Serum KL-6 Research Articles

Serum KL-6 in pulmonary alveolar proteinosis: China compared historically with Germany and Japan

KL-6 is a biomarker of the severity of pulmonary alveolar proteinosis (PAP). We noticed a significant difference in the mean serum KL-6 level between Japanese and Caucasian patients. To assess the clinical value of serum KL-6 in Chinese PAP patients, and to compare the differences in serum KL-6 levels in Chinese patients and patients of other ethnicities. From 2014-2016, we prospectively examined 37 Chinese Han patients with PAP, measured their serum KL-6 levels, evaluated the correlation between initial KL-6 levels and clinical variables, and compared our results with studies from Japan and Germany (similar methods were used). We searched dbSNP for the MUC1 568 (rs4072037) genotype or allele frequency distributions in China, Japan, and Germany. Initial serum KL-6 levels were significantly correlated with baseline PaO2, A-aDO2, DLCO, FVC, and LDH levels (all P<0.001). Compared with Chinese PAP patients, the mean serum KL-6 level was significantly lower in German PAP patients (P<0.001) but not in Japanese PAP patients (P>0.4). In the rs4072037 allele frequency distributions, the frequency of the A/A genotype was significantly higher while that of the G/G genotype was significantly lower in Chinese and Japanese cohorts than in Caucasian cohorts (both P<0.001). Serum KL-6 can be used as a biological indicator for disease monitoring in Chinese patients. The difference in serum KL-6 level among Chinese, German, and Japanese PAP patients may be associated with the distribution of the rs4072037 genotype.

Prognostic Significance of a Tumor Marker Index Based on Preoperative Serum Carcinoembryonic Antigen and Krebs von den Lungen-6 Levels in Non-Small Cell Lung Cancer

Background:We retrospectively analysed the prognostic significance of a tumor marker index (TMI) based on preoperative serum carcinoembryonic antigen (CEA) and Krebs von den Lungen-6 (KL-6) levels in nonsmall cell lung cancer (NSCLC) patients.Materials and Methods:We enrolled 176 NSCLC patients who had preoperative serum CEA and KL-6 level measurements and had undergone curative surgery between 2009 and 2011.Results:The 5-year disease-specific survival of patients with high serum CEA levels was significantly poorer compared with that of patients with normal levels. The value for patients with high serum KL-6 levels was also poor. Patients with both normal serum CEA and KL-6 levels had a favourable prognosis, whereas those with both high serum CEA and KL-6 levels had a poor outcome. The5-year disease-specific survival rate was 82.9% for patients in the low TMI group compared to 47.5% in the high TMI group (p<0.01). Both univariate and multivariate analyses revealed prognostic significance for TMI.Conclusions:TMI based on preoperative serum CEA and KL-6 levels might be useful for the prediction of the prognosis of NSCLC patients.

P1.03-025 Serum KL-6 Levels in Patients with Lung Cancer

Serum levels of KL-6 are widely used as an indicator of activity of interstitial lung disease. Although KL-6 was initially developed as a serum marker for malignancies, it is still unknown if KL-6 can be used as a biological marker of lung cancer. This study aimed to determine the properties of serum KL-6 levels in patients with lung cancer. First, serum KL-6 elimination kinetics after resection of lung cancer was investigated in 7 patients. Postoperative time course of serum KL-6 levels was analyzed using non-linear least square analysis with the fitting equation; C(t)=C0exp(-kt)+Cp, where k is the rate constant of elimination. The biological half-life was calculated as loge2/k. Next, serum KL-6, CEA, and CYFRA levels of patients with lung cancer and benign chest disease were retrospectively reviewed. A total of 226 patients with lung cancer and 103 patients with benign chest disease were included in this study. Serum KL-6 levels were measured using the electrochemiluminescence immunoassay method. The cut-off level of KL-6 was 500 U/ml. Rate constant of elimination and biological half-life of KL-6 in initial 7 patients were 0.827±0.275 day-1 and 0.93±0.35 day, respectively. These data implies that lung cancer cells produce KL-6 molecule and release it into the serum. Among 329 patients, serum KL-6 levels were above the cut-off level in 44 patients (19.5%) with lung cancer and 4 patients (3.9%) with benign chest disease. The mean serum KL-6 level in patients with lung cancer was significantly (p=0.0027) higher (375 ± 232 U/ ml) than that in patients with benign chest disease (296 ± 177 U/ml). Serum KL-6 levels in patients with lung cancer were significantly correlated with tumor size (p<0.0001), stage (p<0.0001), and individual TNM descriptors (T; p<0.0001, N; p=0.0047, M; p=0.0003). ROC analysis revealed that AUC of KL-6 was 0.6348 (p=0.0015), and that was inferior to CEA (AUC=0.8127, p<0.0001) and CYFRA (AUC=0.7103, p<0.0001). The sensitivity, specificity, true positive rate, true negative rate, and accuracy of KL-6 were 19.5%, 95.0%, 91.7%, 35.2%, and 43.5%, respectively. Serum KL-6 levels are well correlated with the progressiveness of lung cancer. KL-6 might be useful as a biological marker to monitor the recurrence and the effect of therapy in lung cancer.

Preoperative Serum Krebs Von Den Lungen-6 and Surfactant Protein-D Levels in Non-Small Cell Lung Cancer Patients with Interstitial Pneumonia

We retrospectively analyzed the prognostic significance of preoperative serum Krebs von den Lungen-6 (KL-6) surfactant protein-D (SP-D) levels in non-small cell lung cancer (NSCLC) patients with interstitial pneumonia (IP). We enrolled 41 NSCLC patients with IP who have undergone curative surgery. Prognostic significance of serum KL-6 and SP-D levels was examined. We found a significant relationship between serum KL-6 and SP-D levels in NSCLC patients with IP. However, the 5-year survival of patients with high serum KL-6 level was poor, whereas serum SP-D level was not related to patients’ survival. Univariate analysis revealed that there was a trend towards an association between serum KL-6 level and patients’ prognosis but this did not reach statistical significance. This might be due to small number of study patients. In conclusion, there is a possibility that serum KL-6 level is a prognostic marker regardless of the presence of IP.

The Serum Level of KL-6 Is Associated with the Risk of Insulin Resistance and New-onset Diabetes Mellitus: The Tanno-Sobetsu Study.

Objective Inflammatory cytokines generated in visceral fat have been shown to contribute to the development of insulin resistance. The involvement of pulmonary inflammation in insulin resistance remains unclear, but smoking is known to be a risk factor for diabetes as well as chronic obstructive pulmonary disease. We herein examined the hypothesis that increased serum levels of lung interstitial injury biomarkers [surfactant protein (SP)-A, SP-D and Krebs von den Lungen (KL)-6] are associated with the risk of diabetes development. Methods For cross-sectional and longitudinal analyses, we enrolled 750 apparently healthy non-diabetic subjects who received annual examinations in 2011 or 2012 in the Tanno-Sobetsu cohort. Results A cross-sectional analysis showed that distinct clinical parameters were associated with SP-A, SP-D and KL-6. In a multiple regression analysis, independent explanatory variables were Brinkman index and brain natriuretic peptide (BNP) for SP-A, sex (women), BNP and body mass index (BMI) for SP-D, and age and BMI for KL-6. A longitudinal analysis of 415 subjects who received annual examinations in both 2011 and 2014 showed that 13 (3.1%) of the patients developed type 2 diabetes during the 3-year follow-up. A multiple logistic regression analysis showed the KL-6 levels, systolic blood pressure and homeostasis model assessment of insulin resistance (HOMA-IR) in 2011 to be independently associated with new-onset diabetes. In a multiple regression analysis for HOMA-IR in 2014, the KL-6 level and BMI in 2011 were selected as explanatory variables. Conclusion A modest elevation of the serum KL-6 level is therefore considered to be associated with the risk for insulin resistance development and new-onset diabetes mellitus in a general population.

Research progress and clinical significance of serum KL-6 mucin and Clara cell secretory protein non small cell lung cancer

KL-6 mucin(KL-6) is a glycoprotein encoded by the MUC1 gene, a number of previous studies had indicated that KL-6 has a positive role in the diagnosis of interstitial lung disease.Recent studies have found that KL-6 has a role in predicting the recurrence of non-small cell lung cancer metastasis, and evaluation for the effect of chemotherapy, radiotherapy and targeted therapy for lung cancer.As a marker of lung injury, the inhibitory effect of Clara cell secretory protein(CC16) on lung cancer has been reported repeatedly in recent years, and the potential value of the two in the detection of non small cell lung cancer is important. Key words: KL-6 mucin; Clara cell secretory protein; Non small cell lung cancer

Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis.

The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study. Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (ΔFVC), and the rate of decline (%ΔFVC). Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in ΔFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 ≥1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-6 <1000ml and no serial increases in KL-6 had the least decline in ΔFVC and %ΔFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values <1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000U/ml (p<0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes >51.8U/ml/year than in those with serial KL-6 changes <51.8U/ml/year (p=0.0009). Thus, serial serum KL-6 measurements can be useful for assessing prognosis in patients with IPF.

全肺洗浄前後で血清KL-6, SP-AおよびSP-D値を測定し得た肺胞蛋白症の1例

全肺洗浄前後で血清KL-6, SP-AおよびSP-D値を測定し得た肺胞蛋白症の1例

Association of anti-aminoacyl-transfer RNA synthetase antibody and anti-melanoma differentiation-associated gene 5 antibody with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease.

We attempted to clarify whether the presence of anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) or anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is associated with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). We retrospectively investigated 22 patients with PM/DM-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab) for whom antibody analysis of conserved serum was possible. We assessed mortality in the first three months as the therapeutic response in the acute phase and compared changes in clinical data for up to one year considered as the chronic phase. We classified the clinical changes over the year into three groups: Improvement (increased % vital capacity [%VC] or diffusing capacity of the lung for carbon monoxide [%DLCO]≥10 or 15%), deterioration (decreased %VC or %DLCO≥10 or 15%), and no change (remainder of the changes). The extent of abnormality demonstrated by high-resolution computed tomography (HRCT) was scored. Positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %DLCO and a decline in the serum KL-6 levels. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by HRCT. Anti-ARS and anti-MDA5 Abs are associated with the therapeutic response of PM/DM-ILD.

Clinical analysis and outcome of interstitial lung disease complicated with juvenile dermatomyositis and juvenile polymyositis

Objectives: The aim of this study was to determine the clinical phenotype and outcome of interstitial lung disease (ILD) complicated with juvenile dermatomyositis (JDM) or juvenile polymyositis (JPM).Methods: This was a single-center retrospective study. From 1984 to 2015, we retrospectively reviewed 29 patients who were diagnosed with JDM/JPM, among whom eight cases were ILD and 21 were non-ILD. The clinical features and laboratory findings included chest computed tomography (CT) images that were compared between the patients with ILD and non-ILD.Results: Eight cases (27.6%) were complicated with ILD. The mean age was 6.3 years, and 75% of the patients were women. We found that high fever, arthralgia, muscle weakness, and high serum Krebs von den Lungen-6 (KL-6) level were significantly associated with the presence of ILD (p < 0.05). Two patients were positive for the anti-Jo-1 antibody, and two other patients were positive for the anti-MDA5 antibody. Three cases were identified as rapidly progressive (RP)-ILD. The chest CT images of the ILD patients appeared to show ground glass opacity (GGO) with a lower lobe predominance, reticulation, and traction bronchiectasis consolidation. Three patients with RP-ILD showed random subpleural GGO with/without consolidation patterns. Further, three patients with RP-ILD died of respiratory failure (p < 0.01).Conclusion: ILD is one of the most serious complications of JDM/JPM. In the early phase of ILD, high levels of serum KL-6 can be detected, regardless of the respiratory symptoms. Additionally, RP-ILD can be predicted based on the presence of anti-MDA5 antibodies and the chest CT findings, including random subpleural GGO with/without consolidation patterns.

Plasma plasmin-α2-plasmin inhibitor complex levels may predict the effect of cyclophosphamide for systemic sclerosis-related interstitial lung disease

Objectives: Intravenous pulse cyclophosphamide (IVCY) is the first-line treatment for systemic sclerosis-associated interstitial lung disease (SSc-ILD). So far, there is no useful predictive marker for IVCY efficacy against SSc-ILD, although potential candidates are parameters reflecting vascular activation. Since plasma levels of plasmin-α2-plasmin inhibitor complex (PIC) serve as a potential biomarker of SSc vasculopathy, we evaluated the usefulness of plasma PIC levels as an indicator for IVCY efficacy against SSc-ILD.Methods: We measured plasma PIC levels in 23 patients with active SSc-ILD and 20 patients with stabilized SSc-ILD, and also retrospectively studied traceable data of patients with active SSc-ILD during IVCY therapy.Results: Plasma PIC levels were significantly elevated in patients with active SSc-ILD as compared to patients with stabilized SSc-ILD. Among patients with active SSc-ILD, baseline plasma PIC concentrations were significantly higher in patients responsive to IVCY than in those refractory to IVCY. After the entire six infusions, plasma PIC levels were significantly decreased compared with baseline in the responders, while not in the nonresponders. In the responders, plasma PIC levels were remarkably decreased after a couple of infusions. Regarding the changes of parameters by the entire infusions, Δ plasma PIC levels correlated positively with Δ serum KL-6 levels and inversely with Δ the percentage of predicted vital capacity.Conclusions: The elevation of baseline plasma PIC levels and the rapid decrease in plasma PIC levels during a couple of infusions may predict the efficacy of the entire IVCY therapy against SSc-ILD.

Prognostic significance of preoperative serum Krebs von den Lungen-6 level in non-small cell lung cancer.

We retrospectively analyzed the prognostic significance of preoperative serum Krebs von den Lungen-6 (KL-6) level in non-small cell lung cancer (NSCLC) patients. We enrolled 175 NSCLC patients who underwent curative surgery between 2009 and 2011. We subdivided the patients into 2 groups: with and without interstitial lung disease (ILD). Prognostic significance of serum KL-6 level was examined. The 5-year survival of patients with high serum KL-6 level was poor. Multivariate analysis also revealed the prognostic significance of serum KL-6 level. Serum KL-6 level was also a prognostic factor for patients without ILD. Although the number of patients with ILD was small, in patients with ILD, there was a trend towards an association between serum KL-6 level and patients' prognosis but this did not reach statistical significance. Serum KL-6 level is a prognostic factor for resected NSCLC patients, especially patients without ILD. There is a possibility that serum KL-6 level is a prognostic marker regardless of the presence of ILD.

Elevated Serum Krebs von den Lungen-6 in Early Disease Predicts Subsequent Deterioration of Pulmonary Function in Patients with Systemic Sclerosis and Interstitial Lung Disease.

To identify predictors of poor prognosis in patients with systemic sclerosis (SSc) associated with interstitial lung disease (ILD). Fifty patients with early-stage SSc-ILD who had never received disease-modifying drugs and were either observed for ≥ 10 years or died from ILD-related causes were enrolled. The baseline variables of patients who developed endstage lung disease (ESLD) were compared with those of patients who remained ESLD-free, and the Cox proportional hazard model was used to identify initial factors that correlated with ESLD development. Sixteen patients (32%) developed ESLD during 173.5 ± 64.7 months of followup. Elevated serum Krebs von den Lungen-6 (KL-6) at initial assessment was highly correlated with ESLD development (p = 0.0002). Receiver-operating characteristic curve analysis revealed that a KL-6 value of 1273 U/ml effectively discriminated patients who developed ESLD from those who did not. Patients with KL-6 > 1273 U/ml were less likely to remain ESLD-free compared with those with lower KL-6 levels (p < 0.0001). Multivariate analysis showed that KL-6 > 1273 U/ml was the most reliable predictor of ESLD development (OR 51.2, 95% CI 7.6-343, p < 0.0001). Finally, the initial KL-6 level correlated with the forced vital capacity (FVC) decline rate (r = 0.58, p < 0.0001). The natural course of SSc-ILD is highly variable. Baseline serum KL-6 is a biomarker potentially useful for predicting FVC decline.

Increased Serum KL-6 Levels Induced by Pulmonary Mycobacterium Avium Complex Infection in a Patient with RA-associated Lung Disease.

KL-6 is a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, and often shows increased serum levels in patients with interstitial pneumonia. We report a case of mycobacterium avium complex (MAC) infection whose disease activity was correlated with KL-6 levels in serum. During treatment of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) with prednisolone, chest image findings improved in association with decreased KL-6 levels. Following tapering of prednisolone, chest image findings deteriorated again as levels of KL-6 increased, suggesting recurrence of RA-ILD. Bronchoscopic examination revealed active MAC infection. Treatment of MAC infection not only improved chest image findings but also decreased KL-6 levels in serum, suggesting that KL-6 was increased by active MAC infection by itself, not by recurrence of RA-ILD. To the best of our knowledge, this is the first documentation of KL-6 elevation in serum in association with active MAC infection.

MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.

BackgroundKL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP.MethodsTwenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics).ResultsThe frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46 %, A/G 54 %, G/G 0 %; healthy controls, A/A 30 %, A/G 40 %, G/G 30 %; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014).ConclusionsMUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.

The expression and clinical role of KL-6 in serum and BALF of patients with different diffuse interstitial lung diseases

To detect the levels of KL-6 in the serum and the bronchoalveolar lavage fluid (BALF) of patients with different type of diffuse interstitial lung diseases(DILD), and to analyze its correlation with pulmonary function, pulmonary HRCT scores and other parameters. Seventy-three patients with DILD were enrolled, including 34 patients with idiopathic pulmonary fibrosis (IPF), 10 patients with stage Ⅰ sarcoidosis(SAR Ⅰ), 15 patients with hypersensitivity pneumonia (HP), 14 patients with connective tissue diseases (CTD). Enzyme-linked immune sorbent assay (ELISA) was used to detect the levels of KL-6 in the serum and the BALF of these patients. In the IPF group, FVC predicted percentage and DLCO predicted percentage were significantly lower than those of the SAR Ⅰ group[(70±14)% vs (82±6)%, (49±13)% vs(81±6)%, P<0.05], but were no different compared to the CTD-ILD group(P>0.05). In the IPF group, the percentage of neutrophils in BALF was higher than that of the SAR Ⅰ group[(9±7)% vs (6±4)%, P<0.05]], and the percentage of lymphocytes and CD4/CD8 ratio in BALF were lower than those of the SAR Ⅰ group[(12±7)% vs (23±13)%, (1.5±0.8) vs(4.0±5.1), P<0.05]. In the IPF group, the level of KL-6 in serum was higher than that of the SAR Ⅰ and the HP group[(858±516)U/ml vs (339±168)U/ml, (553±287)U/ml, P<0.05], but was no different compared to the CTD-ILD group (P>0.05). In the CTD-ILD group, the level of KL-6 in serum was higher than that of the SAR Ⅰ [(687±350) U/ml vs (339±168)U/ml, P<0.05]]. In the IPF group, the level of KL-6 in BALF was (437±252)U/ml, and was higher than that of other 3 groups(P<0.05). In the IPF group, the level of serum KL-6 was negatively correlated with FVC and DLCO(r=-0.46, -0.58, P<0.01), the level of serum KL-6 was positively correlated with pulmonary HRCT reticular pattern and honeycombing scores(r=0.62, 0.41, P<0.05). In patients with IPF, the levels of KL-6 in serum and BALF were increased and the level of KL-6 in serum was correlated with FVC, DLCO and pulmonary HRCT reticular pattern and honeycombing scores.KL-6 may be a marker for the diagnosis of IPF.

Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study.

It was aimed to evaluate KL-6 glycoprotein levels to determine if it may be a diagnostic marker for the connective tissue diseases (CTDs) predicting CTD-related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between patients and healthy controls. The study included 113 patients with CTD (45 CTD without lung involvement, 68 CTD-ILD) and 45 healthy control subjects. KL-6 glycoprotein levels were analyzed with ELISA in patients and the control group. The relationship between KL-6 glycoprotein levels and CTD-ILD was assessed. In the comparison of all the groups in the study, significantly higher levels of KL-6 were determined in the CTD-ILD group than in either the CTD without pulmonary involvement group or the healthy control group (p < 0.008 and p < 0.001, respectively). There was no statistically significant difference between the KL-6 levels in the healthy control group and the CTD without pulmonary involvement group (p = 0.289). The KL-6 levels did not differ significantly according to the connective tissue diseases in the diagnostic groups (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease, scleroderma, polymyositis/ dermatomyositis). In the healthy control group, there was a statistically significant difference between KL-6 levels in smokers and non-smokers. Smokers had significantly higher serum KL-6 levels compared with non-smokers (p < 0.05). There was no statistically significant difference between smoking status (pack-year) and serum KL-6 levels. There was no statistically significant correlation between serum KL-6 levels and time since diagnosis of CTD and CTD-ILD. The level of KL-6 as a predictive factor could be used to identify the clinical development of ILD before it is detected on imaging modality. Further prospective clinical studies are needed to define whether levels of KL-6 might have prognostic value or might predict progressive ILD.

The clinical effect of airway pressure release ventilation for acute lung injury/acute respiratory distress syndrome

To evaluate the effect of airway pressure release ventilation (APRV) in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS), to evaluate the extent of ventilator-induced lung injury (VILI), and to explore its possible mechanism. A prospective study was conducted in the Department of Critical Care Medicine of the First Hospital of Hebei Medical University from December 2010 to February 2012. The patients with ALI/ARDS were enrolled. They were randomly divided into two groups. The patients in APRV group were given APRV pattern, while those in control group were given lung protection ventilation, synchronized intermittent mandatory ventilation with positive end-expiratory pressure (SIMV+PEEP). All patients were treated with AVEA ventilator. The parameters such as airway peak pressure (Ppeak), mean airway pressure (Pmean), pulse oxygen saturation (SpO2), mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), arterial blood gas, urine output (UO), the usage of sedation and muscle relaxation drugs were recorded. AVEA ventilator "turning point (Pflex) operation" was used to describe the quasi-static pressure volume curve (P-V curve). High and low inflection point (UIP, LIP) and triangular Pflex volume (Vdelta) were automatically measured and calculated. The ventilation parameters were set, and the 24-hour P-V curve was recorded again in order to be compared with subsequent results. Venous blood was collected before treatment, 24 hours and 48 hours after ventilation to measure lung surfactant protein D (SP-D) and large molecular mucus in saliva (KL-6) by enzyme linked immunosorbent assay (ELISA), and the correlation between the above two parameters and prognosis on 28 days was analyzed by multinomial logistic regression. Twenty-six patients with ALI/ARDS were enrolled, and 22 of them completed the test with 10 in APRV group and 12 in control group. The basic parameters and P-V curves between two groups were similar before the test. After 24 hours and 48 hours, mechanical ventilation was given in both groups. The patients' oxygenation was improved significantly, though there were no significant changes in hemodynamic parameters. The Pmean (cmH2O, 1 cmH2O = 0.098 kPa) in APRV group was significantly higher than that in control group (24 hours: 24.20±4.59 vs. 17.50±3.48, P < 0.01; 48 hours: 18.10±4.30 vs. 15.00±2.59, P < 0.05). After ventilation for 24 hours, the ratio of patients with increased Vdelta in APRV group was higher than that in control group (90% vs. 75%), but without statistical difference (P > 0.05). The SP-D level (μg/L) in serum in APRV group showed a tendency of increase (increased from 19.70±7.34 to 27.61±10.21, P < 0.05), in contrast there was a tendency of decrease in control group (decreased from 21.83±7.31 to 16.58±2.90, P > 0.05), the difference between the two groups was statistically significant (P < 0.05). After 48-hour ventilation, SP-D in APRV group was decreased, but no change was found in control group, and no significant difference was found as compared with that of the control group (16.45±8.17 vs. 17.20±4.59, P > 0.05). There was no significant difference in serum KL-6 between the two groups before and after ventilation. The SP-D and KL-6 levels in serum were unrelated with 28-day survival rate of the patients. The odds ratio (OR) of SP-D were 0.900 [95% confidence interval (95%CI) = 0.719-1.125], 1.054 (95%CI = 0.878-1.266), 1.143 (95%CI = 0.957-1.365), and the OR of KL-6 were 1.356 (95%CI = 0.668-2.754), 0.658 (95%CI = 0.161-2.685), 0.915 (95%CI = 0.350-2.394) before the test, 24 hours and 48 hours after ventilation (all P > 0.05). APRV was similar to lung protective ventilation strategy in oxygenation and improvements in the lung mechanics parameters. APRV with a higher Pmean can recruit alveolar more effectively, and it had no impact on hemo-dynamics, but might exacerbate VILI.

Symptomless Pulmonary Cryptococcosis in a Psoriatic Arthritis Patient during Infliximab Therapy.

Dear Editor: Pulmonary cryptococcosis is a common opportunistic infection in immunosuppressed patients1. To our knowledge, this is the first reported case of pulmonary cryptococcosis in a psoriasis patient undergoing treatment with biologics. A 55-year-old man presented with an itching eruption on his head for 2 years. His skin condition got progressively worse and he reported polyarticular pain. At the initial visit, he had a systemic psoriatic eruption (Psoriasis Area and Severity Index [PASI] 14.8) and swollen joints of the shoulders, left wrist, left digitus minimus, and left knee (Disease Activity Score 28 including C-reactive protein [DAS 28-CRP]). Although he had been treated with topical steroids and vitamin D3 ointment, the treatment was not effective. Infliximab therapy (5 mg/kg) was started for both the psoriatic skin lesions and arthritis in December 2012. The screening examination for infliximab therapy revealed normal laboratory data and chest computed tomography (CT), as well as a serum Krebs von den Lungen (KL)-6 level of 266 U/ml (normal is less than 401 U/ml). A raised serum level of KL-6 is known to exist in interstitial pneumonia2. He was then treated with 5 mg/kg of intravenous infliximab that was administered at weeks 2 and 6, and then every 8 weeks thereafter. At 7 months after initiation of the infliximab therapy, although the patient denied cough or sputum or fever, and his β-D glucan, cryptococcal antigen and QuantiFERON-TB Test (Cellestis Ltd., Carnegie, Victoria, Australia) were all within the normal range, his serum KL-6 level was elevated at 585 U/ml. The patient's chest CT showed ground glass opacities bilaterally in the lower lobes and multiple small nodules in the right middle lobe (Fig. 1A). The cytology of the bronchoalveolar lavage fluid revealed encapsulated yeast, indicating the presence of cryptococcus (Fig. 1B). Thus, the patient was diagnosed with pulmonary cryptococcosis. The infliximab therapy was discontinued and oral fluconazole (200 mg/day) treatment was initiated. After 3 months, the abnormal chest CT shadow and the serum KL-6 level improved. Fig. 1 (A) Chest computed tomography showed multiple small nodules at the right middle lobe (circle). (B) Cytology of bronchoalveolar lavage fluid showed encapsulated yeasts (arrows), which is consistent with cryptococcosis species (Papanicolaou stain, ×400). ... Infliximab is a tumor necrosis factor-α (TNF-α) inhibitor for the treatment of psoriasis and other inflammatory diseases. The main, severe adverse events related to anti TNF-α therapy are infectious diseases. Cryptococcosis species infections have been reported at a rate of 5.08 per 100,000 in infliximab-treated patients3. Although there are several case reports of pulmonary cryptococcosis in patients treated with infliximab, one of them is a case of pulmonary cryptococcosis in a Crohn's disease patient who was receiving infliximab monotherapy without other immunosuppressive drugs4. There are no reports of pulmonary cryptococcal infection in psoriasis patients treated with biologics. It is generally accepted that cryptococcosis usually occurs as an opportunistic infection in a compromised host. We speculated that the immunosuppression caused by infliximab treatment must have resulted in pulmonary cryptococcosis in the previously reported in vivo cases5. Dermatologists recognize that continual careful monitoring of unexpected side effects is necessary in psoriasis patients treated with biological drugs. Pulmonary cryptococcosis must now be recognized as a potential severe complication of treatment with biologics in psoriasis patients.

Interstitial lung disease in clinically amyopathic dermatomyositis with and without anti-MDA-5 antibody: to lump or split?

BackgroundInterstitial lung disease (ILD) associated with clinically amyopathic dermatomyositis (CADM-ILD) is often refractory and rapidly progressive. Although the anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody is associated with rapidly progressive ILD (RP-ILD), differences in clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD remain unclear.MethodsTo clarify the differences in the clinical features and prognosis between anti-MDA-5 antibody-positive and -negative cases, we retrospectively reviewed the medical records of patients diagnosed with CADM-ILD with and without anti-MDA-5 antibody at Kurashiki Central Hospital from January 2005 to September 2014.ResultsAnti-MDA-5 antibody was found in 10 of 16 patients (63 %). The levels of Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) at the first visit were significantly lower in positive patients than in negative patients, whereas the levels of aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP), and the CD4+/CD8+ ratio in the bronchoalveolar lavage (BAL) fluid were significantly higher in positive patients than negative patients. Subpleural ground-glass opacity (GGO) or irregular linear opacity was predominant in positive patients. Peribronchovascular consolidation was predominant in negative patients. Positive patients had significantly lower survival rates than negative patients, with all six fatal cases occurring in positive patients who died of refractory ILD within 92 days from the first visit despite intensive treatment.ConclusionsThere are clear differences in the clinical features and prognosis of anti-MDA-5 antibody-positive and -negative CADM-ILD. Low serum KL-6 and SP-D levels, high serum AST and γ-GTP levels, high CD4+/CD8+ ratio in BAL fluid, and predominance of subpleural GGO or irregular linear opacity in HRCT may help to discriminate anti-MDA-5 antibody-positive CADM-ILD with poor prognosis.