Serum KL-6 Levels Research Articles

Changes in serum KL-6 levels during short-term strict antigen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumonitis caused by avian antigens

Bird-related hypersensitivity pneumonitis (BRHP) is the most common type of fibrotic hypersensitivity pneumonitis (HP). Antigen avoidance (AA) is a key step in the diagnosis and management of HP, but not all fibrotic HP patients improve through AA. Because of the poor prognosis of fibrotic HP, predictive biomarkers to identify patients showing rapid progression during AA are urgently needed. From a retrospective review of the medical records of 1941 patients with interstitial lung disease, 75 cases of fibrotic BRHP confirmed by a provocation test or surgical lung biopsy were identified. To identify potential prognostic markers obtained at or around diagnosis, physiological and serological variables at diagnosis and the relative changes in those variables during strict AA were evaluated. Cox proportional hazards models with log-rank testing were used to compare the associations between these variables and survival. Univariate analyses showed that gender, smoking status, and the relative change in the serum levels of Krebs von den Lungen-6 (KL-6) were associated with prognosis (P=0.02, 0.04, and 0.02, respectively), but the presence of honeycombing and the forced vital capacity were not associated with survival. The relative change in KL-6 levels (greater than vs. less than a 10% decrease) was significantly associated with survival in a stratified analysis (73.9 vs. 34.9 months; P=0.04). The relative change in KL-6 levels is associated with the prognosis of patients with fibrotic BRHP independent of previously identified prognostic biomarkers. This finding could help pulmonologists identify fibrotic BRHP patients that are likely to show rapid progression.

Serum Krebs von den Lungen-6 level in the disease progression and treatment of Mycobacterium avium complex lung disease.

The lack of useful biomarkers reflecting the disease state limits the management of Mycobacterium avium complex lung disease (MAC-LD). We clarified the associations between serum KL-6 level, disease progression and treatment response. Resected lung tissues from MAC-LD patients were immunostained for KL-6. We compared serum KL-6 levels between MAC-LD and healthy control or bronchiectasis patients without nontuberculous mycobacterial lung disease (NTM-LD). Serum KL-6 level was assessed in a prospective observational study at Keio University Hospital between May 2012 and May 2016. We investigated associations between serum KL-6 level and disease progression and treatment response in patients untreated for MAC-LD on registration (n = 187). The KL-6+ alveolar type 2 cell population in the lung and serum KL-6 level were significantly higher in MAC-LD patients than in controls. Serum KL-6 level in bronchiectasis patients without NTM-LD showed no significant increase. Of the 187 patients who did not receive treatment on registration, 53 experienced disease progression requiring treatment. Multivariable Cox analysis revealed that the serum KL-6 level (aHR: 1.18, P = 0.005), positive acid-fast bacilli smear (aHR: 2.64, P = 0.001) and cavitary lesions (aHR: 3.01, P < 0.001) were significantly associated with disease progression. The change in serum KL-6 (ΔKL-6) was significantly higher in the disease progression group; it decreased post-treatment, reflecting the negative sputum culture conversion. Serum KL-6 level is associated with disease progression and treatment response. Longitudinal assessment combined with AFB smear status and presence of cavitary lesions may aid MAC-LD management.

Serum KL-6 concentrations as a novel biomarker of severe COVID-19.

Severe acute respiratory syndrome coronavirus 2–induced direct cytopathic effects against type I and II pneumocytes mediate lung damage. Krebs von den Lungen‐6 (KL‐6) is mainly produced by damaged or regenerating alveolar type II pneumocytes. This preliminary study analyzed serum concentrations of KL‐6 in patients with coronavirus disease (COVID‐19) to verify its potential as a prognostic biomarker of severity. Twenty‐two patients (median age [interquartile range] 63 [59‐68] years, 16 males) with COVID‐19 were enrolled prospectively. Patients were divided into mild‐moderate and severe groups, according to respiratory impairment and clinical management. KL‐6 serum concentrations and lymphocyte subset were obtained. Peripheral natural killer (NK) cells/µL were significantly higher in nonsevere patients than in the severe group (P = .0449) and the best cut‐off value was 119 cells/µL. KL‐6 serum concentrations were significantly higher in severe patients than the nonsevere group (P = .0118). Receiver operating characteristic analysis distinguished severe and nonsevere patients according to KL‐6 serum levels and the best cut‐off value was 406.5 U/mL. NK cell analysis and assay of KL‐6 in serum can help identify severe COVID‐19 patients. Increased KL‐6 serum concentrations were observed in patients with severe pulmonary involvement, revealing a prognostic value and supporting the potential usefulness of KL‐6 measurement to evaluate COVID‐19 patients' prognosis.

THU0115 THE VALUE OF KL-6 AS A PREDICTIVE FACTOR OF ACUTE EXACERBATION IN PATIENTS WITH RHEUMATOID ARTHRITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE.

Background: Acute exacerbation (AE) is a life-threatening complication in connective tissue disease (CTD) associated interstitial lung disease (ILD) (CTD-ILD), including rheumatoid arthritis (RA). Although several risk factors for AE in CTD-ILD have been suggested, these are inconsistent. Krebs von den Lungen-6 (KL-6) is reported as a useful blood marker to detect severe CTD-ILD and RA-ILD, and serum KL-6 levels are significantly higher in patients with AE than in those without AE in RA-ILD patients [1]. However, the predictive value of KL-6 for AE in CTD-ILD or RA-ILD has not been completely confirmed. Objectives: To investigate the predictive factors for AE including initial serum KL-6 levels at RA-ILD onset and sequential changes of KL-6. We also examined the causal relationship between AE and mortality of RA-ILD patients. Methods: We retrospectively reviewed 115 patients with RA-ILD treated in our hospital between 2005 and 2019. Suspected drug-induced pneumonia cases or patients with other coexisting CTD were excluded. Cox regression analyses was used for univariate analysis to detect predictors of AE. Overall survival rate, respiratory-related deaths-free survival rate and AE-free survival rate were analyzed using the Kaplan-Meier method. P Results: Among 115 patients, 29 patients (25.2%) developed AE and 32 patients (27.8%) died. The median follow-up period (IQR) was 57 (25.0-91.5) months, 57.4% were female and the mean age at RA-ILD onset was 72.2 ± 7.9 years old throughout the whole cohort. Among the AE group, methotrexate (MTX), tumor necrosis factor α inhibitor (TNFi) and non TNFi biological-DMARDs were used at AE onset in 10.7%, 0.0%, and 3.6% of patients, respectively. There was a significant difference of serum KL-6 levels at AE onset between AE group and non-AE group (1081.9 ± 624.7 vs 556.1 ± 285.6 U/mL, p 551 U/mL at RA-ILD onset (HR: 2.46; 95%CI: 1.17-5.43; p = 0.018), increasing serum KL-6 levels > 10% before AE onset compared to the previous year (ΔKL-6 > 10%/year) (HR: 4.98; 95%CI: 2.17-11.84; p 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE were also significant prognostic factors for AE when we analyzed only in non-UIP patients (HR: 2.84; 95%CI: 1.15-7.35; p = 0.024, HR: 9.49; 95%CI: 3.02-36.25; p 551 U/mL at RA-ILD onset and ΔKL-6 > 10%/year before AE had a significantly worse AE-free survival rate compared to others (p Conclusion: Serum KL-6 levels at the disease onset and its sequential changes may be able to predict AE in the near future and support the early detection of AE in RA-ILD patients.

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 800.0U/ml and baseline level of serum CXCL13 was higher than the cut-off value of 62.0pg/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.

OP0038 IMPROVING RISK-STRATIFICATION OF RHEUMATOID ARTHRITIS PATIENTS FOR INTERSTITIAL LUNG DISEASE

Background: Interstitial lung disease (ILD) is the most common pulmonary manifestation of rheumatoid arthritis (RA). It has emerged in recent series as a key prognostic factor including survival. The big challenge for rheumatologists is now the risk-stratification of RA patients for ILD. Chest high-resolution computed tomography (HRCT) is the gold standard for RA-ILD diagnosis, but costs and ionizing radiation may limit its use in clinical practice. Thus, circulating biomarkers could aid in this risk-stratification. Objectives: to evaluate the merit of 3 circulating markers for the diagnosis and the progression of RA-ILD. Methods: We included consecutive patients with RA, >18 years of age, from 3 tertiary rheumatology centers (Paris, France, Tokyo, Japan and Zurich, Switzerland) over a 36-month period. All patients had at least one chest HRCT during the inclusion period. In the subset of French patients with ILD, HRCT lung images were obtained both at baseline (time of blood sample collection) and at a follow-up visit. The ILD status of patients with RA was established by chest HRCT. The chest HRCT pattern was classified as usual interstitial pneumonia, UIP or non-specific interstitial pneumonia, NSIP, by the local radiologist. Serum levels of lung epithelial-derived surfactant protein D, SDP, CCL-18 et Krebs von den Lungen-6 glycoprotein, KL-6 were measured by ELISA. Results: 147 patients were included (age: 66+/-12 ans, 69% of women, disease duration 11+/-10 years). Among these patients, 40 (27%) had fibrosing ILD on HRCT: 21 had a UIP pattern, 17 a NSIP pattern, and 2 had NSIP associated with chronic obstructive pulmonary disease. SPD (21.91+/-2.17 vs. 15.76+/-1.34 ng/mL, p=0.017) CCL18 (102+/-13 vs. 78+/-5 ng/mL, p=0.026) and KL6 (961+/-128 vs. 376+/-26 U/mL, p 15% as compared to patients with milder disease. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72-0.86) compared to SPD (AUC: 0.66 95% CI 0.58-0.74) and CCL18 (AUC: 0.62, 95% CI 0.53-0.70) (Figure 1D). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. In the French subset with longitudinal data (n=15), extension of ILD was detected on 7 patients. Baseline KL6 serum levels were significantly increased in patients who experienced ILD progression (1987+/-1294 vs. 799+/-375 U/mL, p=0.027) (Figure 1E). The degree of ILD progression on HRCT was also proportional to baseline KL-6 concentrations (Figure 1F). Conclusion: KL-6 is relevant for the diagnosis and the prognosis of RA-ILD. It may be used as a circulating non-invasive first-line marker to stratify for indication of HRCT. Indeed, given the emerging lung issues in RA patients, this simple and highly reproducible marker, which is already available in routine care in some countries, could be a good prerequisite to chest HRCT in rheumatology clinics. Disclosure of Interests: Jerome Avouac Grant/research support from: Pfizer, Bristol Myers Squibb, Consultant of: Sanofi, Bristol Myers Squibb, Abbvie, Boerhinger, Nordic Pharma, Speakers bureau: Sanofi, Bristol Myers Squibb Abbvie, MSD, Pfizer, Nordic Pharma, Alexia Steelandt: None declared, Anne Cauvet: None declared, Yuichiro Shirai: None declared, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi

Improving risk-stratification of rheumatoid arthritis patients for interstitial lung disease.

ObjectiveTo determine the performance of 3 circulating markers for the diagnosis and the progression of interstitial lung disease (ILD) associated with rheumatoid arthritis (RA).MethodsSerum concentrations of 3 circulating markers, lung epithelial-derived surfactant protein D (SPD), chemokine CCL-18 and Krebs von den Lungen-6 glycoprotein (KL-6), were measured by ELISA in consecutive patients with established RA. These patients were recruited from 3 tertiary centers and they all had been investigated by chest high-resolution computed tomography (HRCT). For a subset of French patients, a follow-up HRCT was available (mean interval between HRCT: 3±1.5 years).ResultsAmong the 147 included patients (age: 66 ± 12 years, 69% women, disease duration 11 ± 10 years), 40 (27%) had RA-ILD on chest HRCT. SPD, CCL18 and KL-6 concentrations were significantly higher in patients with RA-ILD. ROC curve analysis to assess the diagnostic abilities of the three markers for the diagnosis of RA-ILD showed a superiority of KL-6 (Area under the curve, AUC: 0.79 95% CI 0.72–0.86) compared to SPD (AUC: 0.66 95% CI 0.58–0.74) and CCL18 (AUC: 0.62, 95% CI 0.53–0.70). The sensitivity of KL-6 for the diagnosis of RA-ILD was 68% with a specificity of 83%. The combination of KL-6 with SPD and CCL18 improved its diagnostic ability, with increased sensitivity from 68% to 77%, specificity from 83% to 97%. Increased KL-6 levels were independently associated with the presence of RA-ILD after the adjustment on other RA-ILD risk factors. In the French subset with longitudinal data, baseline KL-6 serum levels were predictive of ILD progression and the degree of ILD progression on HRCT was proportional to baseline KL-6 concentrations.ConclusionThese results show that KL-6 is a relevant circulating marker for the diagnosis and might be an interesting marker for the progression of RA-ILD.

Melatonin Supplementation as Adjuvant Therapy for the Prevention of Bronchopulmonary Dysplasia in Neonates

Background: Neonatal bronchopulmonary dysplasia (BPD) is a chronic chest disease caused by prolonged ventilation and oxygenation which leads to neonatal disability.Methods: It was a prospective randomized clinical trial (RCT) (Study ID: TCTR20191211004) which was conducted in Tanta University Hospital (TUH) from July 2016 to March 2018 on 100 preterm neonates who exhibited severe respiratory distress (RD) on mechanical ventilation (MV). The studied neonates were assigned to two groups: group one which received melatonin supplementation and group two which did not. Urinary β2-microglobulin (B2M) and serum Krebs von den Lungen-6 (KL-6) levels were measured 3 and 10 days after hospitalization. The length of neonates’ stay in incubator was determined, and the number of newborns with established BPD was calculated.Results: Significant decreases were detected in urinary B2M and serum KL-6 levels of neonates in group one who received melatonin, as compared to their counterparts in group two who did not take melatonin (P< 0.05). In addition, there was a significant decline in the length of incubator stay of neonates in group one, in comparison to that of newborns in group two (P<0.05). Moreover, neonates in group one who received melatonin displayed a significant decline in the development of established cases of BPD, as compared to group two who did not take melatonin (P<0.05).Conclusion: As evidenced by the obtained results, melatonin supplementation could be used as adjuvant therapy for the prevention of BPD in preterm neonates. Nonetheless, further studies involving a larger number of neonates must be performed on this topic in order to recommend melatonin administration for ventilated premature neonates who are susceptible to the development of neonatal BPD.

Clinical course of Japanese patients with early systemic sclerosis: A multicenter, prospective, observational study

Objectives To investigate the clinical course of Japanese patients with early diffuse cutaneous systemic sclerosis (dcSSc) and early SSc with interstitial lung disease (ILD). Methods We prospectively analyzed the clinical features of 207 Japanese patients with early dcSSc (n = 150) and limited cutaneous SSc (lcSSc) with ILD (n = 57) in 10 medical centers every year for 7 consecutive years. Results Mean modified Rodnan total skin thickness score (mRSS) was 18.3 and 67.4% of the cohort had ILD. Most patients started immunosuppressive therapy and vasodilators during 7 years (83.4% and 87.9%, respectively). Mean value of mRSS of total patients was significantly reduced from the initial registration after the first year. However, other parameters for physical function associated with skin sclerosis including fist closure, hand extension, and oral aperture were not so ameliorated during the study period. Health Assessment Questionnaire-disability index and serum KL-6 levels were constant throughout the course. Percent vital capacity and the presence of ILD, clinically suspected pulmonary arterial hypertension, and digital ulcers were gradually exacerbated during the period. Conclusion In Japanese early dcSSc patients and SSc patients with ILD, mRSS was continuously reduced during 7 years of follow-up, but there was little improvement of physical disability and organ involvement.

Elevated serum KL-6 in pediatric asthma exacerbation: a proof of alveolar injury

Background: Asthma is one of the most popular chronic diseases in children. It is defined as a complicated inflammatory disorder in which the patient suffers from chronic and persistent inflammation of the airways. The sialylated glycoprotein Krebs von den Lungen-6 (KL-6), one of the lung epithelium-specific proteins, has been recognized as a significant biomarker which directly associates with interstitial lung disease (ILD) pathogenesis, indicating the extent of damage and regeneration of type II pneumocytes. Objective: the aim of this study is to investigate the degree of alveolar damage in asthmatic children with acute exacerbation as reflected by serum KL-6 levels. Methods: This cross-sectional controlled study included 50 patients with acute asthma exacerbation diagnosed as per the GINA guidelines definition and 50 age- and sex-matched healthy children as controls. Spirometry was done for all participants. Serum KL-6 level was estimated by Enzyme Linked Immunosorbent Assay (ELISA), and total serum IgE level was measured via the electrochemiluminescence technology. Results: The asthma patients included 35 (70%) males and 15 (30%) females with mean age of 10.76 ±1.9 years. Forty-seven patients (94%) had a positive family history of bronchial asthma and 32 (64%) had other atopic manifestations The mean serum KL-6 level in patients was more than double the mean level of the control group (115.79 vs 55.64). No significant relation was observed between KL-6 serum level and age, family history of asthma, seasonal variation, or atopic manifestation among the cases. Serum total IgE levels were significantly higher in cases compared to controls (P<0.05). Conclusion: Serum KL-6 levels in pediatric asthma patients may be a useful diagnostic tool for detecting and monitoring the severity of airway inflammation. The use of serum KL-6 alone may help to differentiate between asthmatic patients in exacerbation and healthy controls.

Characteristics and clinical significance of pulmonary function test and KL-6 in ASSD-ILD and IPF

Objective: To study the characteristics and clinical significance of pulmonary function test and kerbs von den lungen 6 (KL-6) in anti-synthetase syndrome related interstitial lung disease (ASSD-ILD) and idiopathic pulmonary fibrosis (IPF). Methods: The clinical data of 43 patients with ASSD-ILD (ASSD-ILD group) from May 2015 to May 2017 were collected retrospectively, including 12 males and 31 females, and 34 patients with IPF (IPF group) treated in the First Affiliated Hospital of Zhengzhou University during the same period, including 28 males and 6 females, were also included. The basic information, and the value of pulmonary function test [pulmonary function parameters included the forced vital capacity expressed as percent predicted (FVC%pred), the forced expiratory volume in 1 second expressed as percent predicted (FEV(1)%pred), the ratio of FVC to FEV(1) (FVC/FEV(1)), the peak expiratory flow expressed as percent predicted (PEF%pred), the forced expiratory flow at 25%, 50%, 75% of FVC as percent predicted (FEF(25)%pred, FEF(50)%pred, and FEF(75)%pred), the maximum mid-expiratory flow as percent predicted (MMEF% pred), and the diffusing capacity for carbon monoxide as percent predicted (DLCO% pred)], and serum KL-6 level in ASSD-ILD and IPF were compared. Results: The FEV(1)%pred, FEF(50)%pred, FEF(75)%pred, and MMEF%pred values in ASSD-ILD group were significantly lower than those in IPF group (all P<0.05), while the FVC% pred, FVC/FEV(1), PEF% pred, FEF(25)%pred, and DLCO% pred values in ASSD-ILD group had no significant difference compared with IPF group (all P>0.05). There was no significant difference in serum KL-6 level between ASSD-ILD group and IPF group [(1 169±911) vs (1 210±908) U/ml, t=0.62, P=0.463]. Follow-up analysis showed that the serum KL-6 level of ASSD-ILD patients who died within two years was significantly higher than that of survivors [(2 060±1 168) vs (1 042±858) U/ml, t=2.93, P=0.041]. The serum KL-6 level of patients who died within two years of IPF patients was also significantly higher than that of patients who survived [(1 767±865) vs (1 089±894) U/ml, t=2.53, P=0.026]. The serum KL-6 level in ASSD-ILD group was negatively correlated with FVC%pred (r=-0.43, P=0.004), FEV(1)%pred (r=-0.39, P=0.010) and DLCO% pred (r=-0.41, P=0.006). There was no correlation between serum KL-6 level and pulmonary function test indexes in IPF group (all P>0.05). Conclusions: There is difference in pulmonary function test between ASSD-ILD patients and IPF patients. High serum KL-6 level will be predictive of poor prognosis.

Therapeutic efficacy of combined glucocorticoid, intravenous cyclophosphamide, and double-filtration plasmapheresis for skin sclerosis in diffuse systemic sclerosis

We treated skin sclerosis with triple therapy consisting of a glucocorticoid, intravenous cyclophosphamide, and double-filtration plasmapheresis. The objective of this study was to analyze its effectiveness in a case series of patients who received triple therapy.We enrolled 8 patients with diffuse cutaneous systemic sclerosis (dcSSc) who received triple therapy at our hospital from 2008 to 2016. We analyzed the mean change in the modified Rodnan skin score (mRSS), percentage of the predicted forced vital capacity (%FVC), percentage of the predicted carbon monoxide diffusing capacity (%DLCO), and serum KL-6 levels from baseline to follow-up.All patients were treated with an intermediate dose of oral prednisolone (30.6 ± 2.1 mg/day) initially. The mean cumulative dose of intravenous cyclophosphamide was 1.4 ± 0.2 g. The mean mRSS decreased significantly at follow-up compared with that at baseline (27.0 ± 3.3 vs 15.8 ± 3.5; P = .03). At the end of the treatment, the mean %FVC and %DLCO were improved moderately, although the differences were not significant. The serum KL-6 levels decreased from 578.9 ± 146.5 to 205.3 ± 43.1 U/ml (P = .02). No significant correlation was found between the change in mRSS or disease duration and the initial skin score severity.Triple therapy may improve skin sclerosis, with effectiveness equal or superior to other reported treatments. This preliminary case series demonstrates the potential of triple therapy for treating dcSSc. However, prospective studies with long-term follow-up should be performed to assess its role.

Prognostic Value of Serum Osteopontin in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Background Acute exacerbation (AE) is a common cause of rapid deterioration and high mortality in idiopathic pulmonary fibrosis (IPF) patients. Osteopontin (OPN) plays an important role in IPF, but the studies about serum OPN in AE-IPF are unclear. We aimed to investigate whether OPN had a potential prognostic value in acute exacerbation and mortality in IPF. Methods Thirty-two patients with AE-IPF, 39 with S-IPF, and 20 healthy controls were included. Serum OPN and KL-6 levels were compared between AE-IPF and S-IPF. Logistic regression analysis was applied to identify the predicted value of OPN for AE. Kaplan–Meier curves were used to display survival, and Cox proportional hazards regression was used to identify risk for mortality. Results In AE-IPF patients, serum OPN levels were significantly higher than in S-IPF subjects (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (Conclusion Elevated OPN could be a potential serum predictor for AE status and survival in IPF patients.

Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF.MethodsWe retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group.ResultsForty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months − 6.0% vs 16.7%, 6 months − 10.2% vs 20.2%, KL-6: 3 months − 9.2% vs 6.7%, 6 months − 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = − 0.46 and r = − 0.39, p < 0.01, respectively) and %DLco (r = − 0.67 and r = − 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively).ConclusionsChanges in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.

Use of serum KL-6 level for detecting patients with restrictive allograft syndrome after lung transplantation.

KL-6 is an antigen produced mainly by damaged type II pneumocytes that is involved in interstitial lung disease. Chronic lung allograft dysfunction (CLAD) after lung transplantation (LT) is a major concern for LT clinicians, especially in patients with restrictive allograft syndrome (RAS). We investigated KL-6 levels in serum and bronchoalveolar lavage fluid (BALF) as a potential biomarker of the RAS phenotype. Levels of KL-6 in serum and BALF were measured in 73 bilateral LT recipients, and patients were categorized into 4 groups: stable (ST), infection (LTI), bronchiolitis obliterans syndrome (BOS), and RAS. We also studied a healthy cohort to determine reference values for serum KL-6. The highest levels of KL-6 were found in the serum of patients with RAS (918 [487.8–1638] U/mL). No differences were found for levels of KL-6 in BALF. Using a cut-off value of 465 U/mL serum KL-6 levels was able to differentiate RAS patients from BOS patients with a sensitivity of 100% and a specificity of 75%. Furthermore, higher serum KL-6 levels were associated with a decline in Forced Vital Capacity (FVC) at 6 months after sample collection. Therefore, KL-6 in serum may well be a potential biomarker for differentiating between the BOS and RAS phenotypes of CLAD in LT recipients.

The value of serum Krebs von den lungen-6 as a diagnostic marker in connective tissue disease associated with interstitial lung disease

ObjectivesThe purpose of this study was to evaluate the value of serum krebs von den lungen-6 (KL-6) level as a diagnostic indicator for connective tissue disease associated with interstitial lung disease (CTD-ILD).MethodsOne hundred fifty five patients with newly diagnosed CTD in our hospital were enrolled and divided into two groups by their ILD manifestations, the CTD-ILD group and the CTD group. In parallel, 61 patients with pulmonary infection and 60 cases of healthy subjects were also enrolled into the study. The difference of serum KL-6 level among the four groups were compared. In CTD-ILD group, carbon monoxide diffusing capacity (DLCo) and high-resolution computed tomography (HRCT) of lung were also tested. The serum KL-6 level of 32 patients from the CTD-ILD group who received cyclophosphamide (CTX) pulse therapy were sampled and measured, by enzyme linked immunosorbent assay (ELISA), at three time points: before treatment, 3 months after treatment and 6 months after treatment.ResultsThe serum KL-6 level in the CTD-ILD group (1004.9 (676.41738.1) IU/ml) is significantly higher than three other groups (χ2 = 72.29, P < 0.001). In the CTD-ILD group the level of serum KL-6 was positively correlated with disease severity on HRCT (r = 0.75, P < 0.001), while was negatively correlated with DLCo (r = − 0.50, P < 0.001). In 32 patients who received CTX pulse therapy, the level of serum KL-6 was gradually decreased in 20 cases whose lesions were absorbed within 6 months (F = 13.67, P < 0.001), whereas it remained unchanged in the rest of 12 patients (Z = -1.328, P = 0.198).ConclusionsSerum KL-6 level can potentially serve as a diagnostic marker for CTD-ILD and be utilized to evaluate the effectiveness of CTX pulse therapy.

Correlation between Serum Krebs von den Lungen-6 Levels with Forced Vital Capacity and Modified Rodnan Skin Score of Patients with Restrictive Lung Disease in Diffuse-Type Systemic Sclerosis

Background Pulmonary fibrosis / intersitial lung disease (ILD) in systemic sclerosis (SSc) is a complicated restrictive pulmonary disease and the leading cause of disease-related mortality. Progressive skin fibrosis in diffuse-type SSc (dSSc) is associated with decreased forced vital capacity (FVC). Modified Rodnan Skin Score (mRSS) examination is used as a parameter to assess skin fibrosis, while high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) are used to assess pulmonary fibrosis. The HRCT test remains as the gold standard in diagnosing ILD. However, it costs a lot and is not available in all healthcare facilities. Krebs Von den Lungen-6 (KL-6) is a biomarker to evaluate pulmonary fibrosis. The aim of this study was to analyze the correlation of serum KL-6 levels with FVC and mRSS value of patients with restrictive lung disease in dSSc.&#x0D; Method This was a cross-sectional study that used primary data from dSSc patients who visited rheumatology outpatient clinic in Hasan Sadikin Hospital Bandung, Indonesia, during the period of June-July 2019. History taking, physical examination, mRSS, spirometry, and serum KL-6 levels were performed. Data were analyzed using the Rank Spearman correlation test. &#x0D; Result There were 27 subjects with the mean age of 42 ± 12 years. Based on FVC (%) restrictive lung disease criteria, the majority of subjects (74.1%) had severe restrictive lung disease and the rest of all subjects (25.9%) were non severe restrictive lung disease. Serum KL-6 levels ranged from 0.545 to 8.138 ng/ml. The results showed that there was no correlation between serum KL-6 levels and FVC values (r = -0.118, p = 0.279) and mRSS (r = 0.101, p = 0.312 ).&#x0D; Conclusion There is no correlation between serum KL-6 levels with FVC and mRSS value of patient with restritive lung disease in diffuse type systemic sclerosis.&#x0D; Keywords : diffuse type systemic sclerosis, Forced Vital Capacity, KL-6, mRSS, restrictive lung disease.&#x0D; &#x0D; &#x0D;

Lung ultrasound B-lines and serum KL-6 correlate with the severity of idiopathic inflammatory myositis-associated interstitial lung disease.

ObjectiveIdiopathic inflammatory myositis-associated interstitial lung disease (IIM-ILD) significantly increases morbidity and mortality. Lung ultrasound B-lines and Krebs von den Lungen-6 (KL-6) are identified as new sonographic and serum markers of ILD, respectively. The aim of our work was to assess the role of B-lines and KL-6 as markers of the severity of IIM-ILD. For this purpose, the correlation among B-lines score, serum KL-6 levels, high-resolution CT (HRCT) score, and pulmonary function tests were investigated in IIM-ILD patients.MethodsThirty-eight patients with IIM-ILD underwent chest HRCT scans, lung ultrasound and pulmonary function tests (independently performed within 1 week) examination. To assess severity and extent of ILD at HRCT, the Warrick score was used. The B-lines score denoting the extension of ILD was calculated by summing the number of B-lines on a total of 50 scanning sites. Serum KL-6 levels (U/ml) was measured by chemiluminescent enzyme immunoassay.ResultsA significant correlation was found between the B-lines score and serum KL-6 levels (r = 0.43, P < 0.01), and between the Warrick score and serum KL-6 levels (r = 0.45, P < 0.01). A positive correlation between B-lines score and the Warrick score (r = 0.87, P < 0.0001) was also confirmed. Both B-lines score and KL-6 levels inversely correlated to diffusion capacity for carbon monoxide (r = −0.77, P < 0.0001 and r = −0.42, P < 0.05, respectively) and total lung capacity (r = −0.73, P < 0.0001 and r = −0.36, P < 0.05, respectively). Moreover, B-lines correlated inversely with forced vital capacity (r = −0.73, P < 0.0001), forced expiratory volume in 1 s (r = −0.69, P < 0.0001).ConclusionB-lines score and serum KL-6 levels correlate with HRCT findings and pulmonary function tests, supporting their use as measures of IIM-ILD severity.

Serum KL-6 level as a biomarker of interstitial lung disease in childhood connective tissue diseases: a pilot study.

Krebs von den Lungen-6 (KL-6) has been described as a promising biomarker in the diagnosis and determining the severity of interstitial lung disease in adults with connective tissue disease. This study was performed to determine whether the serum KL-6 level is useful as a biomarker for detecting the interstitial lung disease (ILD) in pediatric cases of connective tissue disease (CTD). In total, 88 patients [36 patients with systemic juvenile idiopathic arthritis (sJIA), 27 patients with juvenile systemic lupus erythematosus (JSLE), 14 patients with juvenile dermatomyositis (JDM), and 11 patients with juvenile systemic sclerosis (JSSc)] and 68 healthy controls were included in this study. Age, sex, and duration of CTD and ILD (if any) were recorded. Blood samples from all the patients and controls were examined by ELISA. Eleven of the 88 patients with CTD (12.5%) had ILD and all of them were symptomatic. Subgroup analysis indicated that eight patients had JSSc, two had JSLE, and one had systemic JIA. The median serum KL-6 level was 1450.5U/mL (interquartile range (IQR) 742.9-2603.2) in the CTD with ILD group, 415.9U/mL (IQR 233.4-748.4) in the CTD without ILD group, and 465.9U/mL (IQR 273.6-1036) in the control group. KL-6 levels were significantly higher in the CTD with ILD group than the CTD without ILD group and the control group (p = 0.003). At a cut-off of 712.5 U/ml identified by ROC curve, serum KL-6 yielded a sensitivity of 81% and specificity of 72% for CTD with ILD group. There was no significant difference in serum KL-6 level among the disease subgroups (sJIA, JSLE, JSSc, JDM), in either the CTD with ILD group or the CTD without ILD group (p > 0.05). In conclusion, KL-6 is a useful biomarker of CTD with ILD in pediatric patients.

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 800.0U/ml and baseline level of serum CXCL13 was higher than the cut-off value of 62.0pg/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.