涎液化糖链抗原-6在老年特发性肺纤维化诊治中的应用

目的探讨涎液化糖链抗原-6（kerbs von den lungen-6, KL-6）在老年特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）诊断和治疗中的评估价值。 方法选取2018年7月至2019年11月牡丹江医学院附属红旗医院收治的普通型间质性肺炎型IPF患者68例，其中老年患者36例（老年IPF组）、非老年患者32例（非老年IPF组），另择同期老年健康体检者32例（老年健康组）作为对照。采用酶联免疫吸附试验测定血清KL-6表达水平，记录所有IPF患者的肺功能指标，并对其普通型间质性肺炎病变程度进行评估。比较各组血清KL-6的表达水平及肺部高分辨率CT（HRCT）评分，分析KL-6与肺功能指标和肺部HRCT评分的相关性。多组间的比较采用方差分析（进一步两两比较采用LSD-t检验）或秩和检验，计数资料的比较采用χ²检验；相关关系采用Pearson相关分析或Spearman秩相关分析。 结果3组患者KL-6表达水平的差异有统计学意义（F=63.425，P<0.05），其中老年IPF组明显高于非老年IPF组和老年健康组（P<0.01）。ROC曲线显示，KL-6诊断老年IPF的临界值为516.21 U/ml，此时敏感度和特异度最高，分别为94.4%和87.5%。无论是老年IPF组还是非老年IPF组，急性加重患者血清KL-6表达水平均明显高于稳定患者（t=2.843、2.215，P<0.05或0.01）；老年IPF组中急性加重患者血清KL-6表达水平均明显高于非老年IPF组（t=2.657，P<0.05）。相关分析显示，无论是68例IPF患者还是老年IPF组患者，其KL-6水平与HRCT评分均呈正相关（r=0.748、0.699，P<0.01）。老年IPF患者血清KL-6表达水平与部分限制性通气功能和弥散功能指标呈负相关（r=-0.515、-0.393、-0.384，P<0.05）。 结论血清KL-6对诊断IPF有一定临床意义，尤其对于老年患者具有较高的诊断敏感度及特异度，且与疾病严重程度及治疗效果呈现一定相关性。     

Clinical Research on Prognostic Evaluation of Subjects With IPF by Peripheral Blood Biomarkers,Quantitative Imaging Characteristics and Pulmonary Function Parameters

IntroductionIdiopathic pulmonary fibrosis (IPF) is an irreversible and progressive fatal interstitial lung disease with a poor prognosis. The aim of this study is to investigate the predictive value of combined blood biomarkers, pulmonary function and quantitative monitoring by computer-aided diagnosis (CAD) system in IPF patients.MethodsPulmonary baseline function and pathological features of 126 patients with IPF were analyzed using spirometry and chest X-ray. Patients were divided into survival group and non-survival group after 5 years follow-up. The relationships the levels of peripheral blood biomarkers, quantitative imaging characteristics and pulmonary function were analyzed between the two groups.ResultsThe baseline level of serum Krebs von den Lungen-6 (KL-6) and C-X-C motif chemokine 13 (CXCL13) were moderately or highly correlated with annual changes in forced vital capacity (FVC), carbon monoxide diffusing capacity (DLCO), total lung capacity (TLC), total interstitial lung disease (ILD) lesions, and the volume changes of reticular. The baseline level of serum KL-6 was higher than the cut-off value of 800.0 U/ml and baseline level of serum CXCL13 was higher than the cut-off value of 62.0 pg/ml. IPF patients with baseline levels of serum KL-6 and CXCL13 lower than the cut-off value had longer median survival time.ConclusionsSerum KL-6 and CXCL13 may be predictive biomarkers for the outcomes of patients with IPF patients and their baseline levels were related to the progression of pulmonary function and quantitative monitoring by CAD system.     

Serum Krebs von den Lungen-6 and lung ultrasound B lines as potential diagnostic and prognostic factors for rheumatoid arthritis–associated interstitial lung disease

Introduction

Rheumatoid arthritis (RA)–associated interstitial lung disease (ILD) (RA-ILD) is a serious systemic RA manifestation with high mortality that needs proper, accurate, and sensitive assessment tools.

Objectives

Firstly, evaluate serum Krebs von den Lungen-6 (KL-6) levels and lung ultrasound B lines (LUS B lines) score in RA-ILD correlating them with the severity of ILD assessed by high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). Secondly, determine cut-off values for LUS and KL-6 in RA-ILD assessment and outcome prediction.

Methods

A case-control study included seventy-five RA-ILD patients with an equal number of matched RA patients without ILD. Clinical assessment includes DAS-28 and PFTs, laboratory assessment of serum KL-6 by latex-enhanced immunoturbidimetric assay, and radiological evaluation of ILD using semiquantitative CT grade and LUS B lines.

Results

RA-ILD patients had significantly higher serum KL6 compared to those without ILD (1025.5?±?419.6 vs. 237.5?±?51.9, p?≤?0.001). Serum KL6 was positively correlated with HRCT and LUS scores (r?=?0.93, r?=?0.97, respectively) with negative correlation with FVC% and FEV1% (r?=???0.93, r?=???0.91, respectively). LUS was positively correlated with KL6 and HRCT (r?=?0.97, r?=?0.944, respectively) while, negatively correlated with PFTs. Cut-off values of KL6 and LUS were 277.5 U/ml and < 5.5, with AUC 0.878 and 1, sensitivity 86.7% and 100%, and specificity 88% and 100%, respectively.

Conclusions

The non-invasive, radiation-free LUS with a score < 5.5 combined with serum KL6 could be helpful for RA-ILD assessment correlating with HRCT and disease severity. Serum KL6 combined with LUS is important new and potential prognostic factor predicting poor outcomes in RA-ILD. Further large-scale, multi-center, and prospective studies are needed to confirm these findings.

Key Points

? Combination of the non-invasive, radiation-free LUS with a score < 5.5 and serum KL6 levels of 277.5 U/ml is recommended as prognostic tools for RA-ILD.

? Easily obtainable tests such as serum KL-6, inflammatory markers, and LUS are sensitive for assessing RA-ILD and the risk of poor outcomes in patients with RA-ILD.

? RA-ILD patients with higher KL6 levels, higher LUS scores had a poor prognosis with short survival.

? LUS B lines could be used as the first imaging tool for the evaluation of RA-ILD decreasing the risk of HRCT radiation exposure in asymptomatic or mild RA-ILD patients.

     

Differing Expression of Cytokines and Tumor Markers in Combined Pulmonary Fibrosis and Emphysema Compared to Emphysema and Pulmonary Fibrosis

This study aimed to explore the different pathogeneses of combined pulmonary fibrosis and emphysema (CPFE) from emphysema and pulmonary fibrosis. The levels of transforming growth factor-β₁ (TGF-β₁), vascular endothelial growth factor (VEGF), Krebs Von Den Lungen-6 (KL-6), matrix metalloproteinase-9 (MMP-9), tissue inhibitors of metalloproteinases-1 (TIMP-1), cytokeratin 19 fragment (CYFRA21-1), squamous cell carcinoma antigen (SCC), and the telomerase activity in peripheral blood were measured in 38 CPFE patients, 50 pulmonary emphysema patients, and 34 idiopathic pulmonary fibrosis (IPF) patients. The results demonstrated that the levels of VEGF and TGF-β₁ in IPF patients were significantly higher than those in emphysema patients (p < 0.05), and no significant differences were detected between CPFE patients and other two groups (p > 0.05). The levels of KL-6 and CYFRA21-1 in IPF patients were significantly higher than those in emphysema and CPFE patients (p < 0.05), and the latter had the similar levels (p > 0.05). Among the three groups, the levels of SCC, MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, and telomerase activity were not different (p > 0.05). Our study showed that VEGF, TGF-β₁, KL-6, and CYFRA21-1 may play a role in the pathogenesis of pulmonary fibrosis. The lower levels of KL-6 and CYFRA21-1 in CPFE patients may be one of the reasons why these patients develop emphysema on the basis of fibrosis.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

Abstract

Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20?pg/ml versus 61 ± 8?pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36?pg/ml versus 413 ± 49?pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258?pg/ml; HGF, 1500 ± 295?pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94?pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43?pg/ml; HGF, 1294 ± 224?pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients.     

Levels of vascular endothelial growth factor and hepatocyte growth factor in sera of patients with rheumatic diseases

 Angiogenesis plays an important role in the progression of rheumatic disease. We measured the levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in sera from patients with rheumatic diseases and investigated whether these angiogenic factors would be useful in the evaluation of rheumatic diseases. Serum VEGF and HGF levels were determined using ELISA in 128 patients with rheumatic diseases and in 11 healthy controls. Serum VEGF and HGF levels were significantly higher in patients with rheumatic diseases compared to healthy controls [VEGF, 312 ± 20 pg/ml versus 61 ± 8 pg/ml (mean ± SE), P < 0.001; HGF, 935 ± 36 pg/ml versus 413 ± 49 pg/ml, P < 0.01]. Serum VEGF and HGF levels were significantly elevated in patients with adult Still's disease (VEGF, 1021 ± 258 pg/ml; HGF, 1500 ± 295 pg/ml) and were relatively increased in patients with active rheumatoid arthritis (RA) (VEGF, 359 ± 94 pg/ml) and systemic sclerosis (SSc) (VEGF, 356 ± 43 pg/ml; HGF, 1294 ± 224 pg/ml). HGF levels correlated with the clinical course and disease severity in rheumatic disease patients. VEGF levels correlated with the presence of Raynaud's phenomenon (P < 0.05), interstitial lung disease (ILD) (P < 0.05), and serum KL-6 levels (P < 0.01), whereas HGF levels correlated with cryoglobulinemia (P < 0.05), ILD (P < 0.05), serum C-reactive protein (CRP) (P < 0.05), thrombomodulin (P < 0.05), and KL-6 levels (P < 0.05) in rheumatic disease patients. VEGF levels correlated with the skin scores and KL-6 levels in SSc patients and also correlated with the disease activity of RA patients. These data suggest that serum VEGF and HGF levels are related to rheumatic disease activity and the presence of complications. Analysis of VEGF and HGF may be useful in the clinical evaluation of rheumatic disease patients. Received: February 19, 2002 / Accepted: August 13, 2002 Acknowledgment We are grateful to Ms. Aki Nomura for assistance with the ELISA of VEGF and HGF.     

Clinical features of chronic summer-type hypersensitivity pneumonitis and proposition of diagnostic criteria

BackgroundTrichosporon asahii (T. asahii) causes chronic summer-type hypersensitivity pneumonitis (C-SHP); however, little is known about the clinical features of this condition. We aimed to elucidate the clinical features of C-SHP and propose practical diagnostic criteria for C-SHP based on the presence of serum anti-T. asahii antibody (TaAb).MethodsPatients diagnosed with C-SHP and idiopathic pulmonary fibrosis (IPF) between January 2010 and May 2017 were reviewed retrospectively. Clinical findings were compared between the two groups. Criteria for C-SHP were proposed on the basis of significant characteristics and applied to the development and validation cohorts.ResultsThirty-one patients with C-SHP and 26 with TaAb-negative IPF were identified. C-SHP patients were more likely to live in wooden houses; their serum Krebs von den Lungen-6 (KL-6) and serum surfactant protein-D (SP-D) levels were higher than those of IPF patients. C-SHP patients were more likely to have subpleural consolidation, micronodules, and extensive ground-glass opacification on high-resolution computed tomography (HRCT). The following 3 items were considered to have diagnostic value: I) TaAb positivity; II) an HRCT pattern consistent with chronic hypersensitivity pneumonitis, including mosaic attenuation or micronodules; and III) elevated serum biomarker levels (KL-6 > 1500 U/mL or SP-D > 250 ng/mL). We defined cases satisfying I) and II) as “probable C-SHP” and those satisfying all 3 criteria as “confident clinical diagnosis of C-SHP”. The areas under the receiver-operating curve were 0.965 and 0.993 in the development and validation cohorts, respectively, which suggested that these criteria had good discriminative ability in clinical evaluations.ConclusionsClinical features could be useful for distinguishing C-SHP from IPF and other etiologies of ILDs.     

Expression of S100A9 and KL-6 in common interstitial lung diseases

By evaluating S100 calcium binding protein A9 (S100A9) and Klebs von den Lungen-6 (KL-6) expression in patients with 4 common interstitial lung diseases (ILDs), we aimed to investigate whether S100A9 or KL-6 can be of any value in the differential diagnosis of these ILDs and simultaneously signal the disease progression.We collected the data of patients diagnosed with the 4 ILDs and underwent fiber-optic bronchoscopy and BAL in the First Affiliated Hospital, China Medical University from January 2012 to December 2020. The data related to BGA, C-reactive protein, pulmonary function test, total number and fraction of cells, T lymphocyte subsets in bronchoalveolar lavage fluid (BALF), and the expression of S100A9 and KL-6 in BALF and serum were collected. We analyzed, whether S100A9 or KL-6 could serve as a biomarker for differential diagnosis between the 4 common ILDs; whether the levels of S100A9 and KL-6 correlated with each other; whether they were correlated with other clinical parameters and disease severity.This study included 98 patients, 37 patients with idiopathic pulmonary fibrosis (IPF), 12 with hypersensitivity pneumonitis, 13 with connective tissue disease-associated ILD, and 36 with sarcoidosis (SAR): stage I (18), stage II (9), stage III (5), and stage IV (4). The expression of KL-6 in BALF was significantly higher in IPF patients than other 3 groups (all P-value < .05). However, there was no significant difference in the levels of S100A9 in BALF and serum between the 4 groups (P-value > .05). The levels of S100A9 in BALF of IPF patients was positively and significantly correlated with KL-6 expression and the percentage of neutrophils in BALF (P-value < .05). Along with the stage increase of SAR patients, the level of S100A9 in BALF gradually increased, which was negatively and significantly correlated with the forced vital capacity/predicted, carbon monoxide diffusing capacity/predicted%, and PaO₂ (all P-value < .05).The expression of KL-6 in BALF can be used as a biomarker to differentiate IPF from the other 3 common ILDs. While, this was not the case with expression of S100A9 in BALF and serum. However, the expression S100A9 in BALF is useful to indicate the progression of SAR. Thus, simultaneous measurement of KL-6 and S100A9 levels in BALF makes more sense in differential diagnosing of the 4 common ILDS.     

Serum Krebs von den Lungen-6 levels are associated with mortality and severity in patients with coronavirus disease 2019

BackgroundThe serum Krebs von den Lungen-6 (KL-6) level is a predictive factor for acute respiratory distress syndrome (ARDS). The development of ARDS has been reported in patients with coronavirus disease 2019 (COVID-19). This study aimed to determine whether serum KL-6 levels are associated with mortality and severity in patients with COVID-19.MethodsAmong 361 Japanese patients with COVID-19 who were hospitalized at Kanagawa Cardiovascular and Respiratory Center between February 2020 and December 2020, 356 patients with data on serum KL-6 levels were enrolled and their medical records were retrospectively analyzed.ResultsA negative correlation was observed between KL-6 levels and the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen on admission. The KL-6 levels on admission and the maximal KL-6 levels were higher in patients with severe disease (n = 60) than in those with nonsevere disease (n = 296). Furthermore, the maximal KL-6 levels were higher in nonsurvivors (n = 6) than in survivors (n = 350). In nonsurvivors, the KL-6 levels increased as the disease progressed. The optimal cutoff value of the maximal KL-6 level for discriminating between survivors and nonsurvivors was 684 U/mL, with a sensitivity of 83.3%, a specificity of 90.5%, and an area under the curve of 0.89.ConclusionsThe serum KL-6 level was associated with disease severity. Patients with KL-6 levels ≥684 U/mL had a significantly poorer outcome than those with KL-6 levels <684 U/mL.     

High serum KL-6 levels predict the deterioration of pulmonary function in patients with rheumatoid arthritis

Abstract

KL-6 has been reported to be a serum marker for interstitial pneumonitis (IP). The purpose of this study was to determine the predictive value of KL-6 on the deterioration of vital capacity (VC) in rheumatoid arthritis (RA) patients with IP. In 32 RA patients we evaluated both the serum KL-6 level and VC in a prospective design. The diagnosis of IP was determined by clinical symptoms, chest X-ray, high-resolution computed tomography (HRCT) scanning and/or pulmonary function tests. Findings such as reticulonodular and/or cystic shadows on HRCT scanning were accepted as IP signs. The IP signs with ground-glass opacity were set as active. The mean period of observation was 31.2 (5.6) months. The initial and/or final serum KL-6 levels were more than 520 U/ml in seven patients (H-KL group). In the other 25 patients, both the initial and final KL-6 levels were 520 U/ml or less (L-KL group). Among the H-KL group patients, their percent VC (%VC) was significantly reduced ( P < 0.01) during the observation period. No significant changes of KL-6 and %VC levels were seen in the L-KL group. Thus, we conclude that in RA patients with IP, abnormal levels of serum KL-6 may predict the deterioration of VC.     

Serum KL-6 Levels in Patients With Pulmonary Complications After Allogeneic Bone Marrow Transplantation

KL-6, a mucinous high—molecular weight glycoprotein expressed on type 2 pneumocytes, has been shown to be elevated in the serum and bronchoalveolar lavage fluid of patients with interstitial pneumonitis (IP). We measured the serum levels of KL-6 in patients after they had undergone allogeneic bone marrow transplantation (BMT) to determine whether KL-6 could be a clinically useful indicator for the development of IP. The serum concentrations of KL-6 were determined by a sandwichtype enzyme-linked immunosorbent assay using an anti—KL-6 monoclonal antibody. A total of 1028 samples were tested from 76 patients (78 transplantations) who received BMTs. The KL-6 values were markedly elevated in patients with pulmonary complications, but not in those with acute and chronic graft-versus-host disease, hemorrhagic cystitis, herpes encephalitis, sepsis, and veno-occlusive disease.The serum levels of KL-6 from patients with pulmonary complications were significantly higher than from those without pulmonary complications (P < .001) and those with other complications (P < .001). Of the 12 patients with pulmonary complications, 6 had idiopathic IP (IIP). The levels were not high at the onset of IIP. Four of 6 IIP patients showed marked elevations of KL-6 levels in parallel with the severity of IP and died of respiratory failure without response to treatment.Assessment of serum KL-6 levels might not be useful for the early diagnosis of IP, but may be a useful indicator for monitoring the severity of IP after BMT.     

Clinical significance of serum KL-6 and SP-D for the diagnosis and treatment of interstitial lung disease in patients with diffuse connective tissue disorders]

OBJECTIVE: To elucidate the clinical significance of serum KL-6 and SP-D for the diagnosis and treatment of interstitial lung disease in connective tissue disorders. METHODS: 139 patients with various connective tissue disorders were subjected for the study, which included 46 cases of rheumatoid arthritis, 43 cases of Sj?gren's syndrome, 16 cases of SLE, 10 cases of systemic sclerosis, 9 cases of polymyositis/dermatomyositis, 6 cases of vasculitis syndrome, 5 cases of Beh?et's disease and 4 cases of MCTD. Serum levels of KL-6 and SP-D were determined by enzyme-immunoassay. The sensitivity, specificity and accuracy of serum KL-6 and SP-D for the diagnosis of interstitial lung disease were compared with serum LDH. The relationship of serum KL-6 and SP-D levels with high resolution CT (HRCT) of the lung and Gallium scintigraphy findings was analyzed. In some cases, serum levels of the two markers were determined monthly in the course of the disease. RESULTS: When the serum levels of KL-6 and SP-D were measured simultaneously, the sensitivity to diagnose interstitial lung disease was 67.7%, the specificity was 98.1%, and the accuracy was 91.4%, while those of serum LDH were 45.2%, 88.9%, 79.1% respectively. In the patients with interstitial lung disease, those who had elevated serum levels of both KL-6 and SP-D showed parenchymal collapse opacity-dominant pattern in HRCT. On the other hand, the patients with interstitial lung disease who had normal levels of serum KL-6 and SP-D or had elevation either in KL-6 or SP-D levels showed ground glass opacity-dominant pattern in HRCT. There was no significant correlation between serum marker levels and Gallium scintigraphy findings. When serum KL-6 and SP-D were measured monthly, the levels of both markers changed more specifically and sensitively to the lung disease activity compared with serum LDH. CONCLUSIONS: Serum KL-6 and SP-D are more specific and useful markers for the diagnosis and evaluation of interstitial lung disease compared with serum LDH in connective tissue disorders.     

特发性肺纤维化患者肺泡灌洗液和血清中Napsin A、KL-6、SP-A、SP-D表达的意义及与肺功能相关性

目的特发性肺纤维化(IPF)是一种不明原因的慢性进行性间质性肺疾病。其发病率、死亡率均较高。但IPF的发病机制至今尚未完全清楚,临床上对此病发生发展的掌握不够,检验指标的敏感性及特异性不高,从而影响诊断及临床判断的准确性。因此寻找IPF发生发展的生物标记物成为近年来较为热门的研究方向。方法挑选2017年3月-2019年3月间在我院就诊并诊断明确的30例IPF患者入组IPF观察组,20例临床症状类似的I期肺结节病患者作为阴性对照组。采用双抗体夹心酶联免疫吸附(ELISA)法检测IPF和I期肺结节病对照组BALF和血清中Napsin A/KL-6/SP-A/SP-D水平,并对患者的肺功能进行检测,评估上述生物标记物与肺纤维化病程进展的相关性。结果IPF组患者的血清/肺泡灌洗液中Napsin A/KL-6/SP-A/SP-D水平均明显高于由I期肺结节病阴性对照组(P<0.05)。灌洗液中Napsin A/KL-6/SP-D含量与肺通气功能呈负相关(P<0.05),而Napsin A/KL-6含量与弥散功能呈现负相关(P<0.05)。血清中Napsin A/KL-6/SP-A/SP-D水平均与肺通气功能呈负相关(P<0.05),Napsin A/KL-6血清含量与肺弥散功能呈明显负相关(P<0.05),与肺泡灌洗液检测结果一致。结论Napsin A/KL-6/SP-A/SP-D在IPF患者灌洗液中的含量亦显著升高。其中血清Napsin A/KL-6水平相关度最高,高水平的血清及灌洗液中Napsin A/KL-6浓度提示IPF病灶进展,且与肺通气功能及弥散指标呈负相关,可作为诊断IPF严重程度判断的指标之一。而SP-A、SP-D也可以作为IPF早期的一种早期预测指标,敏感性特异性差于Napsin A/KL-6,但SP-D对于肺功能下降、肺纤维化早期炎症反应,优于SP-A。     

High serum KL-6 levels predict the deterioration of pulmonary function in patients with rheumatoid arthritis

KL-6 has been reported to be a serum marker for interstitial pneumonitis (IP). The purpose of this study was to determine the predictive value of KL-6 on the deterioration of vital capacity (VC) in rheumatoid arthritis (RA) patients with IP. In 32 RA patients we evaluated both the serum KL-6 level and VC in a prospective design. The diagnosis of IP was determined by clinical symptoms, chest X-ray, high-resolution computed tomography (HRCT) scanning and/or pulmonary function tests. Findings such as reticulonodular and/or cystic shadows on HRCT scanning were accepted as IP signs. The IP signs with ground-glass opacity were set as active. The mean period of observation was 31.2 (5.6) months. The initial and/or final serum KL-6 levels were more than 520 U/ml in seven patients (H-KL group). In the other 25 patients, both the initial and final KL-6 levels were 520 U/ml or less (L-KL group). Among the H-KL group patients, their percent VC (%VC) was significantly reduced (P < 0.01) during the observation period. No significant changes of KL-6 and %VC levels were seen in the L-KL group. Thus, we conclude that in RA patients with IP, abnormal levels of serum KL-6 may predict the deterioration of VC.     

特发性肺纤维化患者辅助性T细胞1/辅助性T细胞2的研究

目的 对特发性肺纤维化(IPF)患者辅助性T细胞1(Th1)/辅助性T细胞2(Th2)进行研究,探讨Th1/Th2能否反映疾病的严重性,能否预测疾病的进展.方法 入选83例IPF患者,应用酶联免疫吸附测定法检测所有受试者血清、支气管肺泡灌洗液(BALF)中γ干扰素(IFNγ)、白细胞介素-4(IL-4)水平,并进行相关性分析.结果 (1)基线资料:IPF患者血清、BALF中IFNγ/IL-4比值(0.8±0.3;0.8±0.3)较对照组(1.4±0.2;1.4±0.2)显著降低;血清、BALF中IFNγ/IL-4比值与病程、呼吸困难评分、第1秒用力呼气容积(FEV1)占预计值百分比、用力肺活量(FVC)占预计值百分比、肺总量(TLC)占预计值百分比、最大去氧饱和度、6分钟步行距离(6MWD)、CT间质纤维化评分显著相关(血清:r值分别为-0.426、-0.623、0.487、0.455、0.517、-0.491、0.263、-0.569,P值均＜0.05;BALF:r值分别为-0.434、-0.637、0.480、0.456、0.501、-0.507、0.253、-0.605,P值均＜0.05);血清中IFNγ/IL-4比值与CT磨玻璃影评分呈正相关(r=0.340,P＜0.01).(2)随访:IPF患者血清中IFNγ、IL-4、IFNγ/IL-4在糖皮质激素治疗者与非糖皮质激素治疗者间差异无统计学意义.随访6个月后的呼吸困难评分、FEV1占预计值百分比、TLC占预计值百分比、CT磨玻璃影评分、CT间质纤维化评分、IFNγ和IL-4较基线值显著恶化.血清中IFNγ/IL-4比值变化与呼吸困难评分、FVC占预计值百分比、TLC占预计值百分比、肺一氧化碳弥散量占预计值百分比、6MWD、CT间质纤维化评分的变化显著相关(r值分别为-0.297、0.462、0.315、0.353、0.420、-0.307,P值均＜0.05).结论 IPF患者血清和BALF中Th1/Th2存在失衡,Th1/Th2可能反映IPF的严重性,随访时血清中Th1/Th2的变化可能会预测IPF的疾病进展.     

基质金属蛋白酶-7和基质金属蛋白酶-28在特发性肺纤维化诊断中的价值

目的 探讨基质金属蛋白酶-7(MMP-7)、基质金属蛋白酶-28(MMP-28)在特发性肺纤维化(IPF)诊断及严重程度评估中的临床价值.方法 选2018年9月至2019年12月在宁夏回族自治区人民医院就诊的30例IPF患者为实验组,30例类风湿性关节炎相关间质性肺病(RA-ILD)及30例健康体检者为对照组.测定所有...     

Comprehensive investigation of novel serum markers of pulmonary fibrosis associated with systemic sclerosis and dermato/polymyositis

OBJECTIVE: To investigate the association between serum levels and clinical signs of lung fibrosis in patients with systemic sclerosis and inflammatory myopathies. METHODS: ELISA tests for a mucin-like glycoprotein KL-6, von Willebrandt factor (vWF), soluble E-selectin (sES) and surfactant protein D (SP-D) were performed in sera of 104 patients with systemic sclerosis, 31 patients with poly/dermatomyositis) and 24 patients with Raynaud's phenomenon as controls. The clinical and laboratory data were evaluated by a simple standard protocol including chest x-ray, lung function tests, echocardiography and, in selected cases, high resolution computer tomography (HRCT). Clinically significant pulmonary fibrosis (PF) defined as a simultaneous presence of radiological sign of pulmonary fibrosis and restrictive impairment. Severe PF was established if HRCT scans showed diffuse interstitial lung disease with low diffusing capacity. End stage PF was determined as severe PF with very low diffusing capacity. RESULTS: Patients with pulmonary fibrosis on chest x-ray showed significantly elevated serum levels of KL-6, SP-D and vWF. Inverse correlation was found between serum levels of KL-6/SP-D and lung function parameters, such as DLCO% and FVC. With regard to HRCT findings, patients with elevated serum level of KL-6 showed significantly more frequently ground glass opacity, diffuse and honeycombing fibrosis than patients with normal level of KL-6. The sensitivity of KL-6 for PF in SSc is increased with the severity of PF (PF on chest x-ray < severe PF < end stage of PF). Lung fibrosis occurred more frequently in patients with simultaneously elevated KL-6 and sES compared to cases with a single positivity of either KL-6 or sES. CONCLUSION: KL-6, SP-D, vWF and ES are good surrogate factors of pulmonary fibrosis but can not replace conventional diagnostic procedures. However, these markers are suitable for the assessment of progression and severity of pulmonary fibrosis in systemic autoimmune disorders once the diagnosis is established.     

Interstitial pulmonary disorders in indium-processing workers.

The production of indium-tin oxide has increased, owing to the increased manufacture of liquid-crystal panels. It has been reported that interstitial pneumonia occurred in two indium-processing workers; therefore, the present study aimed to evaluate whether interstitial pulmonary disorders were prevalent among indium workers. The study was carried out in 108 male workers in the indium plant where the two interstitial pneumonia patients mentioned above were employed, and included high-resolution computed tomography (HRCT) of the lungs, pulmonary function tests and analysis of serum sialylated carbohydrate antigen KL-6 and the serum indium concentration. Significant interstitial changes were observed in 23 indium workers on HRCT and serum KL-6 was abnormally high (>500 U x mL(-1)) in 40 workers. Workers with serum indium concentrations in the highest quartile had significantly longer exposure periods, greater HRCT changes, lower diffusing capacity of the lung for carbon monoxide and higher KL-6 levels compared with those in the lowest quartile. The serum indium concentration was positively correlated with the KL-6 level and with the degree of HRCT changes. In conclusion, the results of the present study indicated that serum KL-6 and high-resolution computed tomography abnormalities were prevalent among indium workers and that these abnormalities increased with the indium burden, suggesting that inhaled indium could be a potential cause of occupational lung disease.     

Serum KL-6 level is a useful biomarker for evaluating the severity of coronavirus disease 2019

BackgroundCoronavirus disease 2019 (COVID-19) is currently spreading worldwide. This study examined whether serum Krebs von den Lungen-6 (KL-6) level is a useful biomarker for evaluating the severity of COVID-19.MethodsWe retrospectively examined patients diagnosed with COVID-19 at the Japanese Red Cross Medical Center between February 1, 2020, and May 15, 2020. Patients were divided into four categories based on clinical and radiological findings: mild, moderate, severe, and critical. Patients who presented with a mild or moderate illness and patients who started with or worsened to a severe or critical illness were classified as the non-severe and severe groups, respectively. The two groups were compared for patient characteristics, including serum KL-6 levels. Receiver operating characteristic curves were used to define the optimum cut-off value of serum KL-6 level to evaluate COVID-19 severity.ResultsA total of 54 patients were enrolled, including 33 in the non-severe group and 21 in the severe group, of which four died. Compared with those in the non-severe group, more patients in the severe group were significantly older and had comorbidities. Serum KL-6 levels were significantly higher in the severe group than in the non-severe group both at diagnosis (median, 338 U/mL) and at peak levels within one week after diagnosis (median, 781 U/mL) (both p < 0.001). Serum KL-6 value at peak level (371 U/mL) was used as the optimal cut-off to evaluate disease severity (sensitivity, 85.7%; specificity, 96.6%).ConclusionsSerum KL-6 levels were significantly elevated in severe COVID-19 and is useful for evaluating its severity.     

血清KL-6检测在COPD合并肺间质纤维化诊断中的意义

目的研究慢性阻塞性肺疾病合并肺间质纤维化患者血清KL-6水平的变化。方法选取COPD合并PIF患者22例,单纯COPD患者23例,另选取20例健康志愿者为对照组。所有入选者均行胸部CT或HRCT及肺功能检查,ELISA检测血清KL-6水平,并分析其与肺功能相关指标的相关性。结果 COPD合并PIF组患者血清KL-6水平(1048±452 U/ml)较单纯COPD组患者(429±226 U/ml)及健康对照组(384±108 U/ml)显著升高(P0.05),而单纯COPD组患者血清KL-6水平与健康对照组相比无显著性差异(P0.05);血清KL-6水平与DL CO呈显著负相关(P0.05),但与用力肺活量(FVC)(P0.05)、1 s用力呼气容积(FEV1)(P0.05)及FEV1/FVC无明显相关性(P0.05)。结论 COPD合并PIF患者血清KL-6水平明显增高,血清KL-6也许可作为诊断COPD合并PIF的血清学指标。