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Objective: Interstitial lung disease (ILD) is an important cause of mortality in patients with rheumatoid arthritis (RA). Early RA-ILD detection is essential to improve prognosis. Here, we investigated eight serological biomarkers that may contribute to RA-ILD detection., Method: Fifty-five patients from the Early Rheumatoid Arthritis Program were evaluated for ILD with high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) using the SCAPIS protocol. Blood samples were obtained for biomarker analysis, and patients' clinical records were reviewed. We defined ILD using five different models based on the measurements used to confirm ILD: Model A = HRCT; B = PFTs; C = A plus B; D = C plus symptoms; and E = D plus inhalations., Results: Among 55 patients, two had an ILD diagnosis before the study, but over one-third fulfilled the ILD criteria. Cancer antigen 15-3 (CA15-3) and matrix metalloproteinase-7 (MMP-7) differentiated between RA with and without ILD (all p < 0.05). Surfactant protein D (SP-D) showed similar trends, as did macrophage inflammatory protein-1β (MIP-1β) and chitinase 3-like protein-1 (YKL-40). Based on Pearson's correlation coefficients, MIP-1β and YKL-40 were significantly correlated with DAS28 (MIP-1β: 0.3; YKL-40: 0.4), ESR (MIP-1β: 0.3; YKL-40: 0.4), and CRP (only MIP-1β: 0.4) (all p < 0.05). CA15-3 was correlated with rheumatoid factor and anti-citrullinated peptide antibodies (Pearson's correlation 0.3; both p = 0.03)., Conclusions: CA15-3 was the most significant biomarker for ILD detection in RA patients with stable low disease activity, closely followed by MMP-7. SP-D, MIP-1β, and YKL-40 may also contribute to RA-ILD diagnosis.

Objectives: To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups., Methods: Participants with sera, high-resolution CT and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. Twenty-seven of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc., Results: A total of 407 participants were identified, 252 (61.9%) with SSc-ILD. The median (interquartile range) follow-up after biomarker measurement was 6.31 (3.11-9.22) years. Sixteen biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality [hazard ratio (HR) 3.55; 95% CI 2.37-5.33; P < 0.001]. Five additional biomarkers had an HR >2: SP-D (2.28, 1.57-3.31; P < 0.001), E-selectin (2.19, 1.53-3.14; P < 0.001), IL-6 (2.15, 1.50-3.09; P < 0.001), MMP-3 (2.05, 1.42-2.95; P < 0.001) and ET-1 (2.03, 1.40-2.92; P < 0.001). Eleven biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at 1-year follow-up: CXCL4 (odds ratio 2.67, 1.46-4.88; P = 0.001), MMP-1 (2.56, 1.43-4.59; P = 0.002) and ET-1 (2.18, 1.24-3.83; P = 0.007)., Conclusion: Multiple biomarkers, especially VCAM-1, E-selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: The serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP., Methods: Among 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups., Results: Among the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan-Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses., Conclusions: Our results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP., (© 2024. The Author(s).)

In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant-associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Pulmonary fibrosis is a characteristic of various interstitial lung diseases (ILDs) with differing etiologies. Clinical trials in progressive pulmonary fibrosis (PPF) enroll patients based on previously described clinical criteria for past progression, which include a clinical practice guideline for PPF classification and inclusion criteria from the INBUILD trial. In this study, we compared the ability of past FVC (forced vital capacity) progression and baseline biomarker levels to predict future progression in a cohort of patients from the PFF Patient Registry., Methods: Biomarkers previously associated with pathobiology and/or progression in pulmonary fibrosis were selected to reflect cellular senescence (telomere length), pulmonary epithelium (SP-D, RAGE), myeloid activation (CXCL13, YKL40, CCL18, OPN) and fibroblast activation (POSTN, COMP, PROC3)., Results: PFF or INBUILD-like clinical criteria was used to separate patients into past progressor and non-past progressor groups, and neither clinical criterion appeared to enrich for patients with greater future lung function decline. All baseline biomarkers measured were differentially expressed in patient groups compared to healthy controls. Baseline levels of SP-D and POSTN showed the highest correlations with FVC slope over one year, though correlations were low., Conclusions: Our findings provide further evidence that prior decline in lung function may not predict future disease progression for ILD patients, and elevate the need for molecular definitions of a progressive phenotype. Across ILD subtypes, certain shared pathobiologies may be present based on the molecular profile of certain biomarker groups observed. In particular, SP-D may be a common marker of pulmonary injury and future lung function decline across ILDs., (© 2024. The Author(s).)

Given the various clinical manifestations that characterize Coronavirus Disease 2019 (COVID-19), the scientific community is constantly searching for biomarkers with prognostic value. Surfactant proteins A (SP-A) and D (SP-D) are collectins that play a crucial role in ensuring proper alveolar function and an alteration of their serum levels was reported in several pulmonary diseases characterized by Acute Respiratory Distress Syndrome (ARDS) and pulmonary fibrosis. Considering that such clinical manifestations can also occur during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we wondered if these collectins could act as prognostic markers. In this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n = 51) at admission (T0) and after seven days (T1) and compared with healthy donors (n = 11). SP-D increased in COVID-19 patients compared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. In light of these results, SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia, and the early detection of SP-D serum levels could be crucial for preventive clinical management.

To test whether circulating and intracoronary biomarkers and coronary plaque strain have additive values to Global Registry of Acute Coronary Events (GRACE) score for predicting long-term cardiovascular events in ACS patients. One hundred ACS patients were enrolled and the GRACE score and plasma levels and intracoronary gradients of a number of biomarkers were measured. Coronary plaque burden and morphology in non-critical stenotic plaques were determined by intravascular ultrasound (IVUS) technique, and the maximal shear strain (SS max ) and maximal area strain (AS max ) were determined by intravascular ultrasound elastography (IVUSE) technique. Patients were followed for cardiovascular events and the predictive values of clinical characteristics, plasma biomarkers and plaque parameters were compared with GRACE score, and the incremental values of these measurements to the GRACE score were assessed. GRACE score, plasma biomarkers and plaque strain were independent predictors of cardiovascular events. Combination of GRACE score, plasma biomarkers and plaque strains significantly improved the predictive value of the GRACE score alone with the receiver-operating characteristic area increased from 0.457 to 0.667 (P=0.014). The combination of circulating and intracoronary biomarkers, plaque strain and GRACE score provides a better predictive tool than GRACE score alone in patients with ACS.

Background: A number of studies have been conducted to investigate the association between serum surfactant protein D (SP-D) concentration and chronic obstructive pulmonary disease (COPD) risk. However, the results are inconsistent. This systematic review and meta-analysis aim to investigate whether serum SP-D concentration is a potential biomarker for COPD diagnosis., Methods: We searched Web of Science, PubMed, China National Knowledge Infrastructure (CNKI), and Wanfang Database from inception through July 18, 2018. The standardized mean difference (SMD) with 95% confidence interval (CI) was used to investigate the effect sizes., Results: Seventeen eligible studies from a total of 4,639 subjects were finally included in this systematic review and meta-analysis. The results indicated that serum SP-D levels in COPD patients were significantly higher than those in controls (SMD = 1.01, 95% CI = 0.62 - 1.41, p < 0.001). We also found that serum SP-D concentration in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients was significantly higher than that in stable COPD patients (SMD = 1.50, 95% CI = 0.92 - 2.08, p < 0.001), and serum SP-D concentration was higher in smokers than in nonsmokers in healthy population (SMD = 1.50, 95% CI = 0.35 - 2.64, p = 0.025)., Conclusions: The current systematic review and meta-analysis indicates that serum SP-D levels may be a promising biomarker for COPD. In particular, increased serum SP-D levels appear to be associated with acute exacerbation of COPD and smoking in healthy population.

SSc is a rare disease of unknown origin associated with multiple organ involvement. One of the major complications that drives the mortality of SSc patients is interstitial lung disease. The course of SSc-interstitial lung disease progression has a wide spectrum. Since the treatment is based on aggressive immunosuppression it should not be given to stable or non-progressing disease. The correct identification of disease with high risk of progression remains a challenge for early therapeutic intervention, and biomarkers remain urgently needed. In fact, eight categories of biomarkers have been identified and classified according to the different biological pathways involved. The purpose of this article is to describe the main biomarkers thought to be of interest with clinical value in the diagnosis and prognosis of SSc-interstitial lung disease., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The article reveals the modern aspects of IPF pathogenesis in with an emphasis on the main proposed prognostic biomarkers. IPF remains the leader among diseases with unknown etiology, the diagnosis and management of which are not very successful, despite the obvious progress in molecular medicine. There is presented analysis of the significance of IPF potential biomarkers and their concentrations in the blood and bronchoalveolar lavage fluids (BAL): endothelin-1, CC-chemokine ligand 18, interleukin-1, surfactant protein SP-D in the review. The role of their changing levels in the blood and BAL for assessing the course of the IPF and its prognosis, as well as the prevailing importance of the polymorphism of the genes encoding them, is shown. Obviously, the progressive accumulation of fibroblast-myofibroblast cells in the lungs IPF patients worsens the prognosis of disease, forms its own environment with a set of cytokines, growth factors, collagen, fibronectin in the extracellular matrix of fibrous lungs. The insufficient amount of studies in the face of the rarity of the disease leaves a lot of controversial issues for solution in the future. Obviously, to assess the prognosis of IPF mortality, it is necessary to include a very large number of patients, to extend the observation period, which increases their cost and reduces the opportunities and desire of pharmaceutical companies to participate in these studies.

Background: Asthma in horses is associated with nonspecific respiratory clinical signs and may be manifested only as exercise intolerance. Its diagnosis relies on bronchoalveolar lavage fluid (BALF) cytology in the presence of compatible clinical signs. The identification of blood biomarkers for this condition would facilitate diagnosis in the field, because there are regional areas where BAL is not routinely performed in clinical practice., Objective: Identification of blood biomarkers for the diagnosis of asthma in horses., Animals: Fourteen horses with asthma with increased neutrophil numbers in BALF (neutrophilic asthma), 9 healthy control horses, and 10 horses with other pathologic conditions (pathologic controls)., Methods: Physical examination, clinical score, hematology, and BALF cytology (in a subset of horses) were performed. Serum concentrations of surfactant protein D (SP-D), haptoglobin, and secretoglobin (SCGB) were measured using commercial ELISA assays., Results: Serum concentration of SP-D > 43 ng/mL, serum concentration of haptoglobin >5730 ng/mL, and serum concentration of SCGB <19 ng/mL allowed differentiation of horses with neutrophilic asthma from horses of the control groups (healthy and pathologic) with sensitivity of 55, 95, and 75%, and specificity of 67, 28, and 60%, respectively. Specificity of 100% and sensitivity of 45% were obtained with the combination of SP-D, haptoglobin, and SCGB at the serum concentrations indicated above. Specificity of 95% and sensitivity of 45% were obtained with the combination of SP-D and SCGB serum concentrations., Conclusions and Clinical Importance: Haptoglobin, SCGB, and SP-D may be diagnostic aids in horses with clinical signs of lower airway disease and neutrophilic pulmonary inflammation., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible condition with poor prognosis that is characterized by a variable clinical course in each patient, which renders it a complex disease with unknown causes. Despite the proven efficacy of novel antifibrotic therapies, including pirfenidone and nintedanib, the diagnosis and follow-up of IPF remain challenging. Hence, the identification of molecular biomarkers for early detection of IPF and to predict biologically determined individual clinical courses, has recently piqued the interest of researchers. Previous studies have demonstrated the diagnostic and prognostic efficacy of blood proteins such as KL-6, Surfactant protein (SP)-A, and SP-D, in patients with IPF. Due to their use in clinical practice in Japan, for approximately twenty years, a significant amount of data about these biomarkers has been accumulated. This paper reviews the recent literature on molecular biomarkers for IPF that have been developed in Japan as well as other potential molecular biomarkers., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Pulmonary involvement is a severe manifestation of systemic sclerosis (SSc). The study was designed to determine the serum level of surfactant protein D (SP-D) in patients with SSc in relation to clinical and laboratory parameters as well as to analyze dynamics of changes of these indices within one year of observation. SP-D was assayed in 41 patients with SSc and 15 healthy controls. Additionally, pulmonary function tests, chest high-resolution computed tomography (HRCT), and inflammatory markers were assessed. All tests were performed twice: at entry and repeated after one year of observation. The serum level of SP-D was significantly higher in patients with SSc than in healthy controls. Serum concentration of SP-D was significantly higher in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD) than in those without SSc-ILD. SP-D was found to correlate with lung involvement evaluated with the Medsger score (diffusing capacity of the lung for carbon monoxide (DLCO), forced vital capacity, radiological changes, and estimated pressure in the pulmonary artery in echocardiography). SP-D correlated with the honeycombing and/or reticular pattern in HRCT and ground glass opacification pattern. Serum concentration of SP-D was elevated in patients with a decreased DLCO. Furthermore, SP-D was higher in patients with diffuse cutaneous type (dcSSc) of the disease than in those with SSc limited type (lcSSc). Because of the small size of the group, it was not possible to perform a statistical analysis for patients who had different results in HRCT, VC, and Medsger score between the first and the second evaluation. SP-D seems to be an index for assessing lung involvement. It reflects the state of pulmonary fibrosis but not the dynamics of the pulmonary fibrosis progression. Further studies are needed to evaluate clinical application of the index, and currently, there is no evidence for the recommendation of the application of SP-D in routine evaluation of patients with SSc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Laboratory animal allergy is a highly prevalent occupational disease among exposed workers. The aim of the study was to validate the biomarkers of airway inflammation in laboratory animal (LA) care workers., Methods: All of the participants in this observational study (63 LA care workers and 64 controls) were administered a clinical questionnaire, underwent spirometry and a skin prick or radioallergosorbent test for common and occupational aeroallergens, and the fraction of exhaled nitric oxide (FeNO 50 ), exhaled breath condensate hydrogen peroxide (EBC H 2 O 2 ) and serum pneumoprotein levels were measured. Multivariate analysis (ANCOVA) was used to assess the interactions of the variables., Results: FeNO 50 levels correlated with exposure (p = 0.002), sensitisation (p = 0.000) and age (p = 0.001), but there was no interaction between exposure and sensitisation when age was considered in the model (p = 0.146). EBC-H 2 O 2 levels were higher in the sensitised workers than in the sensitised controls [0.14 (0.08-0.29) µM vs 0.07 (0.05-0.12) µM; p < 0.05]. Serum surfactant protein A (SP-A) levels were unaffected by exposure, sensitisation or age, although higher levels were observed in symptomatic workers; however, SP-D levels were influenced by exposure (p = 0.024) and age (p = 0.022), and club cell 16 levels were influenced by sensitisation (p = 0.027) and age (p = 0.019)., Conclusions: The presence of the clinical symptoms associated with LA exposure and high FeNO levels should prompt further medical assessments in LA workers. Although EBC-H 2 O 2 levels do not seem to reflect eosinophilic inflammation, serum SP-A levels could be used to monitor progression from rhinitis to asthma.

Objective: To detect the most effective biomarker to confirm ventilator associated pneumonia (VAP)., Methods: Fifty patients with VAP suspicious diagnosis and 30 healthy patients were recruited. Suspicion of VAP was established if patients met the modified CPIS score ≥ 6 points. The confirmation of VAP was defined by the quantitative culture of nonbronchoscopic bronchoalveolar lavage (BAL) >10 5  CFU/ml of pathogenic microorganism. Serum samples for determination of C-reactive protein (CRP), procalcitonin (PCT), pentraxin 3 (PTX3), surfactant protein D (SPD) were collected on suspected VAP., Results: Twenty seven of 50 patients were accepted as confirmed VAP group whose nonbronchoscopic BAL cultures were positive and rest of them were accepted as unconfirmed VAP group. PTX3, PCT and SPD levels were significantly higher in confirmed VAP group, (P = 0.021, P = 0.007, P < 0.001 respectively). There were no significant differences in CRP levels between the two groups (P = 0.062). The most sensitive marker for diagnosing VAP was SPD (P < 0.001). Receiver operating characteristic (ROC) curve for modified clinical pulmonary infection score (CPIS) to confirm VAP was evaluated (AUC 0.741 ± 0.07, P < 0.001) and the optimal cutoff value was >7 with a sensitivity of 51.85% and a specificity of 91.3%. SPD levels were significantly higher in Acinetobacter baumannii and Pseudomonas aeruginosa infected patients than culture negative patients (P < 0.001)., Conclusions: The index findings suggest that serum SPD is the most sensitive biomarker in diagnosis of VAP and it can be used as an early and organism specific marker for Acinetobacter baumannii and Pseudomonas aeruginosa.

Although some toxicological studies have reported that exposure to titanium dioxide nanoparticles (nano-TiO 2 ) may elicit adverse cardiopulmonary effects, related data collected from human are currently limited. The purpose of this study is to explore cardiopulmonary effects among workers who were exposed to nano-TiO 2 and to identify biomarkers associated with exposure. A cross-sectional study was conducted in a nano-TiO 2 manufacturing plant in eastern China. Exposure assessment and characterization of TiO 2 particles were performed in a packaging workshop. Physical examination and possible biomarkers for cardiopulmonary effects were examined among 83 exposed workers and 85 controls. In packaging workshop, the total mass concentration of particles was 3.17 mg/m 3 . The mass concentration of nanoparticles was 1.22 mg/m 3 accounting for 39% of the total mass. Lung damage markers (SP-D and pulmonary function), cardiovascular disease markers (VCAM-1, ICAM-1, LDL, and TC), oxidative stress markers (SOD and MDA), and inflammation markers (IL-8, IL-6, IL-1β, TNF-α, and IL-10) were associated with occupational exposure to nano-TiO 2 . Among those markers, SP-D showed a time (dose)-response pattern within exposed workers. The data strongly suggest that nano-TiO 2 could contribute, at least in part, to the cardiopulmonary effects observed in workers. The studied markers and pulmonary function tests may be useful in health surveillance for workers exposed to nanomaterials.

Background and Aim: SP-D, YKL-40, CCL18 and CA 15-3 are pulmonary markers that have been extensively investigated in different chronic pulmonary diseases. However, in acute pulmonary diseases, such as community-acquired pneumonia (CAP), little is known about the course of these markers and their relationship with the aetiological agent. The aim of this study was to investigate the course of these four markers in CAP and to study influence of disease severity, aetiology and antibiotic use prior to admission on their course., Methods: We included 291 adult patients hospitalised with CAP and 20 healthy controls. Measurements were performed in serum of day 0, 2, and 4, and at least 30 days after admission., Results: Our most important results were: 1) At all time-points, including 30 days after admission, YKL-40 and CCL18 levels were higher in CAP patients compared to healthy controls; and 2) Patients with CAP caused by an intracellular, atypical bacterium had lower YKL-40 and especially CCL18 levels on and during admission in comparison with other or unknown CAP aetiology., Conclusions: Our findings suggest that these pulmonary markers could be useful to assess CAP severity and, especially YKL-40 and CCL18 by helping predict CAP caused by atypical pathogens.

Context: Lung impairment is a new target for late diabetic complications. Biomarkers that could help identify patients requiring functional respiratory tests have not been reported., Objective: Our aim was to examine whether serum surfactant protein D (SP-D) and A (SP-A) could be useful biomarkers of lung damage in obese patients with type 2 diabetes (T2D) without known lung disease., Design and Setting: A case-control study conducted in an ambulatory obesity unit., Patients: Forty-nine obese patients with T2D and 98 subjects without diabetes matched by age, sex, body mass index, and waist circumference were included., Interventions: Serum SP-D and SP-A levels were measured using enzyme-linked immunosorbent assay. Forced spirometry and static pulmonary volume were assessed., Results: Patients with T2D exhibited higher serum SP-D concentrations than control subjects (P = 0.006). No differences in serum SP-A concentrations were observed. There was an inverse association between forced expiratory volume in 1 second (FEV1) and serum SP-D (r = -0.265; P = 0.029), as well as a significant positive relationship between SP-D concentration and residual volume (r = 0.293; P = 0.043). From receiver operating characteristic analysis, the best SP-D cutoff to identify a FEV1 <80% of predicted was 132.3 ng/mL (area under the curve, 0.725; sensitivity, 77.7%; specificity, 69.4%). Stepwise multivariate regression analysis showed that serum SP-D concentration ≥132.3 ng/mL was independently associated with a FEV1 <80% of predicted (R2 = 0.406). Only the existence of T2D contributed independently to serum SD-P variance among all subjects (R2 = 0.138)., Conclusions: Serum SP-D concentration can be a useful biomarker for detecting lung impairment in obese patients with T2D., (Copyright © 2017 Endocrine Society)

Trauma is a major factor that contributes to the risk for acute respiratory distress syndrome (ARDS). Biomarkers that predict the risk, diagnosis, treatment response and prognosis of ARDS after trauma have been widely investigated. In addition to their applications in clinical diagnosis and treatment, these biomarkers provide important insights into our understanding of the pathogenesis of ARDS. This review begins with a brief introduction regarding the incidence and pathogenesis of trauma-associated ARDS. Then, we focus on reviewing the clinical trials that have been designed to investigate the value of biomarkers in ARDS after trauma. Biomarkers with a confirmed value in ARDS have been organized on the basis of key pathogenic processes that are central to ARDS and are described in detail. Among these, angiopoietin 2 (Ang-2), L-selectin, Clara cell protein 16 (CC16), soluable receptor for advanced glycation end products (sRAGE), Surfactant protein D (SP-D) , histones, mtDNAs and some biomarker panels had a certain association with the diagnosis and prognosis of trauma-related ARDS. Further investigations are needed regarding the design of trials, the best sampling approaches and the optimal combinations of the biomarker panels.

Background: Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA., Methods: Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA., Results: Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA., Conclusions: This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

Background. Recent reports indicate that matrix metalloproteinase-7 (MMP-7) and CC-chemokine ligand 18 (CCL18) are potential disease markers of idiopathic pulmonary fibrosis (IPF). The objective of this study was to perform direct comparisons of these two biomarkers with three well-investigated serum markers of IPF, Krebs von den Lungen-6 (KL-6), surfactant protein-A (SP-A), and SP-D. Methods. The serum levels of MMP-7, CCL18, KL-6, SP-A, and SP-D were evaluated in 65 patients with IPF, 31 patients with bacterial pneumonia, and 101 healthy controls. The prognostic performance of these five biomarkers was evaluated in patients with IPF. Results. The serum levels of MMP-7, KL-6, and SP-D in patients with IPF were significantly elevated compared to those in patients with bacterial pneumonia and in the healthy controls. Multivariate survival analysis showed that serum MMP-7 and KL-6 levels were independent predictors in IPF patients. Moreover, elevated levels of both KL-6 and MMP-7 were associated with poorer survival rates in IPF patients, and the combination of both markers provided the best risk discrimination using the C statistic. Conclusions. The present results indicated that MMP-7 and KL-6 were promising prognostic markers of IPF, and the combination of the two markers might improve survival prediction in patients with IPF.

Background: COPD will become the third leading cause of death by 2020. There are many situations in which spirometry, the primary tool for diagnosis of COPD, cannot be performed, and thus, the staging and status of these patients cannot be determined. To date, there is no known biochemical marker used for diagnosing COPD. This study aimed to explore the utility of biomarkers for diagnosis of COPD., Methods: This was an observational study composed of 96 stable subjects with COPD and 96 subjects with normal lung function. Each group contained an equal number of smokers and nonsmokers. Serum levels of superoxide dismutase 3, glutathione peroxidase, catalase, ceruloplasmin ferroxidase activity, C-reactive protein, and surfactant protein D (SPD) were estimated. Ferroxidase activity was estimated by a kinetic method, whereas the other analytes were measured by enzyme-linked immunosorbent assay. The cutoff value, sensitivity and specificity at the cutoff value, and area under the curve for each analyte were determined from receiver operating characteristic curve., Results: Significantly decreased superoxide dismutase 3 and increased ferroxidase activity, SPD, glutathione peroxidase, and C-reactive protein levels were found in subjects with COPD. For all subjects and nonsmoking subjects with COPD, the area under the curve was highest for ferroxidase activity, followed by glutathione peroxidase, SPD, and C-reactive protein, with a sensitivity and specificity of > 73%. For smoking subjects with COPD, the area under the curve was highest for SPD, followed by glutathione peroxidase, ferroxidase activity, and C-reactive protein, with a sensitivity and specificity > 67%. Some combinations of markers were found to give either a sensitivity or specificity of > 95%, which can be utilized to rule in and rule out COPD., Conclusions: Biomarkers can be reliably utilized in the diagnosis of COPD. Of all the markers, SPD appears to be the most promising in smokers, whereas ferroxidase activity shows promise in nonsmokers. To rule out COPD, ferroxidase activity or glutathione peroxidase can be potentially useful, whereas to rule in COPD, ferroxidase activity and glutathione peroxidase appear to be the most promising combination in both nonsmoking and smoking subjects., (Copyright © 2015 by Daedalus Enterprises.)

It has been suggested that allergic diseases might be epithelial disorders driven by various environmental stressors but the epidemiological evidence supporting this concept is limited. In a cross-sectional study of 835 school adolescents (365 boys; mean age, 15.5 yr), we measured the serum concentrations of Club cell protein (CC16), surfactant-associated protein D (SP-D) and of total and aeroallergen-specific IgE. We used the serum CC16/SP-D concentration ratio as an index integrating changes in the permeability (SP-D) and secretory function (CC16) of the airway epithelium. In both sexes, early swimming in chlorinated pools emerged as the most consistent and strongest predictor of low CC16 and CC16/SP-D ratio in serum. Among girls, a low CC16/SP-D ratio was associated with increased odds (lowest vs. highest tertile) for pet sensitization (OR 2.97, 95% CI 1.19-8.22) and for hay fever in subjects sensitized to pollen (OR 4.12, 95% CI 1.28-14.4). Among boys, a low CC16/SP-D ratio was associated with increased odds for house-dust mite (HDM) sensitization (OR 2.01, 95% CI 1.11-3.73), for allergic rhinitis in subjects sensitized to HDM (OR 3.52, 95% CI 1.22-11.1) and for asthma in subjects sensitized to any aeroallergen (OR 3.38, 95% CI 1.17-11.0), HDM (OR 5.20, 95% CI 1.40-24.2) or pollen (OR 5.82, 95% CI 1.51-27.4). Odds for allergic sensitization or rhinitis also increased with increasing SP-D or decreasing CC16 in serum. Our findings support the hypothesis linking the development of allergic diseases to epithelial barrier defects due to host factors or environmental stressors such as early swimming in chlorinated pools., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In heart failure (HF) alveolar-capillary membrane is abnormal. Surfactant-derived proteins (SPs) and plasma receptor for advanced-glycation-end-products (RAGE) have been proposed as lung damage markers., Methods: Eighty-nine chronic HF and 17 healthy subjects were evaluated by echocardiography, blood parameters, carbon monoxide lung diffusion (DLCO) and cardiopulmonary exercise test. We measured immature SP-B, mature SP-B, SP-A, SP-D and RAGE plasma levels., Results: Immature SP-B (arbitrary units), mature SP-A (ng/ml) and SP-D (ng/ml), but not mature SP-B (ng/ml) and RAGE (pg/ml) levels, were higher in HF than in controls [immature SP-B: 15.6 (13.1, 75th-25th interquartile range) Vs. 11.1 (6.4), p<0.01; SP-A, 29.6 (20.1) Vs. 18.3 (13.5), p = 0.01; SP-D: 125 (90) Vs. 78 (58), p<0.01]. Immature SP-B, SP-A, SP-D and RAGE values were related to DLCO, peak oxygen consumption, ventilatory efficiency, and brain natriuretic peptide (BNP), whereas plasma mature SP-B was not. The DLCO Vs. immature SP-B correlation was the strongest one. At multivariate analysis, RAGE was associated to age and creatinine, SP-A to DLCO and BNP, SP-D to BNP, mature SP-B to DLCO and creatinine, and immature SP-B only but strongly to DLCO., Conclusions: Immature SP-B is the most reliable biological marker of alveolar-capillary membrane function in HF.

Objective: To evaluate serum surfactant proteins A and D (SP-A and SP-D), KL-6, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) as biomarkers for monitoring the activity of pulmonary tuberculosis., Methods: Patients with recently diagnosed and sputum smear-positive pulmonary tuberculosis were consecutively recruited between February and April 2013 at the Kanagawa Cardiovascular and Respiratory Center. Serum levels of SP-A, SP-D, KL-6, and CRP, and ESR were measured twice before treatment initiation and after confirmation of disease improvement (indicated by two consecutive negative smears or one negative sputum culture). The relationship of those biomarkers with disease activity was evaluated by comparing the baseline values with the biological and radiological disease severities and by assessing the changes in those values before and after treatment., Results: Twenty-seven patients with pulmonary tuberculosis were enrolled in the study. The median age was 66 years, and the male/female ratio was 19/8 for the entire cohort. The baseline levels of most biomarkers significantly or relatively increased in patients with severe biological and radiological outcomes, which were indicated by findings such as long-term positive sputum culture, and the presence of cavities and shadows on chest radiographs. A second measurement of these biomarkers was performed after a median treatment period of 56 days. The changes in the median levels for these biomarkers were as follows (before/after treatment): SP-A (ng/mL), 55.3/ 39.2 (p < 0.01); SP-D (ng/mL), 71.5/38.5 (p = 0.03); KL-6 (U/ mL), 365/374 (p = 0.43); CRP (mg/dL), 3.8/0.4 (p < 0.01); ESR (mm/hr), 69/46 (p = 0.27). After treatment, the levels of SP-A, SP-D, and CRP significantly decreased., Conclusion: The levels of SP-A, SP-D, and CRP reflected not only the baseline values but also the chronological disease activity. Therefore, these biomarkers could be useful for the management of pulmonary tuberculosis.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that cannot be described by the severity of airflow limitation (forced expiratory volume in the first second of expiration) only. Other measures are needed in clinical practice to assess patients, predict their risk, guide their treatment, and assess their response to it. Over the past few years, there has been a great deal of interest in the identification and validation of biomarkers of potential clinical use in COPD. Here, the authors review some general concepts in the field, discuss currently validated biomarkers in COPD, and speculate on potential future developments., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To investigate whether short-term systemic effects of wood smoke occurred in atopic subjects after experimental wood smoke exposures., Methods: A double-blind climate chamber study was conducted on 20 healthy atopic subjects with exposures to filtered air and wood smoke. Pneumoproteins, coagulation and adhesion factors, and cytokines were measured. Heart rate was monitored with pulse monitors. Data were analyzed with mixed models., Results: Few differences in the outcomes were observed. Plasma tissue factor remained elevated during filtered air exposure (P = 0.002). P-selectin declined independent of exposure (P = 0.0006). Interleukin-6 increased after filtered air (P = 0.03)., Conclusions: The study confirmed previous observations among nonatopics of limited changes after a 3-hour wood smoke exposure.

Background: To evaluate the predictive powers of serum surfactant protein D (SP-D) levels as a biomarker of lung damage in tuberculosis and lung diseases., Methods: This study prospectively included 137 subjects who applied to our hospital. We measured serum SP-D levels from patients with active tuberculosis (TB) (n = 35), chronic obstructive disease (COPD) patients experiencing acute exacerbations (n = 30), patients with pneumonia (n = 45), and control subjects (n = 27)., Results: The mean age of all patients was 54.89 +/- 18.81 years (15 to 100 years); males accounted for two-thirds (70.1%) of the cases. Serum SP-D levels were higher in patients with pnemonia, tuberculosis, and COPD than in control patients (p < 0.001, p < 0.001, and p < 0.001, respectively). Serum SP-D levels in patients with pneumonia, tuberculosis, and COPD were higher than in the control group and mean serum SP-D levels were associated with pulmonary injury scores in patients with pneumonia, severity of COPD attack, and the extent of radiological lung involvement in patients with pneumonia and TB., Conclusions: Serum SP-D may be a useful biomarker of the severity of pneumonia, COPD, and tuberculosis.

Idiopathic pulmonary fibrosis is an intractable disease with a median survival time of 2 to 3 years. Serum levels of Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) are useful biomarkers for idiopathic pulmonary fibrosis and they are widely used in Japan. Based on clinical use in Japan, a combination of KL-6, SPA, and SP-D is useful at diagnosing interstitial lung diseases and predicting the prognoses for patients with these diseases. However, the differential diagnosis of idiopathic pulmonary fibrosis from other interstitial lung diseases is still challenging. Several other biomarkers have been identified and are being studied in Japan.

Knowledge about the pathogenesis and pathophysiology of chronic obstructive pulmonary disease (COPD) has advanced dramatically over the last 30 years. Unfortunately, this has had little impact in terms of new treatments. Over the same time frame, only one new class of medication for COPD has been introduced. Even worse, the rate at which new treatments are being developed is slowing. The development of new tools for the assessment of new treatments has not kept pace with understanding of the disease. In part, this is because drug development tools require a regulatory review, and no interested party has been in a position to undertake such a process. In order to facilitate the development of novel tools to assess new treatments, the Food and Drug Administration, in collaboration with the COPD Foundation, the National Heart Lung and Blood Institute and scientists from the pharmaceutical industry and academia conducted a workshop to survey the available information that could contribute to new tools. Based on this, a collaborative project, the COPD Biomarkers Qualification Consortium, was initiated. The Consortium in now actively preparing integrated data sets from existing resources that can address the problem of drug development tools for COPD.

Background: Emphysema is a key contributor to airflow limitation in chronic obstructive pulmonary disease (COPD) and can be quantified using CT scanning. We investigated the change in CT lung density in a longitudinal, international cohort of patients with COPD. We also explored the potential relation between emphysema and patient characteristics, and investigated if certain circulating biomarkers were associated with decline in CT lung density., Methods: We used a random coefficient model to assess predictors of both CT lung density and its longitudinal change over 3 years in 1928 patients with COPD enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Lung density was measured for every voxel in the CT scan and after correcting for lung volume was expressed as the density at lowest 15th percentile point of the distribution. This study is registered with ClinicalTrials.gov, number NCT00292552., Findings: Lung density at baseline was influenced by age, sex, body-mass index, current smoking status and smoking history, and severity of airflow limitation. The observed decline in lung density was variable (mean decline -1·13 g/L [SE 0·06] per year). The annual decline in lung density was more rapid in women (additional -0·41 [SE 0·14] g/L per year, p=0·003) than men and in current smokers (additional -0·29 [SE 0·14] g/L per year, p=0·047) than in former smokers. Circulating levels of the biomarkers surfactant protein D (SP-D) and soluble receptor for advanced glycation endproduct (sRAGE) were significantly associated with both baseline lung density and its decline over time., Interpretation: This study shows that decline in lung density in COPD can be measured, that it is variable, and related to smoking and gender. We identified potential biochemical predictors of the presence and progression of emphysema., Funding: GlaxoSmithKline., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist., Methods: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1∶1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls., Results: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm(3). Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively)., Conclusions: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Background: The aim of this study was to investigate the effect of breast cancer adjuvant therapies on the levels of circulating surfactant protein-D (SP-D), C-Reactive protein (CRP) and soluble receptor for advanced glycation end-products (sRAGE), as potential biomarkers of subclinical pulmonary inflammation., Materials and Methods: The soluble molecules were serially determined in 38 patients, prior to the initiation of radiation therapy (RT) and during adjuvant treatment, using immunoassays., Results: Significantly higher levels of all three biomarkers were observed in patients prior to the initiation of RT compared to healthy controls (CRP: p<0.001, SP-D: p<0.05, sRAGE: p<0.05). SP-D levels exhibited a gradual increase after RT and during follow-up (p<0.005). Patients treated with a combination of RT and hormonal therapy presented a significant, but less pronounced, increase in SP-D and a significant decrease in CRP compared to those who did not receive hormonal therapy (p=0.0428 and p=0.0116, respectively). Patients treated with a combination of RT and trastuzumab presented a significant increase in SP-D levels (p=0.0310)., Conclusion: The average rate of change in the levels of circulating SP-D and CRP during postoperative irradiation and adjuvant hormonal therapy suggests that the combined therapeutic regiment may potentially exert important anti-inflammatory effects on the lung. On the contrary, combined administration of RT and trastuzumab is likely to induce or provoke pulmonary inflammation.

Chronic obstructive pulmonary disease (COPD) is a progressive disorder that affects 300 million people worldwide and is responsible for 3 million deaths annually. Currently, there are no accepted biomarkers of COPD, which has impaired drug development and management of patients with COPD. Pneumoproteins, which are proteins synthesized predominantly in the lungs, are promising blood biomarkers because they have high specificity for lung disease. The most promising is surfactant protein-D, which is synthesized largely in Type 2 pneumocytes, and its blood concentrations have been associated with COPD and with certain clinical end points such as mortality. In this paper, we discuss surfactant protein-D and other pneumoproteins as promising biomarkers of COPD.

Background: Almost 60% of all patients with severe multiple injuries sustain severe chest trauma with aggravating effect on morbidity and mortality. Diagnosis of lung contusion is performed by early posttraumatic multislice computed tomography. Because this diagnostic procedure requires time, resources, and exposure to radiation, a noninvasive approach with easy follow-up measurements is warranted., Methods: Serum levels of Clara cell protein 16 (CC16) and surfactant protein D as lung-specific biomarkers were obtained on admission from 104 patients with multiple injuries using enzyme-linked immunosorbent assay technique. Patients were divided into those with severe lung injury ([LI]; n = 68) and without LI (NLI; n = 36). Nonsmoking healthy volunteers served as controls. In addition, volume of lung contusions were calculated planimetrically on serial multislice computed tomography scans obtained after admission. Factors influencing CC16 serum levels were determined in uni- and multivariate analyses, and Spearman rank coefficients were calculated for correlations., Results: Patients with LI showed a significant (p < 0.05) elevation of median CC16 levels (10.2 ng/mL) compared with NLI patients (5.4 ng/mL) and controls (5.2 ng/mL). Serum CC16 levels correlated with the volume of lung contusions (r = 0.78, p < 0.0001) and were not influenced by overall injury severity, age, gender, or preclinical ventilation. In contrast, circulating surfactant protein D levels were not associated with the presence of LI or the extent of lung contusions., Conclusions: Our results advocate CC16 as a potential biomarker for LI in severely injured patients because of its high correlation with the volume of contused lung parenchyma. Therefore, this parameter may allow a specified initial treatment of patients with multiple injuries.

Background: Surfactant protein D (SP-D) is a promising blood biomarker in patients with chronic obstructive pulmonary disease (COPD). Nevertheless, circulating levels of SP-D are not related to pulmonary functions. In the present exploratory study, we created a simple index of plasma to bronchoalveolar lavage (BAL) fluid ratio of SP-D (pSP-D/bSP-D), and determined whether this index would relate to the severity of airflow limitation and hence represent a superior biomarker than pSP-D alone., Material/methods: In 50 ex and current smokers (mean age 57.6±7.8 years, 74% men), SP-D was measured in BAL fluid and plasma samples, and the relationships between spirometric variables and a composite parameter - the pSP-D/bSP-D ratio were determined., Results: There was a significant inverse correlation between the pSP-D/bSP-D ratio and the severity of airflow obstruction, as measured by FEV1/FVC (p=0.012). In contrast, no relationship was observed between FEV1/FVC and pSP-D alone., Conclusions: We suggest that integrating both lung and plasma expression of pneumo-proteins may be more useful than plasma expression alone in developing pneumo-proteins as potential biomarkers in COPD.

Background: Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation., Methods: Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation., Results: Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed., Conclusion: Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.

Purpose: Surfactant protein D (SP-D) is found in the epithelial cells of multiple mucosal surfaces. It is commonly used to diagnose and screen for pulmonary diseases. In the present study, serum levels of SP-D were measured in patients with uveitis to ascertain whether SP-D is a clinically useful laboratory parameter to diagnose sarcoidosis., Methods: Sera were obtained from 81 patients with sarcoidosis, 16 patients with Behçet disease, 40 patients with HLA-B27 associated uveitis, 50 patients with Vogt-Koyanagi-Harada (VKH) disease, and 33 healthy volunteers. Serum SP-D levels were quantified with an SP-D enzyme immunoassay kit., Results: In the healthy control subjects, the average serum SP-D level was 39.70 ng/ml; in the uveitis patients with sarcoidosis, the mean serum SP-D level was 57.0 ng/ml, and in the uveitis patients with other etiologies the mean levels were 38.63 ng/ml for Behçet disease, 38.18 ng/ml for HLA-B27 associated uveitis, and 31.32 ng/ml for the VKH patients. The average serum SP-D levels of patients with sarcoidosis were significantly higher than those of patients with any other uveitis etiologies or healthy controls (P < 0.01)., Conclusions: SP-D may be a less invasive and less expensive laboratory examination for sarcoidosis screening. SP-D should be considered as a new laboratory parameter for the diagnosis of uveitis and sarcoidosis.

Acute exacerbation of interstitial pneumonia (IP-AE) can occasionally occur and has a poor prognosis. Direct hemoperfusion with a polymyxin B immobilized fiber column (PMX-DHP) has been shown to have a beneficial effect on acute respiratory distress syndrome, which has similar pathological features to that of IP-AE. This study was aimed to investigate the effects of PMX-DHP on IP-AE and serum indicators for epithelial damage. Nine patients with a clinical diagnosis of interstitial pneumonia, who developed acute exacerbation, were included in this study. Five patients had been given a diagnosis of idiopathic pulmonary fibrosis (IPF) and 3 cases were diagnosed as collagen vascular disease-associated interstitial pneumonia (CVD-IP). On days 30 and 60, 6 and 4 patients were surviving, respectively. On day 60, all 3 patients with CVD-IP were alive, while 4 of 5 patients with IPF had died. In 4 patients who survived for 60 days or longer, serum levels of LDH, CRP, and SP-D were significantly decreased after PMX-DHP, whereas KL-6 level was unchanged. In 5 patients, who died by day 60, no significant changes in the serum markers were observed. These data suggest that serum levels of LDH, CRP, and SP-D might be predictive of successful PMX-DHP treatment in cases of IP-AE.

Surfactant protein (SP)-D is a lung-derived protein that has been proposed as a biomarker for inflammatory lung disease. Serum SP-D was evaluated as a biomarker for components of chronic obstructive pulmonary disease (COPD) in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort and its response assessed to the administration of the anti-inflammatory agent prednisolone. The median level of serum SP-D was significantly elevated in 1,888 individuals with COPD compared to 296 current and former smokers without airflow obstruction (121.1 and 114.3 ng x mL(-1), respectively; p = 0.021) and 201 nonsmokers (82.2 ng x ml(-1); p<0.001). There was no correlation with the severity of COPD. Individuals with COPD who had a serum SP-D concentration that was greater than the 95th percentile of nonsmokers (175.4 ng x mL(-1)) showed an increased risk of exacerbations over the following 12 months (adjusted OR 1.30; 95% CI 1.03-1.63). Treatment with 20 mg x day(-1) prednisolone for 4 weeks resulted in a fall in serum SP-D levels (126.0 to 82.1 ng x mL(-1); p<0.001) but no significant change in post-bronchodilator forced expiratory volume in 1 s. Serum SP-D concentration is raised in smokers and may be useful in identifying individuals who are at increased risk of exacerbations of COPD. It may represent an intermediate measure for the development of novel anti-inflammatory agents.

Objective: 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)., Methods: 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., Results: 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., Conclusion: 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.

Objective: To determine the serum concentrations and clinical association of polymorphonuclear neutrophilic leukocyte (PMN) elastase in patients with systemic sclerosis (SSc)., Methods: Serum PMN elastase levels from 21 patients with limited cutaneous SSc (lSSc) and 32 with diffuse cutaneous SSc (dSSc) were examined by ELISA., Results: Serum PMN elastase levels were elevated in patients with SSc, especially dSSc, compared to healthy controls. SSc patients with elevated serum PMN elastase levels had more frequent presence of pulmonary fibrosis, arthritis, contracture of phalanges, and diffuse pigmentation. Anticentromere antibody was detected less frequently in SSc patients with elevated serum PMN elastase levels than in controls. Consistently, serum PMN elastase levels also correlated positively with serum levels of KL-6 and surfactant protein-D, serological markers for pulmonary fibrosis. Serum PMN elastase levels were also associated with levels of serum 8-isoprostane, an oxidative stress marker in SSc., Conclusion: Serum PMN elastase levels were elevated in patients with SSc, and it was more prominent in patients with pulmonary fibrosis, suggesting that serum PMN elastase is a novel serological marker for SSc-related pulmonary fibrosis.

Surfactant protein (SP) D belongs to the family of collectins, which are humoral molecules of the innate immune system. Collectins belong to pattern recognition receptors and are present in plasma and on mucosal surfaces and recognize several microbial components, the pathogen-associated molecular patterns (PAMPs). While SP-A is primarily expressed in the lung, expression of SP-D is more widely detected including different mucosal surfaces and in serum. Therefore, SP-D is considered a functional candidate in chronic periodontitis. The present study sought to investigate whether plasma concentration of SP-D is altered in chronic periodontitis and whether polymorphisms within the SFTPD gene (Met11Thr, Ala160Thr and Ser270Thr) are associated with chronic periodontitis. The study population comprised 105 patients with chronic periodontitis and 122 healthy, unrelated control individuals. SP-D Plasma concentrations were determined using enzyme-linked immunosorbent assay test. Genotyping of SFTPD polymorphisms was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. Plasma concentrations were significantly increased in patients with chronic periodontitis compared with the controls. The median plasma concentrations were 81.6 ng/ml in the patients and 52.6 ng/ml in the controls (P = 0.00051). In contrast, the three SFTPD polymorphisms displayed no significant association with chronic periodontitis; thus, the increased plasma concentrations were independent on the genotype. The study showed significantly increased SP-D plasma concentrations in patients with chronic periodontitis compared with healthy controls. Thus, SP-D can potentially be used as a biomarker for chronic periodontitis. As no significant associations of SFTPD gene polymorphisms could be detected, other mechanisms influencing SP-D serum/plasma expression might exist.

Background: There is a paucity of surrogate lung-specific biological markers that can be used to track disease progression and predict clinical outcomes in chronic obstructive pulmonary disease (COPD). The principal aim of this pilot study was to determine whether circulating surfactant protein D (SPD) or Clara Cell protein-16 (CC16) levels are associated with lung function or health status in patients with severe COPD., Methods: We studied 23 patients with advanced COPD. Lung function measurements, Chronic Respiratory Disease Questionnaire (CRQ) scores, and serum levels of SPD, CC16, and C-reactive protein (CRP) were determined at baseline and at 3 months., Results: At baseline, FEV(1) was inversely associated with serum SPD levels (P = 0.045) but not with CC16 (P = 0.675) or CRP levels (P = 0.549). Over a 3 month period, changes in SPD levels correlated significantly with changes in CRQ scores (adjusted P = 0.008) such that patients who had the largest declines in serum SPD levels experienced the largest gains in health status. The association was particularly notable between circulating SPD level and the dyspnea domain of the CRQ score (P = 0.018). Changes in CC16 or CRP levels did not correlate with changes in CRQ scores., Conclusion: Changes in serum SPD levels tracked well with changes in health status over a 3 month period in patients with severe COPD. These data suggest that circulating SPD levels may be useful biomarkers to track health outcomes of COPD patients.

The usefulness of selected serum biomarkers (KL-6, SP-A, SP-D, IL-8, MCP-1, CYFRA-21) in diagnosis, monitoring and prognosis prediction of idiopathic pulmonary fibrosis is discussed in this paper.

There are a lot of difficulties in the estimation of interstitial pneumonia and subsequent pulmonary fibrosis associated with connective tissue diseases. Recently, serum KL-6 (KL-6) and serum surfactant protein D (SP-D) have been reported to be useful to estimate the severity of interstitial pneumonia. We investigated the usefulness of these serum markers comparing to the spirometric parameters in patients with interstitial pneumonia associated with connective tissue diseases. We found significant inverse correlation between KL-6 and spirometric % VC. Furthermore, KL-6 was more significantly inverse-related with %DLco. On the other hand, we found neither correlation between SP-D and %VC, nor between SP-D and %DLco, suggesting SP-D level seems to be not affected by the degree of pulmonary fibrosis itself. These results indicate that KL-6 is useful to estimate the severity of pulmonary fibrosis more precisely than SP-D in patients with interstitial pneumonia associated with connective tissue diseases.

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