Krebs Von Den Lungen-6 Research Articles

Exposure to engineered nanomaterials and early biological effects measured in the exhaled breath condensate: First results from the NanoExplore cohort

BACKGROUND AND AIM Activities involving engineered nanomaterials (ENM) may raise concerns of occupational exposure and subsequent health effects. We aimed to build a multicenter prospective cohort to assess the potential effects of ENM exposure using biomarkers of early effects measured in exhaled breath condensate (EBC). METHODS We recruited seven centers in three countries (Switzerland, Spain, and Italy), where we conducted a 4-day exposure monitoring campaign and two EBC samplings, at the beginning (T1) and end (T2) of working week. The recruited workers were split in three groups depending on their exposure and compared in terms of their baseline individual and professional characteristics, and health status. EBC biomarkers of oxidative and nitrosative stress (malondialdehyde, 8-isoprostane, nitrotyrosine), systemic inflammation (High-Sensitivity C-Reactive Protein (hsCRP)), activation of pro-fibrotic cascade and interstitial lung disease (Krebs von den Lungen glycoprotein 6 (KL6)) and inflammatory cytokines (Interleukins (IL-10, IL-1β), Tumor necrosis factor (TNF-α)) were analyzed using multilevel mixed interval regression models. RESULTS The cohort included 140 participants: 43 non-exposed, 55 with negligible to low exposure, and 43 with medium to high exposure. The latter were gradually more often men, older, and in overweight than lowly exposed and non-exposed workers. A statistically significant change between T1 and T2 average concentrations was observed for malondialdehyde and KL6. Between-group differences were observed for all biomarkers but KL6 and nitrotyrosine. In multivariate models adjusted for age, sex and body mass index, a linear exposure-response relationship was observed for malondialdehyde, 8-isoprostane, IL-10, IL-1β, and TNF-α. ENM exposure was also associated with higher hs-CRP and KL6 levels, but not monotonically. CONCLUSION These first results suggest that ENM exposure might lead to early biological effects in workers’ airways. These findings need confirmation and a caution interpretation of their clinical significance, as most effects are non-specific and likely reversible.

KL-6 in ARDS and COVID-19 Patients

The Acute Respiratory Distress Syndrome (ARDS) is a common, devastating clinical pattern characterized by life-threatening respiratory failure. In ARDS there is an uncontrolled inflammatory response that results in alveolar damage, with the exudation of protein-rich pulmonary-edema fluid in the alveolar space. Although severe COVID-19 lung failure (CARDS) often meets diagnostic criteria of traditional ARDS, additional features have been reported, such as delayed onset, binary pulmonary compliant states, and hypercoagulable profile. Increased levels of Krebs von den Lungen 6 (KL-6, also known as MUC1) have been reported in both ARDS and CARDS. KL-6 is a transmembrane protein expressed on the apical membrane of most mucosal epithelial cells and it plays a critical role in lining the airway lumen. Abnormalities in mucus production contribute to severe pulmonary complications and death from respiratory failure in patients with diseases such as cystic fibrosis, chronic obstructive pulmonary disease, and acute lung injury due to viral pathogens. Nevertheless, it is not clear what role KL-6 plays in ARDS/CARDS pathophysiology. KL-6 may exert anti-inflammatory effects through the intracellular segment, as proven in animal models of ARDS, while its extracellular segment will enter the blood circulation through the alveolar space when the alveolar epithelial cells are damaged. Therefore, changes in plasma KL-6 levels may be useful in ARDS and CARDS phenotyping, and KL-6 might guide future clinical trials in ‘personalized medicine’ settings.

Distribution of Presepsin, Krebs von den Lungen 6, and Surfactant Protein A in Umbilical Cord Blood.

Presepsin is an early indicator of infection, and Krebs von den Lungen 6 (KL-6) and Surfactant Protein A (SP-A) are related to the pathogenesis of pulmonary infection and fibrosis. This study aimed to establish reference intervals (RIs) of presepsin, KL-6, and SP-A levels and to evaluate the possible influence of neonatal and maternal factors on presepsin, KL-6, and SP-A levels in umbilical cord blood (UCB). Among a total of 613 UCB samples, the outliers were removed. The RIs for presepsin, KL-6, and SP-A levels were defined using non-parametric percentile methods according to the Clinical and Laboratory Standards Institute guidelines (EP28-A3C). These levels were analyzed according to neonatal and maternal factors: neonatal sex, gestational age (GA), birth weight (BW), Apgar score, delivery mode, the presence of premature rupture of membranes (PROM), gestational diabetes mellitus (GDM), and pre-eclampsia. Presepsin, KL-6, and SP-A levels showed non-parametric distributions and left-skewed histograms. The RIs of presepsin, KL-6, and SP-A levels were 64.9–428.3 pg/mL, 43.0–172.0 U/mL, and 2.1–36.1 ng/mL, respectively. Presepsin, KL-6, and SP-A levels did not show significant differences according to sex, GA, BW, Apgar score, delivery mode, PROM, GDM, and pre-eclampsia. The median level and 97.5th centile RI of KL-6 showed a slight increase with increased GA. We established RIs for presepsin, KL-6, and SP-A levels in large-scaled UCB samples. Further investigation would be needed to determine the clinical significance.

Sarcoidosis: Progression to the chronic stage and pathogenic based treatment (narrative review).

Many factors confirm the autoimmune nature of sarcoidosis and help in determining the strategy of patient management and treatment initiation. However, the causes and the mechanisms of disease progression that result in fibrosis and insufficiency of the affected organ remain unclear. This narrative review aims to analyse the mechanisms and biomarkers of sarcoidosis progression, as well as the pathogenetic basis of sarcoidosis therapy. The following characteristics of progressive chronic sarcoidosis were revealed: the disease develops in patients with a genetic predisposition (SNP in genes GREM1, CARD15, TGF-β3, HLA-DQB1*06:02, HLA-DRB1*07/14/15), which contributes either the decreased ability of antigen elimination or autoimmune inflammation. Various prognostic biomarkers of disease progression (decreased levels of neopterin, elastase, sIL-2R, chitotriosidase, glycoprotein Krebs von den Lungen, Th17 cell count, reduced quantity of TNF-α in peripheral blood or bronchoalveolar lavage fluid) have been described and can potentially be used to determine the group of patients who will benefit from the use of corticosteroids/cytostatic drugs/biologics.

Elevated serum human epididymis protein 4 is associated with disease severity and worse survival in idiopathic pulmonary fibrosis: a cohort study.

BackgroundElevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice.MethodsA total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4.ResultsThe levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=−0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=−0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=−0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients.ConclusionsThe expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

Changes in serum transforming growth factor-beta concentration as a predictive factor for radiation-induced lung injury onset in radiotherapy-treated patients with locally advanced lung cancer.

BackgroundRadiation-induced lung injury (RILI) occurs after chest radiation therapy, which ranges from acute radiation pneumonia to subsequent radiation pulmonary fibrosis. However, they are difficult to predict. The study aimed to examine the predictive utility of serum levels of transforming growth factor-beta (TGF-β) for radiation-induced lung injury.MethodsThis single-center prospective observational study enrolled 21 patients with locally advanced lung cancer who underwent chest radiation therapy. We measured the serum levels of TGF-β, Krebs von Denlungen-6, and granulocyte colony-stimulating factor (GCSF) eight times immediately before irradiation.ResultsSeven, four, eight, and one patient had Grade 0, 1, 2, and 3 radiation-induced lung injury, respectively. Compared with the Grade 0 and 1 RILI groups (RP− group), the Grade 2 and 3 RILI groups (RP+ group) had a significantly higher relative ratio of TGF-β values from immediately before irradiation to the time of 30–48 Gy irradiation (P=0.011). The cut-off value of the TGF-β relative ratio of the RP+ group measured from the receiver operating characteristic curve was 1.31; moreover, the sensitivity, specificity, and positive predictive value were 75%, 100%, and 75%, respectively. There was no significant between-group difference in the levels of the other cytokines.ConclusionsFor patients undergoing radiation therapy for locally advanced lung cancer, the ratio of TGF-β levels before and after 30–48 Gy irradiation may predict the onset of RILI. Our findings may facilitate the identification of predictors of the onset of radiation-induced lung injury.

A Systematic Review and Metaanalysis of Predictors of Mortality in Idiopathic Inflammatory Myopathy-Associated Interstitial Lung Disease.

Idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) can range from rapidly progressive disease with high mortality to indolent disease with minimal morbidity. This systematic review and metaanalysis describe immunological, clinical, and radiographical predictors of mortality in IIM-ILD. MEDLINE and Embase database searches were completed on October 18, 2021, to identify articles providing survival data according to baseline characteristics in patients with concurrent IIM and ILD. Prognostic factors common to more than 5 papers were included in the metaanalysis using a random-effects model to report odds ratios (ORs) for binary variables and Hedges g for continuous variables. Risk of bias was assessed using the Newcastle-Ottawa Scale score and the Egger test for publication bias. From 4433 articles, 62 papers were suitable for inclusion; among these studies, 38 different variables were considered. The OR for risk of death regarding the presence of anti-melanoma differentiation-associated protein 5 (MDA5) antibodies was 6.20 (95% CI 3.58-10.71), and anti-tRNA synthetase antibodies were found to be protective (OR 0.24, 95% CI 0.14-0.41). Neither antinuclear antibodies, anti-52-kDa Ro antigen antibodies, nor SSA significantly altered mortality, nor was MDA5 titer predictive. Examples of prognostic factors that are significantly associated with mortality in this study include the following: age; male sex; acute/subacute onset; clinically amyopathic dermatomyositis; dyspnea; ulceration; fever; raised C-reactive protein, ferritin, lactate dehydrogenase, alveolar to arterial O2 (A-aO2) gradient, ground-glass opacity on high-resolution computed tomography (HRCT), and overall HRCT score; and reduced albumin, lymphocytes, ratio of partial pressure of oxygen in the arterial blood to fraction of inspired oxygen (PF ratio), percentage predicted transfer factor for carbon monoxide, and percentage predicted forced vital capacity. Baseline surfactant protein-D and Krebs von den Lungen-6 levels were not predictors of mortality. Many mortality risk factors were identified, though heterogeneity was high, with a low quality of evidence and a risk of publication bias. Studies regarding anti-MDA5 antibody-positive disease and and those from East Asia predominate, which could mask risk factors relevant to other IIM subgroups or populations.

1087P Predictive value of Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) in patients (pts) with EGFR exon 20 insertion (ex20ins)-positive metastatic non-small cell lung cancer (mNSCLC) receiving mobocertinib therapy

KL-6 and SP-D have been used to assess lung injury with anticancer therapies, including tyrosine kinase inhibitors (TKIs). We evaluated the predictive value of KL-6 and SP-D for lung adverse event incidence and their variation during mobocertinib treatment (tx) as a readout of lung inflammation.

Elevated plasma levels of Krebs von den Lungen-6 and geographic appearance on high-resolution computed tomography are associated with diffuse alveolar damage in autopsy cases of acute respiratory distress syndrome: a retrospective study

BackgroundAlthough diffuse alveolar damage (DAD) is a histopathological hallmark of acute respiratory distress syndrome (ARDS), its detection without lung biopsy is challenging. In patients with ARDS, the specificity of the Berlin definition to diagnose DAD as a reference standard is not adequately high, making it difficult to adequately diagnose DAD. The purpose of this study was to investigate the relationship between DAD and clinical findings, including KL-6 and geographic appearance, in ARDS patients and to identify more specific diagnostic criteria for DAD.MethodsAmong all adult autopsy cases at a tertiary hospital in Japan between January 2006 and March 2021, patients with ARDS who met the Berlin definition criteria were included. The patients’ conditions were classified according to histopathological patterns as DAD or non-DAD, and clinical characteristics, laboratory data, and high-resolution computed tomography (HRCT) findings were compared between the two groups.ResultsDuring the study period, 27 met the Berlin definition (median age: 79 years, 19 men), of whom 18 (67%) had DAD and 9 (33%) did not. In the non-DAD group, histopathologic findings revealed organizing pneumonia in seven patients and pulmonary hemorrhage in two patients. On HRCT at onset, patients with DAD had more geographic appearance than those without DAD (89% vs. 44%). In patients with geographic appearance and elevated KL-6 (> 500 U/mL), the sensitivity and specificity for DAD diagnosis were 56% and 100%, respectively. All three patients with no geographic appearance and normal KL-6 did not have DAD.ConclusionsGeographic appearance on HRCT combined with KL-6 levels may predict the presence of DAD in patients with ARDS.

Krebs von den Lungen-6 glycoprotein circulating levels are not useful as prognostic marker in COVID-19 pneumonia: A large prospective cohort study.

Coronavirus disease 2019 (COVID-19) has rapidly expanded worldwide. Currently, there are no biomarkers to predict respiratory worsening in patients with mild to moderate COVID-19 pneumonia. Small studies explored the use of Krebs von de Lungen-6 circulating serum levels (sKL-6) as a prognostic biomarker of the worsening of COVID-19 pneumonia. We aimed at a large study to determine the prognostic value of sKL-6 in predicting evolving trends in COVID-19. We prospectively analyzed the characteristics of 836 patients with COVID-19 with mild lung disease on admission. sKL-6 was obtained in all patients at least at baseline and compared among patients with or without respiratory worsening. The receiver operating characteristic curve was used to find the optimal cutoff level. A total of 159 (19%) patients developed respiratory worsening during hospitalization. Baseline sKL-6 levels were not higher in patients who had respiratory worsening (median {IQR} 315.5 {209–469} vs. 306 {214–423} U/ml p = 0.38). The last sKL-6 and the change between baseline and last sKL-6 were higher in the respiratory worsening group (p = 0.02 and p < 0.0001, respectively). The best sKL-6 cutoff point for respiratory worsening was 497 U/ml (area under the curve 0.52; 23% sensitivity and 85% specificity). sKL-6 was not found to be an independent predictor of respiratory worsening. A conditional inference tree (CTREE) was not useful to discriminate patients at risk of worsening. We found that sKL-6 had a low sensibility to predict respiratory worsening in patients with mild-moderate COVID-19 pneumonia and may not be of use to assess the risk of present respiratory worsening in inpatients with COVID-19 pneumonia.

Successful rituximab treatment for severe rapidly progressive interstitial lung disease with anti-MDA5 antibody-positive juvenile dermatomyositis: a case report and literature review

BackgroundRapidly progressive (RP) interstitial lung disease (ILD) is a life-threatening complication of juvenile dermatomyositis (JDM); however, it is generally refractory to treatment; to the best of our knowledge, no evidence-based treatment has been established for RP-ILD yet. We present the case of a 2-year-old girl with RP-ILD who showed resistance to treatment with methylprednisolone, cyclosporine A, cyclophosphamide, immunoglobulin, and plasma exchange (PE) and was finally treated with extracorporeal membrane oxygenation. We further present a literature review of 18 cases of JDM with RP-ILD.Case presentationA 2-year-old girl presented with malar rash, mild muscle weakness, and weight loss for a few months before admission. She had a history of dry cough and dyspnea for a few days, followed by rapid respiratory failure. The patient was diagnosed with JDM with RP-ILD through physical examination (malar rashes and Gottron’s sign) and based on the finding of myositis on femoral magnetic resonance imaging, elevated levels of serum muscle enzymes, positive anti-melanoma differentiation-association gene 5 (MDA5) antibody (> 7,500 index), elevated level of Krebs von den Lungen-6 glycoprotein (KL-6; 3,420 U/mL), and extensive ground-glass opacities with consolidation in the bilateral lungs on chest high-resolution computed tomography. She received combination therapy, including methylprednisolone pulse therapy, followed by oral prednisolone and intravenous cyclosporine A, cyclophosphamide, and immunoglobulin. On day 11 of hospitalization, she was placed on ventilation support and PE was initiated. However, her respiratory condition continued to deteriorate and veno-venous extracorporeal membrane oxygenation was started on day 24 of hospitalization. Rituximab was administered on day 28. After 2 weeks of rituximab therapy initiation, her respiratory condition showed gradual improvements. Eventually, on day 52 of hospitalization, the patient could be weaned off extracorporeal membrane oxygenation. Finally, she was discharged with minimal ventilation support and no neurological complications 11 months after admission.ConclusionsOur literature review suggest that JDM with RP-ILD has a high mortality rate. In JDM, rituximab may be a promising treatment option for RP-ILD. In the future, the efficacy of rituximab in the early phases of ILD should be investigated.

Exploring the Association Between Air Pollutant Exposure and Krebs von den Lungen-6 (KL 6) Serum Levels in Outdoor and Indoor Workers in Banyumas District, Central Java

Introduction: Indonesia ranks 8th globally in the air pollution index, with poor air quality causing premature deaths from lung ailments such as interstitial lung diseases. Krebs von den Lungen-6 (KL 6) can be used to detect lung disease caused by air pollution. However, the number of studies investigating the link between air pollutant exposure and KL-6 levels is inadequate. The present study explores the association between air pollutant exposure and KL-6 levels in workers in different settings. Methods: This cross-sectional study recruited 70 individuals who were divided into two groups. Dust levels were measured using a particle counter as a proxy for air pollutant levels. KL-6 levels were measured with ELISA. The Spearman correlation test, Mann-Whitney test, and generalized linear model were used in statistical analyses. Results and Discussion: Air pollutant exposure differed significantly between outdoor and indoor settings (p = 0.000). A significant difference was found in KL-6 serum levels between outdoor and indoor workers (p = 0.000). Air pollutant levels were inversely associated with KL-6 serum levels in outdoor (r = -0.557, p &lt; 0.05) and indoor workers (r = -0.360, p &lt; 0.05). Working duration did not significantly correlate with KL-6 serum levels in either group. A tendency of linear association among air pollutant exposure, overall working duration, and KL-6 serum levels was found in the multivariable model. Conclusion: Work settings were associated with varying exposures to air pollutants and KL-6 serum levels. Higher exposure to pollutants may be associated with an increase in KL-6 serum levels.

One-year follow-up study after patients with severe COVID-19 received human umbilical cord mesenchymal stem cells treatment

BackgroundThe novel coronavirus is still mutating, and the pandemic continues. Meanwhile, many COVID-19 survivors have residual postinfection clinical manifestations. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been shown to be effective in the early stages of COVID-19.ObjectivesThe aim of this study was to investigate long-term safety and efficacy of treatment in patients with severe COVID-19 patients who had received hUC-MSCs therapy.MethodsTwenty-five discharged patients who had severe COVID-19 (including the standard treatment group and the standard treatment plus hUC-MSCs group) were enrolled in a 1-year follow-up. The assessment considered adverse effects (including effects on liver and kidney function, coagulation, ECG, tumor marker, and so on), pulmonary function, St George’s Respiratory Questionnaire (SGRQ), postinfection sequelae and serum concentration of Krebs von den Lungen-6 (KL-6), malondialdehyde (MDA), H2S, carnitine, and N-6 long-chain polyunsaturated fatty acids (N-6 LC-PUFAs).Measurements and main resultsPulmonary ventilation function had significantly improved at the 1-year follow-up in both the hUC-MSCs group and the control group compared with the 3-month follow-up (P < 0.01). Fatigue (60% [15/25]) remained the most common symptom at the 1-year follow-up. The rate of fatigue relief was significantly reduced in the hUC-MSCs group (25% [2/8]) compared to the control group (76.5% [13/17]) (P = 0.028). The level of KL-6 was significantly lower in the hUC-MSCs group (2585.5 ± 186.5 U/ml) than in the control group (3120.7 ± 158.3 U/ml) (P < 0.001). Compared with the control group, the hUC-MSCs group had a lower level of MDA (9.27 ± 0.54 vs. 9.91 ± 0.72 nmol/ml, P = 0.036). No obvious adverse effects were observed in the hUC-MSCs treatment group at 1 year after discharge.ConclusionsIntravenous transplantation of hUC-MSCs was a safe approach in the long term in the treatment of patients with severe COVID-19. In addition, hUC-MSCs had a positive effect on postinfection sequelae in COVID-19 survivors.Trial registrationChinese Clinical Trial Registration; ChiCTR2000031494; Registered 02 April 2020—Retrospectively registered, http://www.medresman.org

Usefulness of monocyte distribution width and presepsin for early assessment of disease severity in COVID-19 patients.

Early predictors of severe coronavirus disease 2019 (COVID-19) would identify patients requiring intensive care. Recently, the monocyte distribution width (MDW) and presepsin level have been used for the early diagnosis of sepsis. Here, we assessed the utility of MDW and presepsin for the early assessment of COVID-19 severity.Eighty-seven inpatients with confirmed COVID-19 were enrolled and divided into 3 groups by the type of respiratory support: (1) mechanical ventilation or high-flow nasal cannula oxygen therapy (MVHF-OT), (2) conventional oxygen therapy, and (3) no oxygen therapy. We measured the complete blood count; MDW; erythrocyte sedimentation rate; and the levels of presepsin, C-reactive protein, procalcitonin, lactate dehydrogenase, ferritin, Krebs von den Lungen-6 (KL-6), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibody.Thirteen (14.9%) patients on MVHF-OT exhibited a significantly higher mortality and a longer hospital stay than did the others. The MDW and presepsin levels were significantly elevated on admission, and correlated with COVID-19 severity (both P < .001). Notably, only the MDW correlated significantly with symptoms in the no oxygen therapy group (P < .012). In the first week after admission, the MDW fell and no longer differed among the groups. The KL-6 level did not differ by disease severity at any time. Neutralizing antibodies were detected in 74 patients (91.4%) and the level of neutralization correlated significantly with COVID-19 severity (P < .001).The MDW and presepsin are useful indicators for early assessment of disease severity in COVID-19 patients.

YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis

YKL-40 (chitinase 3-like-1) and Krebs von den Lungen-6 (KL-6) are 2 promising biomarkers that may have an important role in the management of interstitial lung diseases (ILD). The aim of this study was to investigate the values of KL-6 and YKL-40 as biomarkers in the diagnosis and prognosis of patients with hypersensitivity pneumonitis (HP). A cross-sectional study conducted in 49 patients diagnosed with HP due to exposure to birds (n= 32) or fungi (n= 17), 48 patients with other ILD, and 67 healthy volunteers. Patients with HP were divided into fibrotic and nonfibrotic. Serum and sputum YKL-40 and KL-6 levels were determined using commercial enzyme-linked immunosorbent assay kits. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of both biomarkers for the diagnosis of HP. Pulmonary function tests were performed in patients during follow-up. KL-6 and YKL-40 levels were significantly higher in serum of patients with HP exposed to birds with a fibrotic pattern than in controls (P < .0001 and .0055, respectively). Serum KL-6 levels were also significantly higher in patients with fibrotic HP exposed to fungi compared with the control group (P= .0001). In patients with HP exposed to fungi, sputum KL-6 and YKL-40 levels were higher in those with a fibrotic pattern (P= .0289 and .016, respectively). ROC analysis showed that the range between 55-121 ng/mL for serum YKL-40 levels and 346-1441 U/mL for serum KL-6 levels had the best sensitivity and specificity for discriminating between patients with HP, healthy controls, and patients with idiopathic pulmonary fibrosis (IPF). In patients with HP, serum KL-6 levels correlated negatively with total lung capacity (r=-0.485; P= .0103) and diffusing capacity of the lungs for carbon monoxide (r=-0.534; P= .0002) at 12 months. Both KL-6 and YKL-40 proteins seem to be capable of distinguishing patients with HP from healthy individuals and from patients with IPF. Their sensitivity and specificity confirm their potential role as biomarkers. KL-6 may also be a predictor of disease progression.

Clinical characteristics of pulmonary hypertension in patients with pleuroparenchymal fibroelastosis.

This study aimed to investigate the clinical characteristics and prognosis of patients with pleuroparenchymal fibroelastosis (PPFE) and pulmonary hypertension (PH). We retrospectively analyzed the data of patients who were diagnosed with PPFE and underwent transthoracic echocardiography (TTE) for the evaluation of their right heart systems within 3 months of their first visit between 2011 and 2018. Patients were divided into the PH and non-PH groups based on their peak tricuspid regurgitation velocity (TRV) on TTE (cutoff, 2.8m/s). The clinical characteristics of PH and association between PH and survival among patients with PPFE were investigated. In total, 83 patients were enrolled. Sixteen (19.3%) patients were included in the PH group. The PH group had a lower body mass index, percent predicted forced vital capacity (FVC), 6-min walk distance, and partial pressure of arterial oxygen than the non-PH group. There was no significant difference in the presence of usual interstitial pneumonia patterns in the lower lobes between the two groups. The survival period was significantly shorter in the PH group than in the non-PH group (median survival 16.3 versus 50.2 months, log-rank p<0.001). The multivariate Cox proportional hazard model showed that male sex (hazard ratio [HR]=4.83, p<0.001), Krebs von den Lungen-6 (KL-6) > 550 U/mL (HR=3.48, p=0.005), %FVC < 50% (HR=3.04, p=0.028), and peak TRV > 2.8m/s (HR=3.26, p=0.038) were independently associated with poor survival. PH was not rare in patients with PPFE. Male sex, increased KL-6, lower FVC, and PH were independently associated with poor survival in patients with PPFE.

Serum Biomarkers in a Radiological Pattern of Non-Fibrotic Hypersensitivity Pneumonitis: Implications for Mechanistic Difference and Differential Diagnosis.

Hypersensitivity pneumonitis (HP) is a consequence of immune-mediated reactions caused by recurrent exposure to environmental agents. Recently, clinical practice guidelines for the diagnosis of HP were published and increased interest in HP. On the other hand, novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. Among DRP, the HP pattern (DRP-HP) shows small, poorly defined centrilobular nodules with or without widespread areas of ground-glass opacity or lobular areas of decreased attenuation and vascularity. A similar radiological pattern of non-fibrotic HP can be induced, irrespective of inhalation (non-fibrotic HP) or intravenous administration (DRP-HP). However, their difference has not been well described, although the distribution of lesions in the lungs was slightly different between these two conditions. In this review, we focus on serum biomarkers of lung epithelial cells in order to investigate the difference between DRP-HP and non-fibrotic HP (common-HP). Serum levels of Krebs von den Lungen 6 (KL-6) might be relatively lower (occasionally normal) in DRP-HP than in common-HP, implying a mechanistic difference. KL-6 could be useful in discriminating between DRP and non-fibrotic HP (common type).

Association of serum Krebs von den Lungen-6 and chest CT as potential prognostic factors in severe acute respiratory syndrome SARS-CoV-2: a preliminary experience

PurposeTo correlate in COVID-19 pneumonia CT-based semi-quantitative score of pulmonary involvement with high serum levels of KL-6, a biomarker of disease severity.MethodsBetween March 28 to May 21, 2020, 196 patients with strong suspicion of SARS-CoV-2 were evaluated with RT-PCR for SARS-CoV-2, chest CT scan and blood test, including KL-6 serum protein, in our Emergency Unit. The final population included only patients who underwent blood sampling for KL-6 within 5 days from CT scan (n = 63), including n = 37 COVID-19-positive patients and n = 26 with negative RT-PCR testing for SARS-CoV-2 (control group). A semi-quantitative CT score was calculated based on the extent of lobar involvement (0:0%; 1, < 5%; 2:5–25%; 3:26–50%; 4:51–75%; 5, > 75%; range 0–5; global score 0–25).ResultsCT score was significantly correlated with serum value of KL-6 (r = 27, p = 0.035). This correlation was also present in COVID-19 positive patients (r = 0.423, p = 0.009) and CT score median value was significantly higher in patients with high KL-6 value (> 400 U/mL; 12.00, IQR 5.00-18.00, p-value 0.027). In control group, no statistically significant correlation was found between CT score and KL-6 value and CT score was higher in patients with high KL-6, although this difference was not statistically significant (5.00, IQR:1.75–8.00 versus 3.50, IQR:2.00–6.50). "Crazy paving" at the right upper (n = 8; 61.5%) and middle lobe (n = 4; 30.8%) and "consolidation" at the middle lobe (n=5; 38.5%) were observed in COVID-19 group with a significant difference between patients with high KL-6 value.ConclusionCT score is highly correlated with KL-6 value in COVID-19 patients and might be beneficial to speed-up diagnostic workflow in symptomatic cases.

Novel Biomarkers, Diagnostic and Therapeutic Approach in Rheumatoid Arthritis Interstitial Lung Disease-A Narrative Review.

Rheumatoid arthritis (RA) is considered a systemic inflammatory disease marked by polyarthritis which affects the joints symmetrically, leading to progressive damage of the bone structure and eventually joint deformity. Lung involvement is the most prevalent extra-articular feature of RA, affecting 10–60% of patients with this disease. In this review, we aim to discuss the patterns of RA interstitial lung disease (ILD), the molecular mechanisms involved in the pathogenesis of ILD in RA, and also the therapeutic challenges in this particular extra-articular manifestation. The pathophysiology of RA-ILD has been linked to biomarkers such as anti-citrullinated protein antibodies (ACPAs), MUC5B mutation, Krebs von den Lungen 6 (KL-6), and other environmental factors such as smoking. Patients at the highest risk for RA-ILD and those most likely to advance will be identified using biomarkers. The hope is that finding biomarkers with good performance characteristics would help researchers better understand the pathophysiology of RA-ILD and, in turn, lead to the development of tailored therapeutics for this severe RA manifestation.

Krebs von den Lungen-6 (KL-6), soluble programmed cell death-1 (sPD-1) and its ligand-1(sPDL-1) in systemic sclerosis patients: Relation to disease parameters

Aim of the workThis study aimed to assess the levels of Krebs von den Lungen-6 (KL-6), soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1(sPDL-1) in systemic sclerosis (SSc) patients, and to evaluate their relation with disease parameters. Patients and methodsForty-six SSc patients (31 limited, 15 diffuse) and 43 matched controls were included. Serum levels of KL-6, sPD-1, and sPDL-1 were assessed by enzyme-linked immune-sorbent assay (ELISA). ResultsPatients mean age was 40.2 ± 12.2 years, disease duration 8.04 ± 6.02 years and females: male was 10.5:1. Levels of KL-6, sPD-1, and sPDL-1 were significantly higher in SSc patients compared to the controls 22.4(14.1–637.6) vs. 14.8(8.9–182.3) (p < 0.001), 3.1(1.8–64.2) vs. 1.2(0.68–14.4) (p < 0.001), and 2.8(1.5–84.4) vs. 1.4(0.92–36.4) (p < 0.001) respectively. KL-6 and sPD-1 levels were significantly lower in diffuse SSc subtype than the limited subtype 20.7(14.1–637.6) vs. 24.5(16.2–328.8) (p = 0.01), and 2.5(1.8–64.2) vs. 3.2(2.1–63.4) (p = 0.03) respectively. KL-6 was significantly decreased in SSc patients who developed pulmonary hypertension compared to those without 20.9(14.1–36.3) vs. 27.5(16.5–637.6) (p = 0.02), and in those who received cyclophosphamide 21(14.1–310.9 vs. 31.6(16.2–637.6) (p = 0.019). The three markers were significantly correlated. KL-6 levels with sPD-1 (r = 0.79, p < 0.001) and sPDL-1 (r = 0.79, p < 0.001) and between sPD-1 and sPDL-1 (r = 0.82, p < 0.001) respectively. Both sPD-1 and sPDL-1 significantly correlated with age (r = 0.29, p = 0.048 and r = 0.34, p = 0.021 respectively). ConclusionsKL-6, sPD-1, and sPDL-1 may be considered as potential biomarkers in the diagnosis and assessment of SSc patients. Significantly lower levels of KL-6 were detected in diffuse SSc patients, those with pulmonary hypertension, and patients who received cyclophosphamide.