomyositis (DM) is a rare inflammatory disease. Our research focuses on predicting poor prognosis in DM patients and evaluating the prognostic significance of ferritin and Salivary Sugar Chain Antigen‐6 (KL‐6) through multivariate logistic regression analysis. Methods: Between February 2018 and April 2020, 80 DM patients at our hospital were categorized into MDA5 positive (n = 20) and negative (n = 60) groups. We conducted multivariate logistic regression to determine DM's poor prognosis risk factors and evaluate ferritin/KL‐6′s predictive value for prognosis. Results: Analysis showed no gender, age, body mass index (BMI), or lifestyle (smoking, drinking) differences, nor in dyspnea, muscle weakness, skin ulcers, and acetylcysteine treatment effects (p > 0.05). Significant differences emerged in arrhythmias, interstitial pneumonia, C‐reactive protein, albumin, and lactate dehydrogenase levels (p < 0.05). Before treatment, differences were negligible (p > 0.05), but post‐treatment, serum KL‐6 and ferritin levels dropped. MDA5 positive patients had elevated serum KL‐6 and ferritin levels than survivors (p < 0.05), with a strong correlation to DM. Combined diagnosis using serum KL‐6 and ferritin for DM prognosis showed area under curves of 0.716 and 0.634, significantly outperforming single‐index diagnoses with an area under curve (AUC) of 0.926 (p < 0.05). Conclusion: Serum KL‐6 and ferritin show marked abnormalities in DM, useful as indicators for evaluating polymyositis and DM conditions. However, the study's small sample size is a drawback. Expanding the sample size is essential to monitor serum KL‐6 and ferritin changes in DM patients under treatment more closely, aiming to improve clinical assessment and facilitate detailed research. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) has had a global social and economic impact. An easy assessment procedure to handily identify the mortality risk of inpatients is urgently needed in clinical practice. Therefore, the aim of this study was to develop a simple nomogram model to categorize patients who might have a poor short-term outcome. Methods: A retrospective cohort study of 189 COVID-19 patients was performed at Shanghai Ren Ji Hospital from December 12, 2022 to February 28, 2023. Chest radiography and biomarkers, including KL-6 were assessed. Risk factors of 28-day mortality were selected by a Cox regression model. A nomogram was developed based on selected variables by SMOTE strategy. The predictive performance of the derived nomogram was evaluated by calibration curve. Results: In total, 173 patients were enrolled in this study. The 28-day mortality event occurred in 41 inpatients (23.7%). Serum KL-6 and radiological severity grade (RSG) were selected as the final risk factors. A nomogram model was developed based on KL-6 and RSG. The calibration curve suggested that the nomogram model might have potential clinical value. The AUCs for serum KL-6, RSG, and the combined score in the development group and validation group were 0.885 (95% CI: 0.804–0.952), 0.818 (95% CI: 0.711–0.899), 0.868 (95% CI: 0.776–0.942) and 0.932 (95% CI: 0.862–0.997), respectively. Conclusions: Our results suggested that the nomogram based on KL-6 and RSG might be a potential method for evaluating 28-day mortality in COVID-19 patients. A high combined score might indicate a poor outcome in COVID-19 patients with pneumonia. [ABSTRACT FROM AUTHOR]

Background: The serum level of Krebs von den Lungen-6 (sKL-6) is a biomarker of interstitial pneumonia and has been reported to be elevated in patients with cancers. However, there have been few cases of gastric cancer (GC) with elevated sKL-6 that were treated by chemotherapy. We herein report two cases of GC with elevated sKL-6 that were treated with oxaliplatin plus S-1 (SOX) chemotherapy and discussed the resulting changes in sKL-6. Case presentation: The first patient was a 79-year-old woman complaining of loss of appetite. Esophagogastroduodenoscopy (EGD) showed a type-3 tumor in the gastric antrum and biopsy specimens showed adenocarcinoma. Computed tomography (CT) showed multiple liver metastases. sKL-6 was elevated to 1,292 U/ml, but a CT revealed no obvious lesions of the lungs, including interstitial pneumonia. The tumor was diagnosed as GC with liver metastases and elevated sKL-6. Respiratory function data were normal. SOX therapy using oxaliplatin and S-1 was performed. After 3 courses of SOX therapy, CT showed reductions of the liver metastases as well as the primary tumor, and sKL-6 was decreased to 201 U/ml. After the 44 courses, sKL-6 was slightly elevated. Chest CT showed interstitial pneumonia and chemotherapy was stopped. The patient is still alive without any metastasis 72 months later. The second patient was a 69-year-old woman complaining of upper abdominal pain. EGD revealed a type-3 tumor in the gastric antrum showing adenocarcinoma with HER2-positive pathology. CT showed multiple node metastases around the abdominal aorta. sKL-6 was elevated to 2,239 U/ml, but a respiratory function test showed no abnormalities, and CT of the lungs showed no obvious lesions. The tumor was diagnosed as GC with distant node metastases and elevated sKL-6. The patient received SOX therapy combined with trastuzumab. After 6 courses, the size of the primary tumor and multiple node metastases were reduced, and sKL-6 was decreased to 284 U/ml. Conclusions: These two cases suggest that sKL-6 may be important not only as an indicator of interstitial pneumonia in chemotherapeutic courses, but also as a tumor marker in GC patients with multiple metastases. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) is an important comorbidity of interstitial lung disease (ILD) and has a poor prognosis. The clinical characteristics and outcome of each ILD subtype in LC patients have not been sufficiently investigated. Therefore, this study aimed to evaluate the difference between idiopathic pulmonary fibrosis (IPF) and non-IPF ILD as well as prognostic factors in patients with ILD-LC. Methods: The medical records of 163 patients diagnosed with ILD-LC at Asan Medical Center from January 2018 to May 2023 were retrospectively reviewed. Baseline characteristics and clinical outcomes were compared between the IPF-LC and non-IPF ILD-LC groups, and prognostic factors were analyzed using the Cox proportional-hazard model. Results: The median follow-up period was 11 months after the cancer diagnosis. No statistically significant differences were observed in clinical characteristics and mortality rates (median survival: 26 vs. 20 months, p = 0.530) between the groups. The independent prognostic factors in patients with ILD-LC were higher level of Krebs von den Lungen-6 (≥ 1000 U/mL, hazard ratio [HR] 1.970, 95% confidence interval [CI] 1.026-3.783, p = 0.025) and advanced clinical stage of LC (compared with stage I, HR 3.876 for stage II, p = 0.025, HR 5.092 for stage III, p = 0.002, and HR 5.626 for stage IV, p = 0.002). In terms of treatment, surgery was the significant factor for survival (HR 0.235; 95% CI 0.106-0.520; p < 0.001). Conclusions: No survival difference was observed between IPF-LC and non-IPF ILD-LC patients. A higher level of Krebs von den Lungen-6 may act as a prognostic marker in ILD-LC patients. [ABSTRACT FROM AUTHOR]

The article focuses on investigating the clinicopathological characteristics of interstitial lung disease (ILD) associated with everolimus, an antineoplastic drug. It aims to elucidate the features of everolimus-associated ILD, including its severity, radiological findings, biomarker changes, and lung histopathological features. It highlights the importance of early detection and careful monitoring strategies for ILD in patients undergoing everolimus therapy.

Background: Volume-controlled (VCV) or pressure-controlled ventilation (PCV) modes are most often used during OLV. This is a prospective observational analytical study of patients undergoing thoracic surgery with OLV. Method: 40 patients underwent thoracic surgery using one lung ventilation (OLV) from December 2023 to February 2024. All patients received lung protective ventilation (PLV) with a tidal volume of 6 ml/kgPBW during OLV with PEEP 5-7 cmH2O and were divided into two groups: one with a ventilator in volume-controlled mode (VCV) and the other with pressure-controlled mode (PCV). KL-6, CRP, and p/f ratio were measured before OLV, 2 hours after OLV, and 24 hours after the operation was completed. Respiratory variables during OLV were recorded. Results: KL-6 and CRP levels in PCV and VCV groups were significantly different. There were significant differences in the values of Ppeak (p <0.001), PEEP (p = 0.008), Cstat (p = 0.004) and driving pressure (p <0.001) in both groups. The correlation between changes in KL-6 and CRP levels and the P/F ratio were very weak and insignificant. Cytokines play an important role in the inflammatory response in the lungs. Several determining factors of blood flow are gravity, lung disease, surgery, and hypoxic pulmonary vasoconstriction. Duration of OLV may affect the pulmonary inflammatory response and is correlated with the duration of OLV. Conclusion: There is no association found between KL-6 and CRP in PCV and VCV mode during thoracotomy with OLV. [ABSTRACT FROM AUTHOR]

BackgroundPneumonia and lung cancer have a mutually reinforcing relationship. Lung cancer patients are prone to contracting COVID-19, with poorer prognoses. Additionally, COVID-19 infection can impact anticancer treatments for lung cancer patients. Developing an early diagnostic system for COVID-19 pneumonia can help improve the prognosis of lung cancer patients with COVID-19 infection.MethodThis study proposes a neural network for COVID-19 diagnosis based on non-enhanced CT scans, consisting of two 3D convolutional neural networks (CNN) connected in series to form two diagnostic modules. The first diagnostic module classifies COVID-19 pneumonia patients from other pneumonia patients, while the second diagnostic module distinguishes severe COVID-19 patients from ordinary COVID-19 patients. We also analyzed the correlation between the deep learning features of the two diagnostic modules and various laboratory parameters, including KL-6.ResultThe first diagnostic module achieved an accuracy of 0.9669 on the training set and 0.8884 on the test set, while the second diagnostic module achieved an accuracy of 0.9722 on the training set and 0.9184 on the test set. Strong correlation was observed between the deep learning parameters of the second diagnostic module and KL-6.ConclusionOur neural network can differentiate between COVID-19 pneumonia and other pneumonias on CT images, while also distinguishing between ordinary COVID-19 patients and those with white lung. Patients with white lung in COVID-19 have greater alveolar damage compared to ordinary COVID-19 patients, and our deep learning features can serve as an imaging biomarker.

Background: The presence of fibrotic interstitial lung disease (ILD) is relatively common in patients with emphysema. This has been designated combined pulmonary fibrosis and emphysema (CPFE). CPFE had worse prognosis than emphysema alone. Krebs von den Lungen-6 (KL-6) levels as a biomarker of alveolar type 2 epithelial cell injury, which is widely used to identify the presence of ILD, whether it can differentiate CPFE from COPD remains unknown. Methods: 259 patients from Xiangya Hospital with diagnosis of COPD, with or without ILD, and who had KL-6 tests were recruited for this retrospective analysis. Recorded data included demographic information, comorbidities, inflammatory biomarkers. Results of CT and pulmonary function tests were collected one week before or after KL-6 measurements. Results: Among 259 patients, 52 patients were diagnosed with CPFE. The mean age was 67.39 ± 8.14 yeas. CPFE patients had higher ratio of rheumatic diseases (21.2 % vs 7.2 %, P = 0.003). CPFE patients exhibited higher values of FEV1 (1.97 vs 1.57, P = 0.002) and FEV1/FVC ratio (69.46 vs 57.64, P

Krebs von den Lungen-6 (KL-6) is a glycoprotein mainly expressed by type II pneumocytes and recently known as a lung injury biomarker. However, the number of studies is still limited, especially in Indonesian COVID-19 populations. Therefore, we aim to provide correlation, sensitivity, and specificity analyses of KL-6 and other biomarkers in Indonesian COVID-19 severity and mortality. We conducted a cross-sectional study involving adult COVID-19 patients at Universitas Airlangga Hospital, Surabaya, East Java, Indonesia, between March 26, 2021, and August 25, 2021. KL-6 and other biomarker levels were compared according to severity (severe versus non-severe) and mortality (non-survivor versus survivor). We also included the receiver operating characteristic analysis to define the optimal cut-off, sensitivity, and specificity of KL-6 to determine COVID-19 severity and mortality. We enrolled 78 COVID- 19 patients (23 non-survivors), including 39 non-severe and 39 severe patients. There was no significant difference in serum KL-6 levels, neither in severity nor mortality groups. KL-6 had the strongest positive correlations with ferritin in severe patients (r=0.313) and non-survivors (r=0.467). We observed that the best sensitivity was KL-6 combined with platelet-to- lymphocyte ratio (PLR) (0.818) in severe patients and with neutrophil-to-lymphocyte ratio (NLR)/PLR/ferritin/C-reactive protein (0.867) in non-survivors. In contrast, the best specificity was found when KL-6 was combined with NLR/D-dimer (0.750) in severe patients and with D-dimer (0.889) in non-survivors. Serum KL-6 is a useful auxiliary laboratory evaluation index for COVID-19 lung injury to depict its severity and mortality.

Abstract Purpose Interstitial lung diseases (ILDs) are caused by inflammation and/or fibrosis of alveolar walls resulting in impaired gas exchange. Hypersensitivity pneumonitis (HP) is the third most common type of ILDs. Corticosteroids are the mainstay treatment for HP. The use of intramuscular (IM) betamethasone or intravenous (IV) dexamethasone as weekly pulse doses has shown higher benefit than daily oral prednisolone for HP patients. The aim of this study is to directly compare different corticosteroids in terms of effectiveness and in monetary values and perform an economic evaluation. Methods One hundred and seven patients were tested for pulmonary function tests (PFTs) and inflammatory markers to assess the treatment effectiveness. A cost-effectiveness analysis (CEA) was performed. ICERs between 3 treatment groups were calculated. Results Post treatment, Krebs von den Lungen-6 (KL-6) levels significantly improved in betamethasone group from 723.22 ± 218.18 U/ml to 554.48 ± 129.69 U/ml (p = 0.001). A significant improvement in erythrocyte sedimentation rate (ESR) occurred in the dexamethasone group from 56.12 ± 27.97 mm to 30.06 ± 16.04 mm (p = 0.048). A significant improvement in forced expiratory volume (FEV1), forced vital capacity (FVC) and six-minute walk distance (6MWD) was observed within the three treatment groups. A significant improvement in oxygen desaturation percentage (SpO2) occurred within dexamethasone and betamethasone groups. Betamethasone and dexamethasone were found more cost-effective than prednisolone as their ICERs fell in quadrant C. Furthermore, ICER between betamethasone and dexamethasone was performed; a small difference in cost was found compared to the higher benefit of betamethasone. Conclusion Betamethasone and dexamethasone were found to be more effective than prednisolone in improving the inflammatory reaction and the clinical features of HP patients. Betamethasone was found to be the best intervention in terms of cost against the effect.

OBJECTIVE. To determine the level of KL-6 in the serum of patients with community-acquired COVID-19-associated pneumonia in different periods of the pathological process and to establish its diagnostic significance. MATERIALS AND METHODS. We examined 58 patients in different periods of coronavirus disease (COVID-19). The severity of dyspnoea, anamnesis, objective status, KL-6 level, computed tomography data, pulse oximetry, lung ultrasound, spirometry, body plethysmography, and DLco were assessed. Parametric. A clinical case is presented. RESULTS AND DISCUSSION. In the acute period, the level of KL-6 didn’t differ from the control (p>0.05). In the early post-acute period, the level of KL-6 was significantly higher than in the control (p0.05), but there were patients with elevated levels, which may indicate fibroblast hyperactivity and the initiation of fibrotic changes in the lungs. In subgroup 4, the level of KL-6 was similar to healthy control (p>0.05) and indicates that 6-12 months after the onset of the first symptoms of the disease, interstitial lung disorders mostly don’t increase, while changes in clinical and functional parameters may be observed. CONCLUSIONS. The determination of KL-6 levels in the serum of patients with community-acquired COVID-19-associated pneumonia can be used to monitor the severity and duration of immunological changes in the lungs, especially after the critical course of the acute period of the disease.

Abstract Background Pulmonary involvement is still regarded as a common cause of morbidity in Polymyositis/Dermatomyositis. Interstitial lung disease can result in potentially fatal consequences such as ventilatory failure, secondary pulmonary arterial hypertension, or cor pulmonale. Early diagnosis of interstitial lung disease is hence a top priority in Polymyositis/Dermatomyositis patients. Krebs von den Lungen-6 is a transmembrane mucoprotein that has recently been identified as a promising marker for interstitial lung disease diagnosis and progression. As a result, it is regarded as a powerful predictor of interstitial lung disease severity. Thirty polymyositis/dermatomyocitis patients were enrolled in this study. Thirty age and sex matched healthy individuals were selected as control group. Cutaneous Dermatomyositis Disease Area Severity index(CDASI) was used for evaluation of skin severity, KL6 was measured using Elisa kit, High-resolution computed tomography, pulmonary function tests were made. Results Sixteen female and 14 male patients had a mean age of 41.64–8.02 and amedian of the disease duration of 4 years. Fifteen patients (50%) had normal readings on High-resolution computed tomography of the chest HRCT chest, while the other half had significant HRCT chest findings. KL-6 concentrations were seen to be higher in Polymyositis/Dermatomyositis patients mainly those with ILD (mean ± SD 38.66 ± 22.98), compared to the control group (Mean ± S 589.04 ± 409) and in patients without ILD (Mean ± SD 86.70 ± 8.99), (p

Purpose: Interstitial lung diseases (ILDs) are caused by inflammation and/or fibrosis of alveolar walls resulting in impaired gas exchange. Hypersensitivity pneumonitis (HP) is the third most common type of ILDs. Corticosteroids are the mainstay treatment for HP. The use of intramuscular (IM) betamethasone or intravenous (IV) dexamethasone as weekly pulse doses has shown higher benefit than daily oral prednisolone for HP patients. The aim of this study is to directly compare different corticosteroids in terms of effectiveness and in monetary values and perform an economic evaluation. Methods: One hundred and seven patients were tested for pulmonary function tests (PFTs) and inflammatory markers to assess the treatment effectiveness. A cost-effectiveness analysis (CEA) was performed. ICERs between 3 treatment groups were calculated. Results: Post treatment, Krebs von den Lungen-6 (KL-6) levels significantly improved in betamethasone group from 723.22 ± 218.18 U/ml to 554.48 ± 129.69 U/ml (p = 0.001). A significant improvement in erythrocyte sedimentation rate (ESR) occurred in the dexamethasone group from 56.12 ± 27.97 mm to 30.06 ± 16.04 mm (p = 0.048). A significant improvement in forced expiratory volume (FEV1), forced vital capacity (FVC) and six-minute walk distance (6MWD) was observed within the three treatment groups. A significant improvement in oxygen desaturation percentage (SpO2) occurred within dexamethasone and betamethasone groups. Betamethasone and dexamethasone were found more cost-effective than prednisolone as their ICERs fell in quadrant C. Furthermore, ICER between betamethasone and dexamethasone was performed; a small difference in cost was found compared to the higher benefit of betamethasone. Conclusion: Betamethasone and dexamethasone were found to be more effective than prednisolone in improving the inflammatory reaction and the clinical features of HP patients. Betamethasone was found to be the best intervention in terms of cost against the effect. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung diseases (ILDs) encompass a diverse group of disorders affecting the lung interstitium, leading to inflammation, fibrosis, and impaired respiratory function. Currently, the identification of new diagnostic and prognostic biomarkers for ILDs turns out to be necessary. Several studies show the role of KL-6 in various types of interstitial lung disease and suggest that serum KL-6 levels can be used as a prognostic marker of disease. The aim of this study was to analyze KL-6 expression either in serum or bronchoalveolar lavage samples in order to: (i) make a serum vs. BAL comparison; (ii) better understand the local behavior of fibrosis vs. the systemic one; and (iii) evaluate any differences in patients with progressive fibrosis (PPF) versus patients with non-progressive fibrosis (nPPF). Methods: We used qRT-PCR to detect KL-6 expression both in serum and BAL samples. Mann–Whitney's U test was used to compare the differential expression between groups. Results: In serum, KL-6 is more highly expressed in PPF than in non-progressive fibrosis (p = 0.0295). This difference is even more significant in BAL (p < 0.001). Therefore, it is clear that KL-6 values are related to disease progression. Significant differences were found by making a comparison between BAL and serum. KL-6 was markedly higher in serum than BAL (p = 0.0146). Conclusions: This study identifies KL-6 as a promising biomarker for the severity of the fibrosing process and disease progression in ILDs, with significantly higher levels observed in PPF compared to nPPF. Moreover, the marked difference in KL-6 levels between serum and BAL emphasizes its potential diagnostic and prognostic relevance, providing enlightening insights into both the local and systemic aspects of ILDs. [ABSTRACT FROM AUTHOR]

Background: Pulmonary involvement is still regarded as a common cause of morbidity in Polymyositis/Dermatomyositis. Interstitial lung disease can result in potentially fatal consequences such as ventilatory failure, secondary pulmonary arterial hypertension, or cor pulmonale. Early diagnosis of interstitial lung disease is hence a top priority in Polymyositis/Dermatomyositis patients. Krebs von den Lungen-6 is a transmembrane mucoprotein that has recently been identified as a promising marker for interstitial lung disease diagnosis and progression. As a result, it is regarded as a powerful predictor of interstitial lung disease severity. Thirty polymyositis/dermatomyocitis patients were enrolled in this study. Thirty age and sex matched healthy individuals were selected as control group. Cutaneous Dermatomyositis Disease Area Severity index(CDASI) was used for evaluation of skin severity, KL6 was measured using Elisa kit, High-resolution computed tomography, pulmonary function tests were made. Results: Sixteen female and 14 male patients had a mean age of 41.64–8.02 and amedian of the disease duration of 4 years. Fifteen patients (50%) had normal readings on High-resolution computed tomography of the chest HRCT chest, while the other half had significant HRCT chest findings. KL-6 concentrations were seen to be higher in Polymyositis/Dermatomyositis patients mainly those with ILD (mean ± SD 38.66 ± 22.98), compared to the control group (Mean ± S 589.04 ± 409) and in patients without ILD (Mean ± SD 86.70 ± 8.99), (p < 0.001). KL-6 serum concentrations were shown to have a significant connection with the HRCT score (r = 0.803, P < 0.001). Forced vital capacity (FVC%) (r = − 0.910, P < 0.001), forced expiratory volume in 1 s (FEV1%) (r = − 0.767, P < 0.001), and FEV1/FVC% (r = − 0.228, P = 0.112) were all inversely related to KL-6 concentrations. Conclusion: Individuals with PM and DM with concomitant ILD have increased KL-6 serum concentrations in comparison to myositis individuals without ILD, denoting its potential role in diagnosis and follow up of PM/DM with ILD. Further studies are needed to discuss the role of KL6 in large sample of the patient's population, and its correlation with other organ affection rather than ILD. Also to clarify the potentiality of adding the KL6 biomarker to the guidelines of treat to target for Rheumatic diseases with lung affection and to see the effect of treatment on KL6 serum level. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the diagnostic value of Krebs von den Lungen-6 (KL-6), Surfactant protein-A (SP-A), SP-D and molecular matrixmetalloproteinase-7 (MMP-7) in discriminating patients with interstitial lung diseases (ILDs) from disease control subjects. Methods: Serum levels of KL-6, SP-A, SP-D and MMP-7 were measured in both the ILD and non-ILD (NILD) groups. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic potential of these markers and laboratory indices. High-resolution computed tomography (HRCT) fibrosis scores were determined, and their correlation with the serum markers was analyzed. Results: Serum levels of KL-6 and MMP-7 were significantly elevated in the ILD group compared to the control group, while no significant differences were observed for SP-A and SP-D. ROC analysis of KL-6 demonstrated superior diagnostic accuracy, with a sensitivity of 76.36%, specificity of 91.07%, and an area under curve (AUC) of 0.902 (95%CI 0.866–0.945). These findings were consistent across an additional cohort. Correlation analysis revealed a link between KL-6 levels at initial diagnosis and HRCT fibrosis scores, indicating disease severity. Moreover, a negative correlation was found between KL-6 and pulmonary function indices, reflecting disease progression. Patients with increased 12-month HRCT fibrosis score showed higher lactate dehydrogenase (LDH) levels, with LDH exhibiting an AUC of 0.767 (95% CI: 0.520–0.927) as a predictor of progression. Conclusions: Serum KL-6 detection proves to be a valuable tool for accurately distinguishing ILDs from control subjects. While KL-6 shows a correlation with HRCT fibrosis scores and a negative association with pulmonary function indices, its predictive value for ILDs prognosis is limited. Trial registration: This study received retrospective approval from the Ethical Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (institutional review board ID: TJ-IRB20210331, date: 2021.03.30).

Introduction We report a rare case of marked rectal stenosis due to Douglas' pouch metastasis of renal pelvic urothelial carcinoma successfully treated with enfortumab vedotin. Case presentation A 77‐year‐old female presented with difficulty in defecation and abdominal distension. She had received two courses of cisplatin plus gemcitabine followed by four courses of maintenance avelumab for postoperative lymph node metastasis of renal pelvic urothelial carcinoma. KL‐6 levels were elevated, and a computed tomography scan revealed an irregularly shaped large mass occupying Douglas' pouch, with marked rectal stenosis. Metastatic urothelial carcinoma was pathologically diagnosed, and enfortumab vedotin was initiated after colostomy. After 12 courses of enfortumab vedotin, metastatic lesions showed marked shrinkage and KL‐6 levels decreased. Conclusion Enfortumab vedotin elicited a remarkable response in treating rectal stenosis due to metastasis of renal pelvic urothelial carcinoma in Douglas' pouch. Furthermore, serum KL‐6 levels were correlated with the severity of metastatic urothelial carcinoma.

Community-acquired pneumonia is a common cause of acute hospitalisation. Identifying patients with community-acquired pneumonia among patients suspected of having the disease can be a challenge, which causes unnecessary antibiotic treatment. We investigated whether the circulatory pulmonary injury markers surfactant protein D (SP-D), Krebs von den Lungen-6 (KL-6), and Club cell protein 16 (CC16) could help identify patients with community-acquired pneumonia upon acute admission. In this multi-centre diagnostic accuracy study, SP-D, KL-6, and CC16 were quantified in plasma samples from acutely hospitalised patients with provisional diagnoses of community-acquired pneumonia. The area under the receiver operator characteristics curve (AUC) was calculated for each marker against the following outcomes: patients’ final diagnoses regarding community-acquired pneumonia assigned by an expert panel, and pneumonic findings on chest CTs. Plasma samples from 339 patients were analysed. The prevalence of community-acquired pneumonia was 63%. AUCs for each marker against both final diagnoses and chest CT diagnoses ranged between 0.50 and 0.56. Thus, SP-D, KL-6, and CC16 demonstrated poor diagnostic performance for community-acquired pneumonia in acutely hospitalised patients. Our findings indicate that the markers cannot readily assist physicians in confirming or ruling out community-acquired pneumonia.

BackgroundIdiopathic 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.ObjectiveThis 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.MethodsPatients 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.ResultsThe 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.ConclusionThis 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.

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. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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 b 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. Conclusion: 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. [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]

Background: Serum mid-regional proadrenomedullin (MR-proADM) has emerged as a marker of organ failure (mainly lungs and kidneys) and poor prognosis in patients admitted to intensive care (IC); some reports also suggest it and other markers, such as Krebs von den Lungen-6 (KL-6) and interleukin-6 (IL-6), as a prognostic biomarker of COVID-19. The aim of the study was to evaluate the performance MR-proADM in hospitalized COVID-19 patients for predicting in-hospital mortality and need for non-invasive or invasive respiratory support. Methods: We enrolled 74 patients hospitalized in the COVID Unit of Siena Hospital from March to May 2020, for whom serum samples were available on admission for assay of MR-proADM, KL-6 and IL-6. Demographic data, comorbidities, medical history and clinical laboratory data on days 1–3 of admission and Simplified Acute Physiology Score and Simplified Organ Failure Assessment scores calculated at day 1 were collected retrospectively, as well as mortality and IC admission data. Results: 12 patients died in hospital (16%) and 14 patients were admitted to IC (19%). Serum concentrations of MR-proADM on admission and on day 1 were higher among non-survivors than among survivors (p = 0.015 and p = 0.045, respectively), while those on day 3 were not significantly different. Patients needing respiratory support had higher MR-proADM concentrations on admission than the others (p = 0.046), and those requiring invasive mechanical ventilation had higher MR-proADM on day 1 (p = 0.017). Serum concentrations of KL-6 and IL-6 were significantly higher in non-survivors (p = 0.03 and p = 0.004, respectively). ROC curve analysis showed that serum MR-proADM on day 1 had the best accuracy in predicting death and/or IC admission (AUC = 0.9583, p = 0.0006); the combination of all three biomarkers further improved the accuracy of prediction of death or IC admission (AUC = 0.9793; p = 0.00004). Conclusions: Our data sustain the potential of serum MR-proADM as a reliable prognostic biomarker of hospitalized COVID-19 patients and confirms the utility of the three markers in the management and risk stratification of hospitalized patients. The markers are collected mini-invasively and are quick to analyze and cost-effective. [ABSTRACT FROM AUTHOR]

Background: Interstitial lung diseases (ILDs) encompass a diverse group of disorders affecting the lung interstitium, leading to inflammation, fibrosis, and impaired respiratory function. Currently, the identification of new diagnostic and prognostic biomarkers for ILDs turns out to be necessary. Several studies show the role of KL-6 in various types of interstitial lung disease and suggest that serum KL-6 levels can be used as a prognostic marker of disease. The aim of this study was to analyze KL-6 expression either in serum or bronchoalveolar lavage samples in order to: (i) make a serum vs. BAL comparison; (ii) better understand the local behavior of fibrosis vs. the systemic one; and (iii) evaluate any differences in patients with progressive fibrosis (PPF) versus patients with non-progressive fibrosis (nPPF). Methods: We used qRT-PCR to detect KL-6 expression both in serum and BAL samples. Mann–Whitney’s U test was used to compare the differential expression between groups. Results: In serum, KL-6 is more highly expressed in PPF than in non-progressive fibrosis (p = 0.0295). This difference is even more significant in BAL (p < 0.001). Therefore, it is clear that KL-6 values are related to disease progression. Significant differences were found by making a comparison between BAL and serum. KL-6 was markedly higher in serum than BAL (p = 0.0146). Conclusions: This study identifies KL-6 as a promising biomarker for the severity of the fibrosing process and disease progression in ILDs, with significantly higher levels observed in PPF compared to nPPF. Moreover, the marked difference in KL-6 levels between serum and BAL emphasizes its potential diagnostic and prognostic relevance, providing enlightening insights into both the local and systemic aspects of ILDs.

Abstract Background Krebs von den Lungen 6 (KL-6) is a high-molecular-weight mucin-like glycoprotein, which is also known as MUC1. KL-6 is mainly produced by type 2 pneumocytes and bronchial epithelial cells, and, therefore, elevated circulating KL-6 levels may denote disorders of the alveolar epithelial lining. The objective of this study is to verify if KL-6 serum level might support ICU physicians in predicting mortality, risk stratifying and triaging severe COVID-19 patients. Methods A retrospective cohort study, including all the COVID-19 patients who measured KL-6 serum values at least once during their ICU stay, was performed. The study sample, 122 patients, was divided in two groups, according to the median KL-6 value at ICU admission (median log-transformed KL-6 value: 6.73 U/ml; group A: KL-6 lower than the median and group B: KL-6 higher than the median). Results One-hundred twenty-two ICU patients were included in this study. Mortality was higher in group B than in group A (80 versus 46%; p

Abstract Background Although diffuse alveolar damage (DAD) is a histopathological hallmark of acute respiratory distress syndrome (ARDS), its detection without lung biopsy is challenging. In patients with ARDS, the specificity of the Berlin definition to diagnose DAD as a reference standard is not adequately high, making it difficult to adequately diagnose DAD. The purpose of this study was to investigate the relationship between DAD and clinical findings, including KL-6 and geographic appearance, in ARDS patients and to identify more specific diagnostic criteria for DAD. Methods Among all adult autopsy cases at a tertiary hospital in Japan between January 2006 and March 2021, patients with ARDS who met the Berlin definition criteria were included. The patients’ conditions were classified according to histopathological patterns as DAD or non-DAD, and clinical characteristics, laboratory data, and high-resolution computed tomography (HRCT) findings were compared between the two groups. Results During the study period, 27 met the Berlin definition (median age: 79 years, 19 men), of whom 18 (67%) had DAD and 9 (33%) did not. In the non-DAD group, histopathologic findings revealed organizing pneumonia in seven patients and pulmonary hemorrhage in two patients. On HRCT at onset, patients with DAD had more geographic appearance than those without DAD (89% vs. 44%). In patients with geographic appearance and elevated KL-6 (> 500 U/mL), the sensitivity and specificity for DAD diagnosis were 56% and 100%, respectively. All three patients with no geographic appearance and normal KL-6 did not have DAD. Conclusions Geographic appearance on HRCT combined with KL-6 levels may predict the presence of DAD in patients with ARDS.

The development of a progressive phenotype of interstitial lung disease (ILD) is still unpredictable. Whereas tools to predict mortality in ILD exist, scores to predict disease progression are missing. The aim of this study was to investigate whether baseline serum KL-6 as an established marker to assess disease activity in ILD, alone or in combination with clinical variables, could improve stratification of ILD patients according to progression risk at any time. Consecutive patients with fibrotic ILD, followed at our institution between 2008 and 2015, were investigated. Disease progression was defined as relative decline of ≥10% in forced vital capacity (FVC) or ≥15% in diffusing capacity of the lung for carbon monoxide (DLco)% from baseline at any time. Serum KL-6 was measured using an automated immunoassay (Fujirebio Europe, Gent, Belgium). A stepwise logistic regression was performed to select variables to be included in the score. A total of 205 patients (49% idiopathic pulmonary fibrosis (IPF), 51% fibrotic nonspecific interstitial pneumonia (NSIP)) were included, of them 113 (55%) developed disease progression during follow up. Male gender (G) and serum KL-6 strata (K) were significant predictors of progression at regression analysis and were included in the GK score. A threshold of 2 GK score points was best for discriminating patients at high risk versus low risk to develop disease progression at any time. Serum KL-6 concentration, alone or combined in a simple score with gender, allows an effective stratification of ILD patients for risk of disease progression at any time. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: We investigated serum KL-6 test results in Korean adults by the type of medical institution visited between October 2019 and December 2021. Results: 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. Conclusions: This study will help to understand patient populations and test utilization for KL-6 in clinical laboratories in Korea. [ABSTRACT FROM AUTHOR]

Abstract Background Serum Krebs von den Lungen 6 (KL-6), which reflects alveolar epithelial injury, was reported to be useful to predict the progression of pneumonitis induced by COVID-19 in the early phase. This study aimed to evaluate the peak value of serum KL-6 during hospitalization for COVID-19 to discover a more useful biomarker for predicting prognosis in COVID-19 patients. Methods In this retrospective, single-center, observational study, we analyzed the data of 147 hospitalized patients who required supplemental oxygen, high-flow oxygen therapy, or invasive mechanical ventilation for respiratory failure due to COVID-19 from March 2020 to February 2021. We extracted data on patient sex, age, comorbidities, treatment, and biomarkers including the initial and peak values of KL-6. Inclusion criteria were examination of the studied biomarkers at least once within 3 days of admission, then at least once a week, and at a minimum, at least twice during the entire hospitalization. Area under the receiver operating curve (AUC) was analyzed to determine the accuracy of several biomarkers including KL-6 and LDH for predicting poor prognosis defined as survivors requiring invasive mechanical ventilation for over 28 days or non-survivors of COVID-19. Univariable and multivariate logistic regression analyses were performed to investigate the prognostic value of the baseline characteristics and biomarkers. Results Among the 147 patients, 108 (73.5%) had a good prognosis and 39 (26.5%) had a poor prognosis. The AUC analysis indicated that peak KL-6 showed precise accuracy in the discrimination of patients with poor prognosis (AUC 0.89, p

Yu-Hsiang Chiu,1,2 Chen-Chih Chu,1 Chun-Chi Lu,1 Feng-Cheng Liu,1 Shin-En Tang,3 Shi-Jye Chu,1 San-Yuan Kuo,1 Hsiang-Cheng Chen1 1Division of Rheumatology/Immunology/Allergies, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 2Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands; 3Division of Thoracic Medicine, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, TaiwanCorrespondence: Hsiang-Cheng Chen, Division of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec, 2, Cheng-Gong Road, Neihu 114, Taipei, Taiwan, R.O.C, Tel +886 2 87927135, Fax +886 2 87927136, Email hccheng@mail.ndmctsgh.edu.twObjective: Krebs von den Lungen-6 (KL-6) is expressed on regenerating type II pneumocytes and has been recognized as biomarkers in interstitial lung disease (ILD). We aim to identify the role of the serum KL-6 level in patients with newly diagnosed Sjögren syndrome (SS), as well as the correlation between the immunoassays.Methods: Patients with newly diagnosed SS and receiving HRCT for clinical reason during follow-up were included. Baseline KL-6 level was measured via enzyme-linked immunosorbent assay (ELISA) and latex particle-enhanced turbidimetric immunoassay (LETIA).Results: Of the 39 patients, 21 (53.85%) developed interstitial lung disease (ILD) by the conclusion of the follow-up period. The median time to diagnosis of ILD was 2.24 years (IQR 1.15– 4.34) in the ILD group. The median serum KL-6 level, measured using ELISA, was 1232 U/mL (IQR 937– 2242) and 764.5 U/mL (IQR 503.25– 1035.75) in the ILD group and the non-ILD group, respectively (p = 0.001). The median LETIA for serum KL-6 was 329 U/mL (IQR 235– 619) and 245 U/mL (IQR 215.25– 291) in the ILD group and the non-ILD group, respectively (p = 0.074).Conclusion: Serum KL-6 levels were higher in newly diagnosed SS patients with ILD diagnosis during follow-up. Thus, the serum KL-6 level can serve as a valuable biomarker to identify hidden ILD in patients with newly diagnosed SS patients. However, the immunoassay procedure may influence the efficacy of the prediction and its clinical association.Keywords: Sjögren syndrome, interstitial lung disease, KL-6

ObjectiveTo 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.MethodsWe 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.ResultsSerum 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.ConclusionSerum 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.

This 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. Forty-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). Patients 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). KL-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. [ABSTRACT FROM AUTHOR]

Background: Krebs von den Lungen 6 (KL-6) is a novel biomarker for interstitial lung disease, and it reflects acute lung injury. We explored the usefulness of KL-6 to predict clinical outcomes in hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: In a total of 48 hospitalized COVID-19 patients, KL-6 levels were measured using the HISCL KL-6 assay (Sysmex, Kobe, Japan) with the HISCL 5000 automated analyzer (Sysmex). Clinical outcomes (intensive care unit [ICU] admission, ventilator use, extracorporeal membrane oxygenation [ECMO] use, and 30-day mortality) were analyzed according to KL-6 percentiles. Age, initial KL-6 level, Charlson comorbidity index (CCI), and critical disease were compared using the receiver operating characteristic (ROC) curve and Kaplan-Meier methods for clinical outcomes. Results: KL-6 quartiles were associated with ICU admission, ventilator use, and ECMO use (all p < 0.05), except 30-day mortality (p = 0.187). On ROC curve analysis, initial KL-6 level predicted ICU admission, ventilator use, and ECMO use significantly better than age, CCI, and critical disease (all p < 0.05); age, initial KL-6 level, CCI, and critical disease predicted 30-day mortality comparably. On Kaplan–Meier survival analysis, hazard ratios (95% confidence interval) were 4.8 (1.2–19.3) for age, 4.7 (1.1–21.6) for initial KL-6 level, 3.9 (0.9–16.2) for CCI, and 2.1 (0.5–10.3) for critical disease. Conclusions: This study demonstrated that KL-6 could be a useful biomarker to predict clinical outcomes in hospitalized COVID-19 patients. KL-6 may contribute to identifying COVID-19 patients requiring critical care, including ICU admission and ventilator and/or ECMO use. [ABSTRACT FROM AUTHOR]