Coronavirus disease 2019 (COVID-19) in patients before, during, or after lung irradiation, and serum SP-A and SP-D levels.

BACKGROUND: The correlation between COVID-19 and RT has not been determined to date and remains a clinical question. The aim of this study was to evaluate coronavirus disease 2019 (COVID-19) pneumonia before, during, and after radiation therapy (RT) regarding the radiation doses, radiation pneumonitis, and surfactant protein levels. METHODS: We evaluated patients diagnosed with COVID-19 before, during, or after RT for the lung between August 2020 and April 2022. In patients with breast cancer, the RT dose to the ipsilateral lung was determined. In all other patients, bilateral lung RT doses were determined. Patients diagnosed with COVID-19 after RT were evaluated to determine whether radiation pneumonitis had worsened compared with before RT. The serum levels of the surfactant proteins SP-A and SP-D were measured before, during, and after RT. RESULTS: The patients included in the study comprised three men (27.3%) and eight women (72.7%). The primary cancer sites were the breast (n = 7; 63.7%), lung (n = 2; 18.1%), esophagus (n = 1; 9.1%), and tongue (9.1%). COVID-19 was diagnosed before RT in four patients, during RT in two patients, and after RT in five patients. Six (54.5%) patients developed COVID-19 pneumonia. Radiation pneumonitis grade ≥2 was not identified in any patient, and radiation pneumonitis did not worsen after RT in any patient. No rapid increases or decreases in SP-A and SP-D levels occurred after the diagnosis of COVID-19 in all patients regardless of RT timing. CONCLUSIONS: COVID-19 did not appear to result in lung toxicity and surfactant protein levels did not change dramatically.

Baseline plasma KL-6 level predicts adverse outcomes in patients with idiopathic pulmonary fibrosis receiving nintedanib: a retrospective real-world cohort study.

BACKGROUND: Nintedanib is effective for treating idiopathic pulmonary fibrosis (IPF), but some patients may exhibit a suboptimal response and develop on-treatment acute exacerbation (AE-IPF), hepatic injury, or mortality. It remains unclear which patients are at risk for these adverse outcomes. METHODS: We analysed the demographic and clinical data, baseline plasma levels of Krebs von den Lungen-6 (KL-6) and surfactant protein A (SPA), and longitudinal clinical courses of a real-world cohort of IPF patients who received nintedanib ≥ 14 days between March 2017 and December 2020. Cox proportional-hazards regression, subdistribution hazards regression, and sensitivity analyses were performed to investigate the association between baseline predictors and AE-IPF, mortality, and nintedanib-related hepatic injury. The relationship between baseline predictors and pulmonary function decline was determined. RESULTS: Fifty-seven patients were included, of whom 24 (42%) developed hepatic injury, 20 (35%) had AE-IPF, and 16 (28%) died on-treatment. A baseline plasma KL-6 level ≥ 2.5 ng/mL, and diffusion capacity for carbon monoxide (DLCO) < 55% predicted, were associated with increased risk of hepatic injury (adjusted hazard ratio [aHR] was 3.46; 95% CI 1.13-10.60; p = 0.029 for KL-6, and 6.05; 95% CI 1.89-19.32; p = 0.002 for DLCO). Both factors also predicted severe and recurrent hepatic injury. Patients with baseline KL-6 ≥ 2.5 ng/mL also had a higher risk of AE-IPF (aHR 4.52; 95% CI 1.63-12.55; p = 0.004). For on-treatment mortality, baseline KL-6 ≥ 3.5 ng/mL and SPA ≥ 600 pg/mL were significant predictors (aHR 5.39; 95% CI 1.16-24.97; p = 0.031 for KL-6, and aHR 12.28; 95% CI 2.06-73.05; p = 0.006 for SPA). Results from subdistribution hazard regression and sensitivity analyses supported these findings. Patients with elevated baseline plasma KL-6 levels also exhibited a trend towards faster pulmonary function decline. CONCLUSIONS: For patients with IPF who are receiving nintedanib, we have identified baseline predictors, in particular plasma KL-6 levels, for the risk of adverse outcomes. Patients with these predictors may require close monitoring for unfavourable responses during treatment. Our findings also support the prognostic role of molecular markers like KL-6 and may contribute to future formulation of more individualized therapeutic strategies for IPF.

Plasma Surfactant Protein-A Levels In Healthy Subjects And Chronic Obstructive Pulmonary Disease Patients.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is the leading cause of morbidity and mortality across the globe. Currently, there is a dearth of biomarkers which can accurately diagnose and evaluate the prognosis of the disease. Systemic Surfactant Protein- A (SP-A) levels are generally higher in smokers compared to non-smokers as well as elevated in COPD patients as compared to controls. The objective of the study was to estimate and compare plasma surfactant protein-A levels in male and female COPD patients and healthy subjects and to evaluate the role of SP-A as a possible bio-marker for COPD patients. METHODS: A Comparative study, conducted at the department of Physiology & Cell Biology, University of Health Sciences, Lahore between August 2013 and April 2015. A total of 84 subjects of both sexes between 30-80 years of age were included in this study. Subjects were taken from local community and were divided into four groups (A- D). COPD was diagnosed on the basis of relevant history and spirometry showing post bronchodilator FEV1/FVC <0.70. RESULTS: Plasma SP-A levels were not different between controls and COPD patients and between male and female COPD patients. However, SP-A levels were directly correlated with cotinine levels (r= 0.503, p=0.001). Female patients were usually more symptomatic than males and developed COPD at an earlier age compared with male patients. CONCLUSION: Plasma SP-A levels were not significantly different between groups. Plasma cotinine levels (an indication of the tobacco use) were positively correlated with plasma SP-A levels in study subjects. Female patients developed COPD at an early age compared to male counterparts with similar tobacco exposure.

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

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

Differential levels of surfactant protein A, surfactant protein D, and progesterone to estradiol ratio in maternal serum before and after the onset of severe early-onset preeclampsia.

PROBLEM: Preeclampsia (PE), a multifactorial disorder characterized by impaired placental development, elevated inflammatory response and dysregulated placental steroidogenesis. PE may be preventable if predicted early on. METHOD OF STUDY: The study evaluated the potential of immunomodulatory collectins, surfactant protein A (SP-A), surfactant protein D (SP-D), and mannose binding lectin (MBL), to predict PE before the disease onset, in a prospective study cohort of healthy pregnant women (n = 922). In addition, a cross-sectional study was conducted to determine the serum and placental profile of collectins in PE women after the disease onset (early-onset PE [EOPE], n = 33; late-onset PE [LOPE], n = 24); and controls [n = 75]. The serum profiles of estradiol (E2) and progesterone (P4) were evaluated to determine their correlation with collectins. RESULTS: In the prospective cohort, significantly decreased serum levels of SP-A, SP-D, P4/E2 ratio were observed in women who subsequently developed severe EOPE. Interestingly, after the disease onset, there was a significant increase in serum and placental levels of collectins in women with severe EOPE, whereas women with LOPE had significantly decreased levels of collectins. Serum P4/E2 ratio was significantly altered in severe EOPE and positively correlated with serum levels of SP-A and SP-D. CONCLUSION: Collectins are differentially expressed in the serum during progression of PE. Decreased serum levels of SP-A, SP-D, P4/E2 ratio and increased E2 during 10-20 weeks of gestation are novel plausible risk factors for early prediction of EOPE in Indian women.

Pirfenidone Improves Familial Idiopathic Pulmonary Fibrosis without Affecting Serum Periostin Levels.

Background: Antifibrotic agents have been approved for the treatment of idiopathic pulmonary fibrosis (IPF). However, the efficacy of these drugs in the treatment of familial IPF (FIPF) has not been previously reported. Case presentation: We report the case of a 77-year-old man with FIPF, successfully treated with pirfenidone. His uncle died due to IPF, and his niece was diagnosed with the disease. He had worsening dyspnea two months prior to admission to our hospital. Upon admission, he had desaturation when exercising and broad interstitial pneumonia. Administration of pirfenidone improved his dyspnea, desaturation, and the reticular shadow on his chest radiograph. Increased fibrotic marker levels KL-6 and SP-D were also normalized in six months; treatment had no effect on his serum periostin level. Pirfenidone has been effective for over two years. Conclusion: Antifibrotic agents such as pirfenidone may be useful for the management of FIPF, as well as cases of sporadic IPF.

Rice Consumption and Subclinical Lung Disease in US Adults: Observational Evidence From the Multi-Ethnic Study of Atherosclerosis.

Rice accumulates arsenic, an established lung toxicant. Little is known about the association of rice consumption with arsenic-related health effects, particularly interstitial lung disease. Between 2000 and 2002, 6,814 white, black, Hispanic, and Chinese adults from 6 US cities were enrolled in the Multi-Ethnic Study of Atherosclerosis. We included 2,250 participants who had spirometry data, 2,557 with full-lung computed tomography (CT) scans, and 5,710 with cardiac CT scans. Rice consumption and 310 participants with urinary arsenic were assessed at baseline. Spirometry and full-lung CT-derived measures of total lung capacity and high attenuation area (HAA), and interstitial lung abnormalities were measured at examination 5. Cardiac CT-derived HAA was measured at 1-3 visits. Twelve percent of participants reported eating at least 1 serving of rice daily. Comparing data between that group with those who ate less than 1 serving weekly, the mean difference for forced vital capacity was -102 (95% confidence interval (CI): -198, -7) mL, and for forced expiratory volume in 1 second was -90 (95% CI: -170, -11) mL after adjustment for demographics, anthropometrics, dietary factors, and smoking. The cross-sectional adjusted percent difference for total lung capacity was -1.33% (95% CI: -4.29, 1.72) and for cardiac-based HAA was 3.66% (95% CI: 1.22, 6.15). Sensitivity analyses for urinary arsenic were consistent with rice findings. Daily rice consumption was associated with reduced lung function and greater cardiac-based HAA.

Significance of molecular biomarkers in idiopathic pulmonary fibrosis: A mini review.

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.

[Clinical value of surfactant protein-A in exudate pleural effusion].

OBJECTIVE: To evaluate the clinical value of surfactant protein-A (SP-A) in exudate pleural effusion (EPE).
 Methods: This clinical study was prospective, observational and cross-sectional. Two hundred and fifteen patients with pleural effusion were divided into the transudate pleural effusions (TPE) group and the EPE group. TPE patients served as the control group. The concentrations of pleural effusions SP-A (SP-Apl) and serum SP-A (SP-Ase) were measured by ELISA, and receiver operator characteristic (ROC) curve and multivarate Cox analysis of SP-A was analysed for its clinical value.
 Results: SP-Apl concentrations in the EPE group were significantly higher than that in the TPE group [(189.8±43.4) ng/mL vs (22.3±5.1) ng/mL, P<0.01]; SP-Ase concentrations in the EPE group were higher than that in the TPE group [(78.9±11.3) ng/mL vs (25.8±12.4) ng/mL, P<0.05]; SP-Apl concentrations were significantly higher than the concentrations of SP-Ase in the EPE group (P<0.01). In EPE group, SP-Apl and SP-Ase concentration in the patients with primary lung adenocarcinomas were the highest. The cut off value of SP-Apl concentrations was more than 484.5 ng/mL, yielding a 85.4% sensitivity and 95.2% specificity for diagnosing primary lung adenocarcinomas, with an area under the curve (AUC) of 0.943 (95% CI 0.852 to 0.934, P<0.01); when SP-Ase concentration was more than 84.2 ng/mL, it yielded a 76.4% sensitivity and 94.3% specificity for diagnosing primary lung adenocarcinomas, with an AUC of 0.910 (95% CI 0.921 to 0.953, P<0.01).
 Conclusion: While SP-Apl concentration is more than 484.5 ng/mL and/or SP-Ase concentration is more than 84.2 ng/mL, it may be helpful for the diagnosis of primary lung adenocarcinomas with the usage of pleural effusion.

Serum Surfactant Protein Levels in Patients Admitted to the Hospital with Acute COPD Exacerbation.

Surfactant proteins (SPs) have been studied in COPD patients as biomarkers of disease severity and as predictive factors of unfavorable outcomes. The aim of this exploratory study was to evaluate serum levels of SP-A, SP-B, SP-C, and SP-D in patients with COPD both during AECOPD and in stability and to test their possible associations with disease severity and with the development of new exacerbation events. 20 consecutive COPD patients hospitalized for AECOPD were included. Serum SP levels were measured on admission, at discharge, and on stability. SP-A levels were significantly lower both on admission and at discharge in patients with early relapse compared to those with late or no relapse (29.2 ± 9.1 vs. 43.9 ± 16.9 ng/ml, p = 0.037, and 24.3 ± 2.8 vs. 39.3 ± 14.2 ng/ml, p = 0.011, respectively). SP-B levels were found to have a trend to be higher at discharge and significantly higher on stability in patients experiencing an early relapse compared to those with late or no relapse (52.5 ± 31.6 vs. 31.4 ± 32.3 ng/ml, p = 0.052 and 64.8 ± 32.6 vs. 32.8 ± 25.6 ng/ml, p = 0.024, respectively). Finally, the ROC analysis showed that serum SP-A, SP-B, and SP-C levels at discharge, seemed to be significant predictors of early relapse. Our conclusion is that serum levels of SPs might be related to disease outcomes in COPD patients.

Clinical Course of Histologically Proven Multifocal Micronodular Pneumocyte Hyperplasia in Tuberous Sclerosis Complex: A Case Series and Comparison with Lymphangiomyomatosis.

BACKGROUND: Multifocal micronodular pneumocyte hyperplasia (MMPH) is a rare pulmonary manifestation of tuberous sclerosis complex (TSC). Because of its rarity, no previous study has described the detailed clinical course of this disease. OBJECTIVES: This study aimed to clarify the longitudinal clinical characteristics of subjects with MMPH. METHODS: Nine patients with MMPH diagnosed at Hokkaido University Hospital were retrospectively analyzed. Changes in computed tomography findings and pulmonary function were compared during the follow-up period. Serum levels of KL-6, surfactant protein (SP)-A, and SP-D were measured to clarify their potentials as blood biomarkers of the disease. Fourteen cases of lymphangiomyomatosis (LAM) were also included to compare their clinical characteristics with those of subjects with MMPH. RESULTS: Of the 9 patients, 7 were female and 2 were male. The median age at diagnosis was 43 years (range, 19-56), and all cases were diagnosed following incidental abnormal radiographic findings. During the follow-up, 1 patient died of lung cancer, but others were radiographically stable and had stable pulmonary function. Serum levels of SP-A in 5 patients (mean, 146.4 ng/mL) and SP-D in 6 patients (mean, 337.3 ng/mL) were elevated in subjects with MMPH, whereas KL-6 levels were within the reference range (mean, 230 U/mL) in all patients. Levels of SP-A and SP-D were significantly higher in subjects with MMPH than those with LAM (p < 0.05). CONCLUSIONS: Radiographic findings and pulmonary function were stable in all cases of MMPH. Serum SP-A and SP-D, but not KL-6, may be useful markers for suspicion of the presence of MMPH in patients with TSC.

Effects of probiotics on ghrelin and lungs in children with acute lung injury: A double-blind randomized, controlled trial.

AIM: To assess the effects of probiotics on serum ghrelin levels and protection for lungs in children with acute lung injury (ALI). METHODS: This study was performed as a double-blind, randomized, and controlled trial in a pediatric intensive care unit (PICU). The eligible children with ALI were assigned to either probiotic treatment or an identical placebo for 10 days. Serum ghrelin, SP-A(surfactant protein-A), TNF-α, and IL-6 concentrations were assessed at baseline and at the end of trial. Meanwhile, pulmonary function test and echocardiography were examined, then VPEF (volume to peak tidal expiratory flow), TPEF/TE (the ratio of time taken to reach peak expiratory flow to total expiratory time), MAP (mean arterial pressure), and PAP (pulmonary artery pressure) were recorded. RESULTS: Eighty participants fulfilled the study requirements with 40 children for each group. The groups were comparable in baseline characteristics. Serum SP-A, TNF-α, and IL-6 levels in the probiotic group were 212.6 ± 52.9 ng/mL, 401.9 ± 56.4 pg/mL, and 245.1 ± 55.1 pg/mL on day 10, respectively, significantly lower levels compared to the control group where the same parameters were 248.2 ± 57 ng/mL, 449.4 ± 60.1 pg/mL, and 308.3 ± 92.2 pg/mL (P < 0.01). However, ghrelin concentrations were elevated in the intervention group (P < 0.05). On measurement of pulmonary function, the probiotic group demonstrated a VPEF of 26.1 ± 4.2 mL and TPEF/TE of 29.1 ± 4.7%, which were higher than the control group (24.7 ± 4.3 mL and 26.9 ± 4.7%, respectively) (P < 0.05). MAP and PAP also improved in the probiotic group (P < 0.05). Furthermore, ghrelin, SP-A, TNF-α, IL-6, and PAP were negatively correlated. Positive correlations were found between ghrelin, TPEF/TE, and MAP. There were no probiotic-associated adverse events during the observation. CONCLUSION: Probiotics administrated to children with ALI alleviates the inflammation of lungs, improves pulmonary function and circulation by ghrelin.

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

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

Obstructive Sleep Apnea and Subclinical Interstitial Lung Disease in the Multi-Ethnic Study of Atherosclerosis (MESA).

RATIONALE: Obstructive sleep apnea (OSA) has been postulated to contribute to idiopathic pulmonary fibrosis by promoting alveolar epithelial injury via tractional forces and intermittent hypoxia. OBJECTIVES: To determine whether OSA is associated with subclinical interstitial lung disease (ILD) and with biomarkers of alveolar epithelial injury and remodeling. METHODS: We performed cross-sectional analyses of 1,690 community-dwelling adults who underwent 15-channel in-home polysomnography and thoracic computed tomographic imaging in the Multi-Ethnic Study of Atherosclerosis. We measured the obstructive apnea-hypopnea index (oAHI) by polysomnography and high-attenuation areas (HAAs) and interstitial lung abnormalities (ILAs) by computed tomography. Serum matrix metalloproteinase-7 (MMP-7) and surfactant protein-A (SP-A) were measured by ELISA in 99 participants. We used generalized linear models to adjust for potential confounders. RESULTS: The mean age was 68 years, and the mean forced vital capacity was 97% predicted. The median oAHI was 8.4 events/h, and 32% had an oAHI greater than 15. After adjusting for demographics, smoking, and center, an oAHI greater than 15 was associated with a 4.0% HAA increment (95% confidence interval [CI], 1.4-6.8%; P = 0.003) and 35% increased odds of ILA (95% CI, 13-61%; P = 0.001). However, there was evidence that these associations varied by body mass index (BMI) (P for interaction = 0.08 and 0.04, respectively). Among those with a BMI less than 25 kg/m2, an oAHI greater than 15 was associated with a 6.1% HAA increment (95% CI, 0.5-12%; P = 0.03) and 2.3-fold increased odds of ILA (95% CI, 1.3-4.1; P = 0.005). Among those with a BMI greater than 30 kg/m2, an oAHI greater than 15 was associated with 1.8-fold greater odds of ILA (95% CI, 1.1-2.9; P = 0.01) but was not associated with HAA. There were no meaningful associations detected among those with a BMI of 25-30 kg/m2. Greater oAHI was associated higher serum SP-A and MMP-7 levels, particularly among those with a BMI less than 25 kg/m2. CONCLUSIONS: Moderate to severe OSA is associated with subclinical ILD and with evidence of alveolar epithelial injury and extracellular matrix remodeling in community-dwelling adults, an association that is strongest among normal-weight individuals. These findings support the hypothesis that OSA might contribute to early ILD.

Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis in general; however, it is heterogeneous to detect relative biomarkers for predicting the disease progression. Serum biomarkers can be conveniently collected to detect and help to differentially diagnose IPF and predict IPF prognosis. This meta-analysis aimed to evaluate the use of serum surfactant proteins A and D (SP-A and SP-D) for differential diagnosis and prognosis of IPF. METHODS: Relevant articles were searched in PubMed, Embase, and Chinese National Knowledge Infrastructure databases and reviewed by 2 independent readers. Standard mean difference (SMD) and 95% confidence interval (CI) were calculated to assess the difference in serum levels of SP-A/D among patients with IPF, when compared to patients with non-IPF interstitial lung disease (ILD), pulmonary infection, and healthy control. Hazard ratio (HR) and 95% CI were used to compare the relative risk of mortality. RESULTS: Twenty-one articles (totalling 1289 IPF patients) were included in final meta-analysis. Serum SP-A levels were significantly higher in patients with IPF than in patients with non-IPF ILD (SMD: 1.108 [0.584, 1.632], P < .001), or pulmonary infection (SMD: 1.320 [0.999, 1.640], P < .001) and healthy controls (SMD: 2.802 [1.901, 3.702], P < .001). There was no significant difference in serum SP-D levels between patients with IPF and those with non-IPF ILD patients (SMD: 0.459 [-0.000, 0.919], P = .050). Serum SP-D levels were significantly higher in patients with IPF than in patients with pulmonary infection (SMD: 1.308 [0.813, 1.803], P < .001) and healthy controls (SMD: 2.235 [1.739, 2.731], P < .001). Risk of death in patients with IPF and elevated serum SP-A was increased 39% compared to patients with low SP-A groups. Elevated SP-D increased risk by 111% when compared to low SP-D. In acute exacerbation of IPF, serum SP-A/D were higher than those in stable stage. The comparisons and prognosis might be different in Asian and Caucasian patients. CONCLUSIONS: Serum SP-A/D detection might be useful for differential diagnosis and prediction of survival in patients with IPF.

Relationship between Fractional Exhaled Nitric Oxide Level and Efficacy of Inhaled Corticosteroid in Asthma-COPD Overlap Syndrome Patients with Different Disease Severity.

This study explored the relationship between the fractional exhaled nitric oxide (FeNO) level and the efficacy of inhaled corticosteroid (ICS) in asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) patients with different disease severity. A total of 127 ACOS patients with ACOS (case group) and 131 healthy people (control group) were enrolled in this study. Based on the severity of COPD, the ACOS patients were divided into: mild ACOS; moderate ACOS; severe ACOS; and extremely severe ACOS groups. We compared FeNO levels, pulmonary function parameters including percentage of forced expiratory volume in 1 second (FEV1) to predicted value (FEV1%pred), ratio of FEV1 to forced vital capacity (FEV1/FVC), inspiratory capacity to total lung capacity (IC/TLC) and residual volume to total lung capacity (RV/TLC), arterial blood gas parameters, including PH, arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2), total serum immunoglobulin E (IgE), induced sputum eosinophil (EOS), plasma surfactant protein A (SP-A), plasma soluble receptor for advanced glycation end products (sRAGE), sputum myeloperoxidase (MPO), sputum neutrophil gelatinase-associated lipocalin (NGAL) and Asthma Control Test (ACT) scores, and COPD Assessment Test (CAT) scores. Compared with pre-treatment parameters, the FeNO levels, RV/TLC, PaCO2, total serum IgE, induced sputum EOS, plasma SP-A, sputum MPO, sputum NGAL, and CAT scores were significantly decreased after 6 months of ICS treatment, while FEV1%pred, FEV1/FVC, IC/TLC, PH, PaO2, plasma sRAGE, and ACT scores were significantly increased in ACOS patients with different disease severity after 6 months of ICS treatment. This finding suggests that the FeNO level may accurately predict the efficacy of ICS in the treatment of ACOS patients.

Cholesterol, lipoproteins and subclinical interstitial lung disease: the MESA study.

We investigated associations of plasma lipoproteins with subclinical interstitial lung disease (ILD) by measuring high attenuation areas (HAA: lung voxels between -600 and -250 Hounsfield units) in 6700 adults and serum MMP-7 and SP-A in 1216 adults age 45-84 without clinical cardiovascular disease in Multi-Ethnic Study of Atherosclerosis. In cross-sectional analyses, each SD decrement in high density lipoprotein cholesterol (HDL-C) was associated with a 2.12% HAA increment (95% CI 1.44% to 2.79%), a 3.53% MMP-7 increment (95% CI 0.93% to 6.07%) and a 6.37% SP-A increment (95% CI 1.35% to 11.13%), independent of demographics, smoking and inflammatory biomarkers. These findings support a novel hypothesis that HDL-C might influence subclinical lung injury and extracellular matrix remodelling.

Prognostic significance of surfactant protein A, surfactant protein D, Clara cell protein 16, S100 protein, trefoil factor 3, and prostatic secretory protein 94 in idiopathic pulmonary fibrosis, sarcoidosis, and chronic pulmonary obstructive disease.

BACKGROUND: Identification of serum and bronchoalveolar lavage fluid (BALF) biomarkers may facilitate diagnosis and prognostication in various lung disorders. OBJECTIVE: Serum and BALF levels of surfactant protein A (SP-A), surfactant protein D (SP-D), Clara cell protein 16 (CC16), S100 protein, trefoil factor 3 (TFF3), and prostatic secretory protein 94 (PSP94) were evaluated in 94 consecutive patients (idiopathic pulmonary fibrosis (IPF; n=18), sarcoidosis (n=25), chronic obstructive pulmonary disease (COPD; n=51)), and in 155 healthy controls. METHODS: Biomarkers were measured at diagnosis and compared with disease characteristics. Both uniparametric and multiparametric analyses were used. RESULTS: Seven significant correlations were found: 1) BALF PSP94 level correlated with prognosis of sarcoidosis (P=0.035); 2) BALF SP-D level with pulmonary functions in IPF (P=0.032); 3) BALF SP-D and TFF3 with IPF mortality (P=0.049 and 0.017, respectively); 4) serum TFF3 level with COPD mortality (P=0.006,); 5) serum SP-A with pulmonary functions impairment in IPF (P=0.011); 6) serum SP-D level was associated with HRCT interstitial score in IPF (P=0.0346); and 7) serum SP-A was associated with staging of COPD according to spirometry (P<0.001). Moreover, our analysis showed that some biomarker levels differed significantly among the diseases: 1) BALF SP-D level differed between sarcoidosis and IPF; 2) serum SP-A level differed among IPF, sarcoidosis, COPD and was also different from healthy controls; 3) serum S100A6, S100A11 levels differed among IPF, sarcoidosis, COPD from healthy controls 4) serum SP-D, CC16, TFF-3 levels distinguished IPF patients from healthy controls; and 5) serum CC16, TFF3, PSP94 distinguished COPD patients from healthy controls. Our study shows that some of selected biomarkers should have prognostic value in the analysed lung disorders. On the other hand, these biomarkers do not appear to be unequivocally suitable for differential diagnosis of these disorders.

Deleted in malignant brain tumors 1 protein is a potential biomarker of acute respiratory distress syndrome induced by pneumonia.

Acute respiratory distress syndrome (ARDS) is associated with high mortality and morbidity. Early diagnosis and risk stratification in patients with ARDS should improve prognosis. Unfortunately, no clinical biomarkers are available for use in early diagnosis. Quantitative proteomics is a powerful tool for biomarker discovery in cancer, autoimmune diseases, and ARDS. Here, we employed isobaric tags for relative and absolute quantitation (iTRAQ) technology to identify potential biomarkers for early ARDS diagnosis and predict the risk for increased disease severity induced by pneumonia. We collected the bronchoalveolar lavage fluid (BALF) and plasma from ARDS patients with differing degrees of ARDS severity. We identified 338 proteins dysregulated in ARDS through iTRAQ, 18 of which showed significant differences with at least 1.5-fold differential expression in patients with mild or severe ARDS. Differential plasma expression of pulmonary surfactant associated protein A, apolipoprotein A1, and deleted in malignant brain tumors 1 protein (DMBT1) was verified in plasma samples. Our results indicate that DMBT1 can potentially serve as a biomarker for early ARDS diagnosis and disease severity assessment.

Comparative Study of Circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as Disease Markers of Idiopathic Pulmonary Fibrosis.

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.