Biomarker For Interstitial Lung Disease Research Articles

Are There Prognostic Biomarkers For Interstitial Lung Diseases?

Are There Prognostic Biomarkers For Interstitial Lung Diseases?

Biomarkers in interstitial lung disease: moving towards composite indexes and multimarkers?

Interstitial lung disease (ILD) covers a large spectrum of lung disorders that affects the parenchyma and is often associated with inflammation and/or fibrosis. Clinically, there is a great need for biomarker development for these disorders, to help diagnosis, treatment selection and assessment of efficacy as well as to predict progression. Thus far, no broadly validated biomarker exists for ILD, due to the existence of a very large number of disorders of often-unknown etiology, overlapping symptoms and disorders associated with a spectrum of multi-morbidities involving similar chronic inflammatory and fibrotic biochemical processes. We discuss here the development of biomarkers in IPF, sarcoidosis, connective tissue disease-associated ILD (CTD-ILD), and chronic hypersensitivity pneumonitis. We further discuss the need and opportunity to develop a multimarker approach that would be clinically meaningful for patients with ILD. Such composite index could include clinical symptoms, pathological assessment, and lung physiology measurements added to molecular information derived from bronchoalveolar lavage and serum. We also discuss the increased opportunity for patients to be involved in research as recent technological advances now allow the serial measurement of lung function using handheld spirometers, combined with handheld devices allowing measurement of patient reported outcomes, mobility, exercise, and sleep.

αvβ6 integrin may be a potential prognostic biomarker in interstitial lung disease

Idiopathic pulmonary fibrosis (IPF) and fibrotic nonspecific interstitial pneumonitis are progressive interstitial lung diseases (ILDs) with limited treatment options and poor survival. However, the rate of disease progression is variable, implying there may be different endotypes of disease. We hypothesised that immunophenotyping biopsies from ILD patients might reveal distinct endotypes of progressive fibrotic disease, which may facilitate stratification when undertaking clinical trials of novel therapies for IPF.43 paraffin-embedded, formalin-fixed lung tissue sections were immunostained for five molecules implicated in the pathogenesis of the fibrosis: α-smooth muscle actin (αSMA), αvβ6 integrin, pro-surfactant protein C (SP-C), hepatocyte growth factor (HGF) and tenascin-C (TenC). Levels of immunostaining and numbers of fibroblastic foci were quantified using operator-dependent and -independent methods. The relationship of all these markers to overall survival was analysed.Staining revealed high levels of αSMA, αvβ6 integrin, pro-SP-C, HGF and TenC, and fibroblastic foci. Immunostaining varied across samples for all molecules but only the extent of αvβ6 integrin immunostaining was associated with increased mortality. There was no association with the other markers measured.Our data suggest high levels of αvβ6 integrin may identify a specific endotype of progressive fibrotic lung disease.

(510) - Serum KL-6 Levels Are Associated With Long-Term Prognosis in Lung Transplant Recipients

Bronchiolitis obliterans syndrom (BOS), a life threatening complication after lung transplantation, is characterized by a non-reversible obstruction of the small airways and a progressive fibrosis. KL-6, a novel biomarker for interstitial lung diseases, has been found to be increased in serum from lung transplant recipients with BOS. The aim of this study was to investigate the association of serum KL-6 levels with the prognosis after lung transplantation.

Nested Case Control Study of Proteomic Biomarkers for Interstitial Lung Disease in Japanese Patients With Non–Small-Cell Lung Cancer Treated With Erlotinib: A Multicenter Phase IV Study (JO21661)

BackgroundInterstitial lung disease (ILD) is a serious adverse drug reaction associated with epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR TKIs). Its risk factors are yet to be fully elucidated. We sought to identify proteomic biomarkers associated with ILD development in erlotinib-treated Japanese patients with non–small-cell lung cancer (NSCLC) to build predictive models. Patients and MethodsWe conducted a nested case-control study. The participants were patients with NSCLC enrolled in a phase IV study of erlotinib in whom ILD developed within 120 days after erlotinib administration. The controls were randomly selected patients without ILD from the overall study cohort who were also treated with erlotinib. Serum samples were obtained before the first administration of erlotinib and were assayed by liquid chromatography–mass spectroscopy/mass spectroscopy (LC-MS/MS). Logistic regression analysis was performed to identify the peptide and proteins associated with ILD. ResultsA total of 645 patients were enrolled in the cohort; 15 case patients and 64 controls were analyzed. When multiplicity was taken into account, we were unable to statistically verify any genuine association between individual markers and ILD. Investigation of the predictive power based on leave-one-out cross-validation (LOOCV) showed that the area under the receiver operating characteristic curve was 0.73 at a maximum. Additional analysis suggested that 3 proteins (C3, C4A/C4B, and APOA1) have a stronger association with ILD than do the other proteins tested. ConclusionWe were unable to demonstrate predictive serum protein markers for ILD development. However, C3, C4A/C4B, and APOA1 are worthy of further investigation.

Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels

KL-6 is a high-molecular-weight glycoprotein classified as human Mucin-1 (MUC1). KL-6 has been reported to be a sensitive biomarker for interstitial lung diseases (ILDs) in the Japanese population. It is also known that polymorphisms in the MUC1 gene affect serum levels of KL-6. This study was conducted to evaluate serum levels of KL-6 and MUC1 polymorphisms in both German and Japanese populations. Serum levels of KL-6 were measured in 267 patients with ILDs (152 German and 115 Japanese) and 186 healthy subjects (HS) (76 German and 110 Japanese). In addition, rs4072037 single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction. The optimal cutoff values for discriminating patients with ILDs from HS was determined by receiver operating characteristic analysis based on ethnicity and rs4072037 genotypes. The serum KL-6 levels in patients with ILDs were significantly higher compared with HS in both the German and the Japanese cohorts (both p<0.001). The discriminating cutoff value of serum KL-6 in the German cohort was significantly higher than the value in the Japanese cohort. The difference in the serum levels of KL-6 was significantly associated with the rs4072037 genotype distribution. Even in the German cohort, the serum KL6 levels were significantly higher in patients with ILDs than HS. Because of differences in the genotype distribution of rs4072037, the KL-6 cutoff value for the German cohort that discriminated patients with ILDs from HS was significantly higher than the value in the Japanese cohort.

232 - Nested Case Control Study of Proteomic Biomarkers for Interstitial Lung Disease in Japanese Patients With Non-Small Cell Lung Cancer Treated With Erlotinib

ABSTRACT Background Interstitial lung disease (ILD) is a serious adverse drug reaction associated with EGFR tyrosine kinase inhibitors, but its risk factors are yet to be elucidated. We sought to identify the proteomic biomarkers associated with ILD in Japanese patients with non-small cell lung cancer treated with erlotinib, and to build predictive models for development of ILD using the proteomic biomarkers. Methods We conducted a nested case control study. The cases were subjects in whom ILD developed within 120 days after the administration of erlotinib following enrolment in the cohort, and the controls were randomly selected from patients without ILD who were treated with erlotinib. For the proteomics analysis, albumin and IgG were removed from serum samples obtained before the first administration of erlotinib, then the samples were digested with protease and the resultant peptide fragments were separated, identified and assayed by LC–MS/MS. Logistic regression analysis was used for the identification and examination of predictability for ILD. Results A total of 645 patients were enrolled in the cohort, 15 cases and 64 controls were analysed. Logistic regression analysis was performed to identify the peptide peaks and proteins assossiated with ILD. When multiplicity was taken into account, we were unable to statistically verify any genuine association between individual markers and ILD. Investigation of the predictive power based on leave-one-out cross-validation showed that the area under the ROC curve was 0.73 at a maximum. However, additional analysis suggested that three proteins (C3, C4A/C4B and APOA1) have a stronger association with ILD than the other proteins tested. Conclusions We were unable to conclude from the results of this study that any promising serum protein markers for predicting ILD had been identified. However, C3, C4A/C4B and APOA1 were suggested to be worth further investigation. Disclosure N. Katakami: corporate-sponsored research (Chugai Pharmaceutical Company). S. Atagi: corporate-sponsored research (Chugai Pharmaceutical Company). H. Yoshioka: corporate-sponsored research (Chugai Pharmaceutical Company). M. Fukuoka: other substantive relationships (Chugai, Astra Zeneca). A. Ogiwara: corporate-sponsored research (Chugai, Astra Zeneka). M. Imai: M Imai is employee of Chugai Pharmaceutical Co., Ltd. M. Ueda: M Ueda is employee of Chugai Pharmaceutical Co., Ltd. All other authors have declared no conflicts of interest.

Acute megakaryoblastic leukemia and severe pulmonary fibrosis in a child with down syndrome: Successful treatment with ultra low-dose cytarabine using GATA1 mutation to monitor minimal residual disease

Acute megakaryoblastic leukemia and severe pulmonary fibrosis in a child with down syndrome: Successful treatment with ultra low-dose cytarabine using GATA1 mutation to monitor minimal residual disease

Circulating Biomarkers of Interstitial Lung Disease in Systemic Sclerosis

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). Although a large proportion of SSc patients have only limited interstitial involvement with an indolent course, in a significant minority ILD is progressive, requiring prompt treatment and careful monitoring. One of the main challenges for the clinician treating this highly variable disease is the early identification of patients at risk of progressive ILD, while avoiding potentially toxic treatments in those whose disease is inherently stable. Easily available and repeatable biomarkers that allow estimation of the risk of ILD progression and early response to treatment are highly desirable. In this paper, we review the evidence for circulating biomarkers with potential roles in diagnosis, monitoring of disease activity, or determining prognosis. Peripheral blood biomarkers offer the advantages of being readily obtained, non-invasive, and serially monitored. Several possible candidates have emerged from studies performed so far, including SP-D, KL-6, and CCL18. Presently however, there are few prospective studies evaluating the predictive ability of prospective biomarkers after adjustment for disease severity. Future carefully designed, prospective studies of well characterised patients with ILD, with optimal definition of disease severity and outcome measures are needed.

KL‐6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis

To investigate whether Caucasian patients with polymyositis (PM) or dermatomyositis (DM) and interstitial lung disease (ILD) have elevated serum levels of KL-6 compared with patients without ILD and whether KL-6 could be used as a marker for ILD activity and treatment efficacy of ILD in PM/DM. Thirty patients with PM/DM (seven with ILD) and 17 age- and sex-matched healthy controls were included in a retrospective, cross-sectional analysis. Twelve patients were followed for longitudinal evaluation. ILD was defined as restrictive lung function impairment with radiographic signs of ILD. Serum KL-6 levels were measured using a sandwich enzyme immunoassay kit. Groups were compared by Mann-Whitney U-test. PM/DM patients with ILD had significantly higher median serum KL-6 levels compared with those without ILD: 995 (range 533-2318) versus 322 (range 132-1225) U mL(-1) (P = 0.0002). Median serum levels of healthy controls were 225 (range 136-519) U mL(-1) . Serum levels of KL-6 were inversely correlated with percentages of forced expiratory volume in 1 s (FEV1), vital capacity (VC), total lung capacity (TLC), forced VC, diffusing capacity of carbon monoxide (DLco), maximal voluntary ventilation at 40 breaths min(-1) and residual volume (RV). Changes in KL-6 levels showed a significant inverse correlation with changes in percentage FEV1, TLC, DLco and RV. At a cut-off level of 549 U mL(-1) (mean ± 2.5 SD for controls), the sensitivity and specificity for diagnosis of ILD were 83% and 100%, respectively. The level of serum KL-6 may serve as measure of ILD in patients with PM/DM and is a promising biomarker for use in clinical practice to assess clinical response to treatment.

Levels of Surfactant Proteins A and D and KL-6 Are Elevated in the Induced Sputum of Chronic Obstructive Pulmonary Disease Patients: A Sequential Sputum Analysis

Background: Recent clinical studies have suggested that serum surfactant protein (SP) A, SP-D and Krebs von den Lungen-6 (KL-6) are potential biomarkers for interstitial lung diseases. Serum levels of SP-A and SP-D have also been found to be elevated in chronic obstructive pulmonary disease (COPD), but their significance has not been evaluated or compared in induced sputum samples obtained directly from the airways. Objective: A sequential sputum analysis was conducted to assess the value of SP-A, SP-D and KL-6 levels in COPD. Methods: The study material consisted of induced sputum samples from 61 subjects, 28 with COPD and 33 with prolonged cough (cough lasting >3 weeks and normal spirometry). Sputum was collected in 3 fractions (3 periods of 5 min each). Sputum levels of these proteins were measured, and receiver operating characteristic curve analysis was carried out to evaluate the sensitivity, specificity and area under the curve (AUC) for each fraction. Results: The levels of SP-A, SP-D and KL-6 were higher in patients with COPD than in those with prolonged cough in each of the fractions. Sputum levels of these proteins correlated inversely with obstruction and positively with ageing, smoking history, sputum macrophages and eosinophils. Sputum fractionation had a relatively minor effect on the levels and AUC of these proteins. Conclusion: Sequential sputum analysis from 3 consecutive fractions indicated a significant difference in the levels of SP-A, SP-D and KL-6 between COPD and prolonged cough. However, sputum fractionation itself had a relatively minor effect on the levels of these proteins.

Surfactant Protein D and KL-6 as Serum Biomarkers of Interstitial Lung Disease in Patients with Scleroderma

To assess whether serum concentrations of surfactant protein D (SP-D) and Krebs von den Lungen-6 (KL-6), glycoproteins expressed by type II pneumocytes, correlate with the presence of "alveolitis" and measures of lung function in patients enrolled in the Scleroderma Lung Study (SLS). Serum obtained at baseline screening of patients with systemic sclerosis (SSc, scleroderma) in the SLS was assayed. "Alveolitis" was defined by either bronchoalveolar lavage or thoracic high-resolution computed tomography (HRCT) by SLS criteria. SP-D and KL-6 levels were measured by ELISA in 66 SSc patients (44 with "alveolitis," 22 without "alveolitis") and in 10 healthy controls. These were compared to clinical measures of lung disease and "alveolitis" in the SLS patients. SP-D levels were 300+/-214 ng/ml (mean+/-SD) in the SSc patients compared to 40+/-51 ng/ml in controls (p<0.0001). KL-6 levels were 1225+/-984 U/ml in the SSc patients and 333+/-294 U/ml in controls (p<0.0001). SSc patients with "alveolitis" had higher levels of both SP-D and KL-6 than those without "alveolitis." The level of SP-D was 353+/-219 ng/ml in patients with "alveolitis" and 161+/-143 ng/ml without "alveolitis" (p=0.0002). The level of KL-6 was 1458+/-1070 U/ml in patients with "alveolitis" and 640+/-487 U/ml without "alveolitis" (p=0.0001). Receiver operator characteristic curve analysis demonstrated high sensitivity and specificity of both SP-D and KL-6 for the determination of "alveolitis." KL-6 and SP-D were positively correlated with maximum fibrosis scores, but not with maximum ground-glass opacities, on HRCT. Serum levels of SP-D and KL-6 appear to be indicative of "alveolitis" in SSc patients as defined by the SLS, and are significantly higher than in SSc patients without "alveolitis." Serum SP-D and KL-6 may serve as noninvasive serological means of assessing interstitial lung disease in patients with SSc.

Serum biomarkers in interstitial lung diseases

The use of biomarkers in medicine lies in their ability to detect disease and support diagnostic and therapeutic decisions. New research and novel understanding of the molecular basis of the disease reveals an abundance of exciting new biomarkers who present a promise for use in the everyday clinical practice. The past fifteen years have seen the emergence of numerous clinical applications of several new molecules as biologic markers in the research field relevant to interstitial lung diseases (translational research). The scope of this review is to summarize the current state of knowledge about serum biomarkers in interstitial lung diseases and their potential value as prognostic and diagnostic tools and present some of the future perspectives and challenges.

GRADUATE SURVEYS: AN OPPORTUNITY FOR RESIDENCY RESEARCH

<h3>Objectives</h3> To determine whether engineering controls and respiratory protection had measurable short-term impact on indium exposure and respiratory health among current indium-tin oxide production and reclamation facility workers. <h3>Methods</h3> We documented engineering controls implemented following our 2012 evaluation and recorded respirator use in 2012 and 2014. We measured respirable indium (In_resp) and plasma indium (In_P) in 2012 and 2014, and calculated change in In_resp (∆In_resp) and In_P (∆In_P) by the 13 departments. We assessed symptoms, lung function, serum biomarkers of interstitial lung disease (Krebs von den Lungen (KL)-6 and surfactant protein (SP)-D) and chest high-resolution CT at both time points and evaluated workers who participated in both 2012 and 2014 for changes in health outcomes (new, worsened or improved). <h3>Results</h3> Engineering controls included installation of local exhaust ventilation in both grinding departments (Rotary and Planar) and isolation of the Reclaim department. Respiratory protection increased in most (77%) departments. ∆In_P and ∆In_resp often changed in parallel by department. Among 62 workers participating in both 2012 and 2014, 18 (29%) had new or worsening chest symptoms and 2 (3%) had functional decline in lung function or radiographic progression, but average KL-6 and SP-D concentrations decreased, and no cases of clinical indium lung disease were recognised. <h3>Conclusions</h3> Increased engineering controls and respiratory protection can lead to decreased In_resp, In_P and biomarkers of interstitial lung disease among workers in 2 years. Ongoing medical monitoring of indium-exposed workers to confirm the longer-term effectiveness of preventive measures is warranted.

Serum levels of surfactant proteins A and D are useful biomarkers for interstitial lung disease in patients with progressive systemic sclerosis.

To find a less-invasive and lung-specific clinical biomarker, we measured serum levels of surfactant proteins A and D (SP-A and SP-D) by sandwich enzyme-linked immunosorbent assays in 42 patients with progressive systemic sclerosis (PSS) to evaluate their significance in relation to the presence of interstitial lung disease (ILD) and to assess their diagnostic merits. The patients were divided into two groups based on findings by chest computed tomography (CT): 30 patients with ILD (CT-positive ILD group), and 12 patients without any lung abnormalities (CT-negative ILD group). The CT-positive ILD group was further divided into two groups: 24 patients with ILD detectable by chest plain radiography (X-ray-positive ILD group) and six patients with ILD showing no abnormality (X-ray-negative ILD group). The levels of SP-A and SP-D in sera were significantly higher in the CT-positive ILD group than in the CT-negative ILD group. They were also significantly higher in the X-ray-positive ILD group than in the CT-negative ILD group. In the X-ray-negative ILD group, their levels were higher than those of the CT-negative ILD group. We next estimated sensitivity and specificity of SP-A, SP-D, and X-ray for detecting ILD on CT. Sensitivity of SP-D was high (77%) as well as that of X-ray (80%), whereas SP-A showed a low sensitivity (33%). Remarkably, five of six patients in the X-ray-negative ILD group showed SP-D concentrations over its cut-off level, thereby demonstrating that an SP-D assay contributes to the detection of ILD overlooked by X-ray. Moreover, a combination of X-ray and SP-D dramatically increases sensitivity to 97%. Specificity of SP-A, SP-D, and X-ray to the CT-negative ILD group was 100%, 83%, and 100%, respectively. In conclusion, this study indicates that elevated levels of serum SP-A and SP-D reflect well the presence of ILD and that the combination of SP-D and X-ray contributes to reduce the risk of clinicians overlooking ILD complicated by PSS, although a repetition in another set of subjects is needed to confirm these indications.