Elevated KL-6 Levels Research Articles

Associations of the Serum KL-6 with Severity and Prognosis in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

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. 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. 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. 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.

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

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

KL-6 as a Tumor Marker of Primary Peritoneal Cancer in Patients with Connective Tissue Diseases.

We herein report two patients with connective tissue disease who developed primary peritoneal cancer (PPC). Serum Krebs von den Lungen-6 (KL-6) levels increased when PPC was diagnosed, and these levels were correlated with the treatment and worsening of PPC in both cases. In one patient with systemic sclerosis, serum KL-6 levels increased despite stable interstitial lung disease (ILD), leading to a diagnosis of PPC. In the other patient with dermatomyositis and no ILD, PPC was diagnosed with elevated KL-6 levels four months post-treatment, without ILD development. Clinicians should be reminded that KL-6 is a tumor marker in various cancers.

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

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

KL-6 as an Immunological Biomarker Predicts the Severity, Progression, Acute Exacerbation, and Poor Outcomes of Interstitial Lung Disease: A Systematic Review and Meta-Analysis.

ObjectInterstitial lung disease (ILD) is a specific form of chronic fibrosing interstitial pneumonia with various etiology. The severity and progression of ILD usually predict the poor outcomes of ILD. Otherwise, Krebs von den Lungen-6 (KL-6) is a potential immunological biomarker reflecting the severity and progression of ILD. This meta-analysis is to clarify the predictive value of elevated KL-6 levels in ILD.MethodEBSCO, PubMed, and Cochrane were systematically searched for articles exploring the prognosis of ILD published between January 1980 and April 2021. The Weighted Mean Difference (WMD) and 95% Confidence Interval (CI) were computed as the effect sizes for comparisons between groups. For the relationship between adverse outcome and elevated KL-6 concentration, Hazard Ratio (HR), and its 95%CI were used to estimate the risk factor of ILD.ResultOur result showed that ILD patients in severe and progressive groups had higher KL-6 levels, and the KL-6 level of patients in the severe ILD was 703.41 (U/ml) than in mild ILD. The KL-6 level in progressive ILD group was 325.98 (U/ml) higher than that in the non-progressive ILD group. Secondly, the KL-6 level of patients in acute exacerbation (AE) of ILD was 545.44 (U/ml) higher than stable ILD. Lastly, the higher KL-6 level in ILD patients predicted poor outcomes. The KL-6 level in death of ILD was 383.53 (U/ml) higher than in survivors of ILD. The pooled HR (95%CI) about elevated KL-6 level predicting the mortality of ILD was 2.05 (1.50–2.78), and the HR (95%CI) for progression of ILD was 1.98 (1.07–3.67).ConclusionThe elevated KL-6 level indicated more severe, more progressive, and predicted the higher mortality and poor outcomes of ILD.

Clinical relevance of serum Krebs von den Lungen-6 levels in patients with coronavirus disease 2019.

The clinical relevance of Krebs von den Lungen-6 (KL-6) levels in patients with coronavirus disease 2019 (COVID-19) is unclear. This study aimed to evaluate the correlation between KL-6 levels, laboratory parameters, and clinical outcomes. We enrolled 364 patients with confirmed COVID-19 who were hospitalized within 1 week of symptom onset. Their serum KL-6 level was measured on admission. Demographic data, symptoms, comorbidities, and laboratory parameters were recorded at the time of admission. Days to nucleic acid conversion and days of hospitalization were defined as clinical outcomes for evaluating the clinical relevance of serum KL-6 levels in COVID-19. Patients with elevated KL-6 levels were significantly older; had more reported instances of fever, cough, fatigue, and wheezing; and a longer hospital stays than those with normal KL-6 levels; the difference was statistically significant (p < 0.001). Furthermore, KL-6 levels was associated with the days of hospitalization and various laboratory parameters that influence the severity and prognosis of COVID-19. Elevated KL-6 levels have also been shown to be an independent risk factor for prolonged hospitalization. Our data suggest that serum KL-6 levels on admission can serve as an indicator for assessing the clinical outcomes of COVID-19.

ボルテゾミブ・シクロホスファミド・デキサメタゾン(VCD) 3剤併用療法にて完全寛解を達成した血清KL-6高値多発性骨髄腫

ボルテゾミブ・シクロホスファミド・デキサメタゾン(VCD) 3剤併用療法にて完全寛解を達成した血清KL-6高値多発性骨髄腫

Prospective cohort study of serum sialylated glycoprotein (KL-6) as a prognostic marker in patients (pts) with non-small cell lung cancer (NSCLC) receiving gefitinib monotherapy: Okayama Lung Cancer Study Group 0703.

e19023 Background: Gefitinib is now crucial in the treatment of EGFR-mutant NSCLC. Its anti-tumor activity could be modulated by MUC1 mucins [Cancer Res 2006], similar to KL-6 in the biochemical property, currently used as an indicator for interstitial lung diseases (ILDs). Our preliminary retrospective study showed the elevated serum KL-6 level is a potential negative prognostic value in pts with advanced NSCLC receiving gefitinib therapy [Lung Cancer 2008]. We conducted an observational study to evaluate this issue prospectively. Methods: Consecutive, EGFR-TKI-naïve NSCLC pts who were to receive gefitinib were enrolled and stratified by pretreatment KL-6 levels (&lt; 500 U/ml: normal group [NG] and ≥ 500 U/ml: abnormally elevated group [EG]). The primary endpoint was overall survival (OS). The planned accrual number of pts was 150, assuming an estimated HR of 2.0, α=0.05, ß=0.10). We also evaluated ILD events during the gefitinib treatment. Results: Between 2007 and 2012, 154 pts were registered (NG: 89 [58%] and EG: 65 [42%] with median KL-6 score of 305 and 1,050 IU/mL, respectively). Those with pretreatment pulmonary fibrosis were similarly distributed between the groups. Median follow-up time was 13.7 months. The EG had significantly worse OS in the univariate analysis (log-rank p=0.0011), which was retained in the multivariate analysis (hazard ratio [HR]: 1.95, 95% confidence interval [95% CI]: 1.34-2.81). Exploratory analyses showed an interaction between EGFR-mutation status and KL-6; HR of KL-6 for OS: 1.96, [1.30-2.97], and HR: 4.80, [1.05-21.95] in pts with EGFR-mutant and wild-typed tumors, respectively (interaction p=0.07). As for ILD event it occurred similarly during the gefitinib therapy (HR: 2.76, [0.62-12.33]). Conclusions: The elevated KL-6 level could predict a poor prognosis in NSCLC pts with gefitinib therapy, and this association seemed modulated by EGFR-mutation status. Further studies are needed to clarify the biological behavior of KL-6 expression on tumor progression especially in the EGFR pathway.

Hard Metal Lung Disease Successfully Treated with Inhaled Corticosteroids

We herein report a case of hard metal lung disease that was successfully treated with inhaled corticosteroids. A 46-year-old man was admitted to our hospital due to coughing and an abnormal shadow on a chest radiograph. He had worked as a hard metal tool sharpener for five years. Chest computed tomography scans showed centrilobular micronodules and areas of ground-glass opacity in the bilateral lung fields. Video-associated lung biopsy specimens revealed bronchocentric interstitial pneumonia and cellular bronchiolitis. A high-energy dispersion X-ray microanalysis detected tungsten. The patient was diagnosed with hard metal lung disease. Inhaled corticosteroid therapy (800 μg of ciclesonide hydrofluoroalkane daily) resolved the patient's symptoms, elevated KL-6 level, abnormal areas of chest opacity and obstructive, restrictive and diffusion impairments.

Elevation of serum KL-6 levels in 3 patients with rheumatoid arthritis treated with adalimumab

We describe 3 cases of rheumatoid arthritis presenting with elevated serum KL-6 levels during treatment with adalimumab, which was discontinued because of suspected onset of complications. However, no complications were observed following discontinuation despite comprehensive assessments, and KL-6 levels subsequently returned to baseline levels. In our institutes, 3 out of 29 cases treated with adalimumab showed elevated KL-6 levels. The baseline levels were 445, 347, and 547 U/ml, while the peak levels were 1010, 546, and 2007 U/ml, respectively. The elevated KL-6 levels seem to have been innocuous; nevertheless, further careful observation is deemed necessary.

Comparison of biomarkers of subclinical lung injury in obstructive sleep apnea

Obstructive sleep apnea (OSA) has both systemic and local effects partly through the increased oxidative stress caused by intermittent hypoxia and reoxygenation. However, lung-specific biomarkers in OSA have not been fully assessed in comparison with systemic biomarkers such as C-reactive protein (CRP), although results of a recent study having a small sample size indicated KL-6 as one candidate. Subjects of the present study were 197 patients suspected to have OSA. In addition to polysomnography, we also measured serum levels of KL-6, surfactant protein-D (SP-D) and CRP and pulmonary function. We examined the relationships of different biomarkers with OSA severity and pulmonary function. The apnea/hypopnea index (AHI) was significantly positively correlated with serum KL-6 levels even after adjustment for body mass index (BMI) and smoking (p=0.03), but not with SP-D and CRP. Also, a significant trend for an increase in serum KL-6 was noted in accordance with the severity of OSA even after adjustment for BMI and smoking (β coefficient=0.18, p=0.02). Additionally, elevated KL-6 levels were significantly associated with restrictive lung function disturbance and gas exchange derangement after adjustment for obesity and smoking, which contrasted with CRP whose elevations were significantly associated with worsened airflow limitation and increased lung volume. Serum KL-6 levels may reflect the degree of subclinical lung injury associated with OSA independently of obesity or smoking, unlike CRP. We consider that KL-6 can be a potential candidate as a lung-specific biomarker of OSA and might provide complementary information on systemic biomarkers in assessing OSA.

Prediction of postoperative exacerbation of interstitial pneumonia in patients with lung cancer and interstitial lung disease

Postoperative exacerbation of interstitial pneumonia in patients with lung cancer and interstitial lung disease has emerged as a serious problem. Therefore, the risk factors for postoperative exacerbation of interstitial pneumonia in patients with interstitial lung disease must be identified. We analyzed 22 patients diagnosed as having lung cancer with interstitial lung disease who underwent surgical treatment at the Kitasato University Hospital. Among the patients with lung cancer and interstitial lung disease, 5 patients (22.7%) had postoperative exacerbation of interstitial pneumonia. The prognosis of the patients with postoperative exacerbation was significantly poorer than that of patients without. Patients with postoperative exacerbation had a significantly higher age (≥75 years) and a significantly lower frequency of postoperative administration of steroid than patients without postoperative exacerbation. Almost all patients with postoperative exacerbation underwent lobectomy, had elevated KL-6 levels in the serum pre-operatively, and had significantly advanced stages of disease. Of the 5 patients with postoperative exacerbation, 2 had a history of inflammation prior to their exacerbation: 1 had a common cold and the other pyothorax. In patients with lung cancer and interstitial lung disease, advanced age, advanced stage disease, no postoperative administration of steroid and a pre-operative episode of inflammation are all risk factors for postoperative exacerbation of interstitial pneumonia.

Comparison of pulmonary thin section CT findings and serum KL-6 levels in patients with sarcoidosis

This study aimed to compare thin-section CT images from sarcoidosis patients who had either normal or elevated serum KL-6 levels. 101 patients with sarcoidosis who underwent thin-section CT examinations of the chest and serum KL-6 measurements between December 2003 and November 2008 were retrospectively identified. The study group comprised 75 sarcoidosis patients (23 male, 52 female; aged 19-82 years, mean 54.1 years) with normal KL-6 levels (152-499 U ml(-1), mean 305.7 U ml(-1)) and 26 sarcoidosis patients (7 male, 19 female; aged 19-75 years, mean 54.3 years) with elevated KL-6 levels (541-2940 U ml(-1), mean 802.4 U ml(-1)). Two chest radiologists, unaware of KL-6 levels, retrospectively and independently interpreted CT images for parenchymal abnormalities, enlarged lymph nodes and pleural effusion. CT findings in sarcoidosis patients consisted mainly of lymph node enlargement (70/75 with normal KL-6 levels and 21/26 with elevated KL-6 levels), followed by nodules (50 and 25 with normal and elevated levels, respectively) and bronchial wall thickening (25 and 21 with normal and elevated levels, respectively). Ground-glass opacity, nodules, interlobular septal thickening, traction bronchiectasis, architectural distortion and bronchial wall thickening were significantly more frequent in patients with elevated KL-6 levels than those with normal levels (p<0.001, p<0.005, p<0.001, p<0.001, p<0.001 and p<0.001, respectively). By comparison, there was no significant difference in frequency of lymph node enlargement between the two groups. These results suggest that serum KL-6 levels may be a useful marker for indicating the severity of parenchymal sarcoidosis.

Chemotherapy for advanced non-small cell lung cancer with interstitial lung disease.

e18122 Background: The treatment of lung cancer with interstitial lung disease (ILD) is challenging because the treatment, including surgery, chemotherapy, and radiotherapy, can itself induce interstitial pneumonia (IP) or exacerbate preexisting ILD. Usually, clinicians hesitate to treat lung cancer with ILD. Information on the treatment of non-small cell lung cancer (NSCLC) with comorbid ILD is extremely limited; additionally, it is not known whether chemotherapy is beneficial in advanced NSCLC patients with ILD, because most clinical trials exclude patients with ILD. Methods: We retrospectively reviewed the medical records of chemotherapy-treated advanced NSCLC patients with comorbid ILD, including idiopathic interstitial pneumonia (IIP), collagen vascular disease interstitial pneumonia (CVD-IP), pneumoconiosis, and pulmonary sarcoidosis at our institution between April 1998 and March 2007 and evaluated the overall survival and acute exacerbation rates. Results: Forty cases were treated with chemotherapy and the median overall survival was 17.5 months (95% confidence interval 15.2–19.9), which is comparable with that for advanced NSCLC without ILD. Multivariate analysis revealed that poor performance status (PS) and an elevated serum KL-6 level predicted a poor overall survival. Five cases (13%) developed an acute exacerbation of preexisting ILD during treatment and two of these patients died of the exacerbation (5%). Acute exacerbation occurred not only in IIP but also in CVD-IP and pneumoconiosis. Conclusions: Chemotherapy might have survival benefit in some NSCLC patients, even with comorbid ILD. However, to treat this safely, it is necessary to avoid those patients at a high risk of acute exacerbation (poor PS, elevated serum KL-6). To determine the efficacy of chemotherapy in NSCLC patients with a good PS, normal KL-6, and comorbid ILD, further prospective study is needed. No significant financial relationships to disclose.

Serum KL‐6 levels in lung cancer patients with or without interstitial lung disease

It is not known whether lung cancer patients with interstitial lung disease (ILD) might have higher serum levels of KL-6, a high molecular weight glycoprotein classified as a polymorphic epithelial mucin. In addition, prognosis of these patients with elevated serum KL-6 levels might be poorer than that with normal KL-6 levels, but it has not been well clarified. Serum KL-6 levels in 273 lung cancer patients with or without ILD, and prognostic significance of elevated serum KL-6 levels in these patients were studied using uni- and multivariate analyses. Serum KL-6 levels were elevated (>500 U/ml) in 73.5% of lung cancer patients with ILD and in 33.7% of those without ILD. Serum KL-6 levels in lung cancer patients with ILD were significantly higher than those without ILD. In lung cancer patients with ILD, elevated serum KL-6 has no prognostic significance, but in those without ILD, however, it was one of the unfavorable prognostic factors. Elevated serum KL-6 levels can be observed in lung cancer patients both with and without ILD. Having ILD has strong prognostic impact in patients with lung cancer. In those without ILD, however, elevated KL-6 levels may be related to poor prognosis.

Comparison of pulmonary CT findings and serum KL-6 levels in patients with cryptogenic organizing pneumonia

The aim of this study was to retrospectively compare high-resolution CT findings among cryptogenic organizing pneumonia (COP) patients with normal and elevated serum KL-6 levels. Chest CT scans performed between April 1999 and April 2007 in 20 COP patients with a normal KL-6 level and 17 COP patients with an elevated KL-6 level were evaluated retrospectively by two chest radiologists. The CT findings in the COP patients with either a normal or an elevated KL-6 level mainly consisted of consolidation (n = 17 and n = 13, respectively) followed by ground-glass opacity (n = 11 and n = 13, respectively). Traction bronchiectasis and architectural distortion were significantly more frequent in patients with an elevated KL-6 level than in those with normal levels (n = 7 and n = 1, and n = 13 and n = 3, respectively) (p = 0.0077 and p = 0.00017, respectively). In follow-up CT scans, a relapse within 1 year after initial treatment with steroids, performed in 16 patients with a normal KL-6 level and 16 with an elevated KL-6 level, occurred in 2 (12.5%) patients with a normal KL-6 level and in 6 (37.5%) with an elevated KL-6 level. The frequency of relapse in patients with an elevated KL-6 level was higher than in those with a normal KL-6 level; however, no significant difference between the two groups was observed (p = 0.103). In conclusion, CT findings of traction bronchiectasis and architectural distortion in COP patients are associated with increased serum KL-6 levels, which might be related to a relapse after treatment.

Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib

The factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases; however, it was first discovered as a lung cancer-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status. Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods. The serum KL-6 levels ranged from 199 to 9080U/ml (median, 550U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p=0.040) as well as OS (hazard ratio: 4.858, p=0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p=0.0194). Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when treated with gefitinib.

Elevated serum level of sialylated glycoprotein KL-6 predicts a poor prognosis in patients with non-small cell lung cancer treated with gefitinib

18162 Background: The Factors affecting survival after gefitinib treatment in patients with non-small cell lung cancer (NSCLC) remain to be fully elucidated, although epidermal growth factor receptor (EGFR) mutation is a substantial prognostic factor. KL-6 has been studied as a useful indicator for interstitial lung diseases, however, it was first discovered as a pulmonary adenocarcinoma-related antigen. The aim of this study was to investigate the prognostic value of the serum KL-6 levels in advanced NSCLC patients treated with gefitinib and thus determine its association with the EGFR mutation status. Methods: Between September 2002 and September 2005, 41 patients with NSCLC were treated with gefitinib after having their serum KL-6 levels measured at Okayama University Hospital. EGFR mutations were analyzed by direct sequence methods. Results: The serum KL-6 levels ranged from 199 to 9080 U/ml (median, 550 U/ml), and 54% of 41 patients showed a level higher than the cut-off level of 500 U/ml. The median progression-free survival (PFS) time and the median overall survival (OS) time were 4.7 months and 13.9 months, respectively. Multivariate analyses revealed that the elevated KL-6 level was an independent adverse prognostic factor for PFS (hazard ratio: 2.278, p = 0.040) as well as OS (hazard ratio: 4.858, p = 0.002) in NSCLC patients treated with gefitinib. The EGFR mutation status was analyzed in 22 patients (54%). Among those with wild-type EGFR, the patients with high serum KL-6 levels also had a worse survival than those within normal serum KL-6 levels (6.5 months versus 13.3 months, p = 0.0194). Conclusions: Our data suggest that NSCLC patients with high serum KL-6 levels tended to have a poor clinical outcome when treated with gefitinib. No significant financial relationships to disclose.

Serum KL-6 Level is Elevated in Chronic Hepatitis C Patients with Combination Therapy of Pegylated Interferon and Ribavirin

The aim of this study was to evaluate whether or not combination therapy of pegylated interferon (IFN) and ribavirin for chronic hepatitis (CH) C patients enhances the serum level of KL-6, a sensitive marker for interstitial pneumonia. CH C patients proven histologically and treated with combination therapy of pegylated IFN-alpha-2b and ribavirin, IFN monotherapy or untreated for 48 weeks were retrospectively selected in chronological order in groups of 25. Serum levels of KL-6 were measured by enzyme-linked immunosorbent assay by use of serum stored at -80 degrees C before and at 12, 24, 36, 48 weeks after the initiation of treatment or follow up. The average serum KL-6 levels in patients treated with combination therapy of pegylated IFN and ribavirin increased by 21% at 12 weeks after the start, 23% at 24 weeks, and 28% at 48 weeks. In patients treated with combination therapy of pegylated IFN and ribavirin, the serum KL-6 level significantly increased during treatment. Patients achieved an elevated serum KL-6 level of more than 450 U/ml with statistical significance when: 1) combination therapy was given (P=0.011), 2) serum KL-6 level pretreatment was high more than 300 U/ml (P=0.014). The present study suggests that onset of interstitial pneumonia should be carefully checked in the combination therapy of pegylated-IFN and ribavirin.

Increased levels of KL‐6 and subsequent mortality in patients with interstitial lung diseases

KL-6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL-6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL-6 are associated with increased mortality, and to identify the most suitable cut-off level of KL-6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL-6 levels in patients with stable-state ILDs. Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL-6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. During the follow-up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL-6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL(-1) as the most suitable cut-off level by which to distinguish between the two groups of patients. The 95% specificity serum KL-6 level with poor outcome was 2750 U mL(-1). In univariate and multivariate analysis, elevated serum KL-6 (>1000 U mL(-1)) in the stable state indicated poor prognosis (P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). Elevated KL-6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.