KL-6 Levels Research Articles

P-1943. Risk Factors for Coronavirus disease 2019 (COVID-19)-Associated Pulmonary Aspergillosis (CAPA) in Critically Ill Patients: The Predictive Value of KL-6 for CAPA and Mortality

Abstract Background Coronavirus Disease 2019 (COVID-19) is an acute respiratory viral illness that can be complicated by secondary invasive fungal infections, such as COVID-19-Associated Pulmonary Aspergillosis (CAPA). Krebs von den Lungen-6 (KL-6), a mucinous high-molecular-weight glycoprotein found on the surface of type II alveolar epithelial cells, has been known as a biomarker indicative of respiratory epithelial damage. This study aims to evaluate the risk factors for CAPA in critically ill COVID-19 patients, with a focus on the predictive value of KL-6. Overall 30-day survival rates between patients with and without CAPA Methods This single-center retrospective cohort study included critically ill COVID-19 patients (those requiring high-flow respiratory support or mechanical ventilation) admitted from January 2021 through June 2023. CAPA diagnosis was established based on the 2020 European Confederation of Medical Mycology and the International Society for Human and Animal Mycology consensus criteria. The study investigated factors associated with CAPA and compared overall 30-day mortality for patients with and without CAPA. Results Among 238 critically ill COVID-19 patients, 25 (10.5%) were diagnosed with CAPA. Notably, patients with CAPA exhibited significantly higher median serum peak levels of KL-6 (787.4 vs. 290.2 U/mL, P< 0.001), with a cutoff value of 392.9 U/mL determined by the Youden index. Multivariable analysis revealed that a peak KL-6 level ≥ 392.9 U/mL was strongly associated with CAPA (adjusted odds ratio 8.62, 95% confidence interval [CI] 2.43-31.69). Additionally, inotropics/vasopressor support, diabetes mellitus, and tocilizumab were identified as factors associated with the development of CAPA. The overall 30-day mortality was significantly higher in patients with CAPA (60.8%) compared to those without (45.2%) (P=0.020), with the difference persisting after adjustment (adjusted hazard ratio 2.06, 95% CI 1.05-4.03). Furthermore, along with older age, lacticemia, and diabetes mellitus, elevated KL-6 was also associated with increased mortality. Conclusion Our study suggests that KL-6 may be a significant predictor of both the development of CAPA and mortality among critically ill patients with COVID-19. Disclosures All Authors: No reported disclosures

Serum KL-6 and SP-D: Markers of Lung Function in Autoimmune-Related Interstitial Lung Diseases

This study evaluates the usefulness of serum KL-6, SP-D and TGF-β1 levels in assessing lung impairment and predicting interstitial lung disease (ILD) short-term progression in patients with interstitial pneumonia with autoimmune features (IPAF). A total of 24 patients with IPAF, 21 with connective tissue disease-associated ILD (CTD-ILD) and 23 with CTD without ILD were followed for 1 year. Serum levels of KL-6, SP-D and TGF-β1 were measured and their associations with disease severity and progression were analysed. KL-6, SP-D and TGF-β1 levels were significantly higher in IPAF and CTD-ILD patients compared to CTD without ILD (p < 0.0001, p = 0.0005 and p = 0.0001, respectively). KL-6 (r = 0.45, p = 0.002) and SP-D (r = 0.35, p = 0.02) levels correlated with lung involvement in HRCT in the ILD group. In IPAF, KL-6 levels correlated with pulmonary function tests (FVC%, TLCO%, and 6MWD) and SpO2, while SP-D correlated with 6MWD and SpO2. In CTD-ILD, KL-6 and SP-D levels were positively correlated with BAL cell count (KL-6: r = 0.58, p = 0.04; SP-D: r = 0.63, and p = 0.02). KL-6 also showed a negative correlation with the time since symptom onset (r = −0.51, p = 0.02). No significant associations were found between the baseline biomarker levels and ILD progression risk. KL-6 and SP-D may serve as potential biomarkers for assessing lung impairment in IPAF, though their predictive value for short-term prognosis remains uncertain.

Idiopathic pulmonary fibrosis is a risk factor for cardiovascular disease: potential role of KL-6 and systemic inflammation

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal disease of the lungs. It is characterized by pulmonary and extrapulmonary comorbidities. So far, little is known as regards the prevalence of cardiovascular comorbidities in IPF patients. This study aims to investigate the prevalence of cardiovascular comorbidities in patients with IPF and correlate it with different radiological and laboratory indices of disease severity.MethodsThis prospective case–control study was performed on 134 IPF patients above 18 years. Diagnosis of IPF was based on diagnostic radiologic criteria addressed by ATS guidelines. Patients were recruited from the Pulmonology Department, Assiut University Hospitals, from June 2023 to June 2024. Cardiac comorbidities were assessed by ECG and echocardiography. All patients had C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), and lipid profile including cholesterol level, triglyceride level, HDL-cholesterol level, and LDL-cholesterol level measured. Patients were divided into two groups: IPF patients with cardiovascular comorbidities and IPF patients without cardiovascular comorbidities. Comparison between both groups as regards clinical, radiological, and laboratory criteria was carried out.ResultsThe studied group consists predominantly of females (65%). Sixty out of the 134 documented IPF patients had cardiovascular comorbidities (44.7%), cardiomyopathy (mean ± SD: 43.63 ± 10.56), pulmonary hypertension (mean ± SD: 41.67 ± 15.32), ECG-ischemic changes (40.0%), and atrial fibrillation (13.3%). IPF patients with cardiovascular comorbidities vs. patients without had higher radiological HRCT total fibrosis score TFS (P value < 0.001). As regards laboratory serum biomarkers, the group with comorbidities showed significantly higher CRP, KL-6, cholesterol level, triglyceride level, and LDL-cholesterol level (P value < 0.001). Box plot analysis demonstrated significantly higher KL-6 serum level among IPF patients with cardiovascular comorbidities. Sensitivity 90.0%, specificity 94.6%, and accuracy 92.5% were associated with a cutoff value of KL-6 ≥ 299 for prediction of associated cardiovascular comorbidities among the studied IPF group.ConclusionsDyslipidemia and cardiovascular comorbidities were detected in a large group of IPF patients. These comorbidities were associated with a high HRCT TFS score. High serum levels of CRP and KL-6 were predictors of associated cardiovascular comorbidities in IPF.Trial registrationClinicalTrials.gov. NCT06539962.

Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression. In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF). Associations between biomarkers and RA-ILD progression were analyzed using multivariable Cox regression, adjusting for potential confounders. We analyzed 136 patients with RA-ILD (mean age 66.5 yrs, 30% male, 60.3% with usual interstitial pneumonia pattern). During a median 3.0 years of follow-up, 47 patients (34.6%) experienced progression. Higher baseline KL-6 and hSP-D levels were associated with higher risk of ILD progression (multivariable hazard ratios [HRs] 1.37 [95% CI 1.03-1.82] and 1.51 [95% CI 1.09-2.08], respectively), whereas only the highest quartile of MMP-7 showed an increased risk (multivariable HR 2.60 [95% CI 1.07-6.33]). Increasing levels of serum KL-6 at 1 year showed the strongest association with progression (ΔKL-6: multivariable HR 2.00 [95% CI 1.29-3.11]), additionally adjusting for baseline biomarker levels. In this first prospective study to apply PPF criteria to RA-ILD, 34.6% progressed over 3 years. Higher baseline KL-6 and hSP-D were associated with progression. In follow-up, greater change in KL-6 was associated with progression. Serial measurement of pulmonary damage biomarkers may predict RA-ILD progression and may be helpful in monitoring patients and treatment decisions.

Evaluation of the Mucin Glycoprotein (KL‑6) as a Prognostic Factor in COVID‑19 Patients

Lung damage caused by SARS-CoV-2 infection has been described in the literature as resulting from direct cytopathic effects on type II pneumocytes, playing a critical role in the extent and progression of pulmonary injury. This study aimed to evaluate the prognostic value of the mucin glycoprotein KL-6 in predicting clinical outcomes in COVID-19 patients. We prospectively enrolled 260 COVID-19 patients admitted to specialized hospitals in Naples under the ASL Napoli 1 Centro between March 20, 2020, and March 31, 2022, when the state of emergency ended. Our institution, part of the Coronet Lab network designated by the Campania Region and the Ministry of Health, performed 203,368 molecular tests for COVID-19 during this period, identifying 17,650 positive cases (8.67%). The study cohort had a median age (IQR) of 63 years (54–72), comprising 199 males and 61 females. All patients underwent clinical, radiological, and functional assessments in the emergency department. Serum KL-6 levels were measured at admission, after detecting interstitial lung damage, and during hospitalization. Elevated KL-6 concentrations were observed in patients with pulmonary abnormalities, and baseline levels demonstrated good accuracy in identifying those with radiologically documented fibrotic sequelae. In hospitalized COVID-19 patients, serum KL-6 levels also correlated with severe cases requiring mechanical ventilation and predicted the development of fibrotic lung sequelae during follow-up. Finally, KL-6 proved to be an effective predictive marker of disease severity, emphasizing its potential role in guiding clinical management and prognosis.

Serum KL-6 levels reflect the severity of interstitial lung disease caused by immune checkpoint inhibitors.

Tumor immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a powerful strategy in treating malignant tumors, exhibiting efficacy in both first-line and second-line treatments for advanced non-small cell lung cancer (NSCLC). Despite their success, ICIs can lead to adverse reactions, including interstitial lung disease (ILD), with an incidence ranging from 2.7% to 20.0%. The lack of clear correlations with dosage, duration, or drug efficacy, coupled with nonspecific clinical manifestations, poses challenges in timely diagnosis and effective management. This study examined the association between ICIs-related ILD and serum levels of KL-6 and inflammatory markers in NSCLC patients. A total of 382 NSCLC patients with squamous cell carcinoma (SQC, n=81), adenocarcinoma (ACA, n=132), and large cell carcinoma (LCC, n=169) were included, of whom 191 developed ILD following ICIs treatment. Serum KL-6, TNF-α, IL-8, and IL-6 were quantified using ELISA. Results showed significantly elevated serum KL-6 levels in ILD patients (759.35±214.14U/mL) compared to those without ILD (270.81±124.98U/mL). Cancer subtype analysis revealed increased KL-6 levels across SQC, ACA, and LCC ILD patients (SQC: 645.89±255.07, ACA: 797.39±192.30, LCC: 783.57±191.21; p<0.001). ROC analysis identified diagnostic thresholds for KL-6: 277.4U/mL for SQC (sensitivity 0.9756, specificity 0.8250), 346.9U/mL for ACA (sensitivity 0.9583, specificity 0.8333), and 281.3U/mL for LCC (sensitivity 0.9873, specificity 0.6111). Correlation analysis showed a significant relationship between KL-6 and TNF-α (r=0.4626, p=0.0023), IL-8 (r=0.5584, p=0.0001), and IL-6 (r=0.5336, p=0.0003) in SQC ILD patients. These findings suggest that elevated KL-6 levels and inflammatory markers are indicative of ILD in ICIs-treated NSCLC patients, with potential diagnostic implications across cancer subtypes.

Clinical characteristics and prognostic factors for MPO-ANCA positive interstitial lung disease: A comparative study of ANCA associated vasculitis (AAV)-ILD and pulmonary limited vasculitis.

Microscopic polyangiitis (MPA) with interstitial lung disease (ILD) has a significant impact on morbidity and mortality. This study evaluated the clinical characteristics, treatment responses, and prognostic factors of patients with ANCA-associated vasculitis with ILD (AAV-ILD) and pulmonary limited vasculitis (PLV). A retrospective chart review of ILD patients positive for MPO-ANCA was conducted from 2008 to 2021. Patients were classified into AAV-ILD or PLV groups. Data included laboratory test results, pulmonary function tests, and high-resolution computed tomography (HRCT) images. Statistical analyses were used to assess group differences and survival outcomes. Of 114 patients, 80 were diagnosed with PLV and 34 with AAV-ILD. The AAV-ILD group had higher corticosteroid treatment rates, higher serum creatinine levels, and better survival than the PLV group. The PLV group had higher KL-6 levels, lower %VC and % FVC in pulmonary function tests. Survival in the PLV group was significantly worse than that in the AAV-ILD group, and survival of patients with an alternative diagnosis on HRCT was better than that of patients with a UIP pattern. Cox regression analysis identified a diagnosis of MPA and HRCT classification as significant prognostic factors. Patients with AAV-ILD had a better prognosis than those with PLV. HRCT patterns, particularly an alternative diagnosis on HRCT, were associated significantly with a favourable prognosis. The efficacy of corticosteroid treatment in PLV patients was limited. These findings highlight the importance of early and accurate diagnosis, as well as careful consideration of treatment strategies, for patients with in MPO-ANCA-positive ILD.

Predictors of rituximab efficacy in systemic sclerosis-associated interstitial lung disease: machine-learning analysis of the DESIRES trial

Abstract Objectives Rituximab is emerging as a promising therapeutic option for systemic sclerosis-associated interstitial lung disease (SSc-ILD). However, little is known about factors that predict the efficacy of rituximab in SSc-ILD. Methods A post-hoc analysis was performed on prospective data from 48 patients with SSc-ILD in the double-blind, randomized, placebo-controlled DESIRES trial. A total of 28 baseline factors were selected as candidates to predict the efficacy of rituximab on the percentage of predicted forced vital capacity (ppFVC) at 24 weeks. A machine learning causal tree algorithm was used to explore the combination of predictors to identify subpopulations with a good response to rituximab. Results Serum levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) were selected as branches of the decision tree to stratify patients into 3 subpopulations. In the subpopulation with serum CRP levels ≥ 0.055 mg/dl, ΔppFVC was significantly higher in the rituximab group than in the placebo group (difference 8.01% [95% CI: 4.40%, 11.62%]). In the subpopulation with serum CRP levels &amp;lt; 0.055 mg/dl and serum KL-6 levels ≥ 364 U/ml, ΔppFVC was comparable between the two groups (difference 2.47% [95% CI: -1.99%, 6.92%]). In the subpopulation with serum CRP levels &amp;lt; 0.055 mg/dl and serum KL-6 levels &amp;lt; 364 U/ml, ΔppFVC was significantly lower in rituximab than in placebo (difference -6.85% [95% CI: -10.80%, -2.91%]). Conclusion Even slight elevations in serum CRP levels are associated with the improvement in ppFVC and may serve as predictors of rituximab efficacy in SSc-ILD.

Treatment Response Biomarkers for Systemic Sclerosis-Associated Interstitial Lung Disease.

This studied investigated whether changes in circulating biomarkers predict progressive pulmonary fibrosis (PFF) in patients with systemic sclerosis-associated interstitial lung disease (ILD) receiving treatment. Participants of Scleroderma Lung Study (SLS) II, which compared mycophenolate (MMF) versus cyclophosphamide (CYC) for SSc-ILD, who had blood samples at baseline and 12-months were included. Levels for C-reactive protein (CRP), interleukin (IL)-6, chemokine ligand 4 (CXCL4), chemokine ligand 18 (CCL18)and Krebs von den Lungen 6 (KL-6) were measured, and a logistic regression model evaluated relationships between changes in these biomarkers and the development of PPF by 24 months. Ninety-two of the 142 randomized participants had longitudinal biomarker measurements and the required clinical outcome data, with 19 (21%) meeting criteria for PPF. In the whole cohort, changes in KL-6 levels were significantly correlated with PPF. KL-6 increased in patients who developed PPF and decreased in patients who did not (Mean change 365.68 [SD 434.41]) vs -207.45 [SD 670.26]; P<0.001). In the MMF alone arm, changes in CRP and CXCL4 were also significantly correlated with PPF. When added to an existing prediction model based on baseline factors associated with PPF in this cohort (sex, baseline reflux severity and CXCL4 levels), the change in KL-6 remained significantly associated with PFF (OR 1.4; P=0.0002). Changes in the circulating levels of KL-6 after treatment with MMF or CYC predicted PPF, even after adjusting for baseline factors associated with PPF. Measuring longitudinal KL-6 in patients with SSc-ILD may improve how we personalize therapy in SSc-ILD.

Poor prognostic factors for relapse of interstitial lung disease in microscopic polyangiitis: the Japanese multicentre REVEAL cohort study

BackgroundThis study investigated poor prognostic factors for the relapse of interstitial lung disease (ILD) in patients with microscopic polyangiitis (MPA) after remission induction therapy.MethodsWe enrolled patients diagnosed with MPA complicated by ILD according to the Chapel Hill Consensus definition from 2001 to 2023 in multiple institutions in the REVEAL cohort. All patients who were treated with immunosuppressive therapy were followed up, and those who relapsed with ILD were extracted in this study. We explored the risk factors for predicting ILD relapse in patients with MPA-ILD by comparing the demographic, clinical, laboratory, and radiological findings and treatments between the relapsed and non-relapsed groups on admission.ResultsOf 243 patients with MPA, 134 (55.1%) with MPA-ILD were enrolled. Among them, 28 (20.9%) relapsed during a mean follow-up of 4.2 years. The initial serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) levels and the prevalence of usual interstitial pneumonia (UIP) pattern were significantly higher in the relapsed group. The biomarkers were also risk factors for relapse in multivariate Cox regression analysis. The best cut-off values of KL-6, SP-D for predicting ILD relapse were 430 U/mL and 89.5 ng/mL, respectively. We created prediction models based on the best cut-off values for KL-6, SP-D, and the presence of the UIP pattern (KSU model). The 10-year relapse rate was significantly different among patients with MPA-ILD stratified by the number of risk factors based on the KSU model. A higher relapse rate was associated with higher all-cause mortality.ConclusionsThe initial serum high KL-6 and SP-D levels and the prevalence of the UIP pattern were associated with ILD relapse in patients with MPA-ILD. Our multicentre cohort study indicated that the KSU model, which consists of KL-6 ≥ 430 U/mL, SP-D ≥ 89.5 ng/mL, and the presence of the UIP pattern, is a useful predictor of ILD relapse in patients with MPA after immunosuppressive therapy.

Evaluating the diagnostic and prognostic utility of serial KL-6 measurements in connective tissue disease patients at risk for interstitial lung disease: correlations with pulmonary function tests and high-resolution computed tomography

BackgroundInterstitial lung diseases associated with connective tissue diseases (CTD-ILD) necessitate reliable biomarkers for effective management. This study assesses the utility of serial Krebs von den Lungen-6 (KL-6) measurements in predicting disease activity and progression in CTD-ILD patients.MethodsIn a prospective cohort study at a tertiary care center, 50 patients with CTD at risk of or diagnosed with ILD were enrolled. KL-6 levels and pulmonary function tests (PFTs) were measured at baseline, 6, and 12 months, alongside high-resolution computed tomography (HRCT).ResultsInitial KL-6 levels were inversely correlated with PFTs, with mean values starting at 504.96 U/mL (SD ± 508.46), escalating to 739.42 U/mL (SD ± 612.75) at 6 months, and peaking at 1150.27 U/mL (SD ± 1106.70) by 12 months, reflecting disease progression. Higher KL-6 levels were consistently linked with declines in Forced Vital Capacity (FVC) (p = 0.019) and Diffusing Capacity for Carbon Monoxide (DLCO) (p < 0.001). Radiologically, increased KL-6 correlated with subpleural thickening (p = 0.003), septal thickening (p = 0.036), ground-glass opacities (p = 0.018), and other signs of advanced ILD. Sensitivity and specificity of KL-6 for detecting ILD were 86.7% and 71.4%, respectively, at a ≥ 400 U/mL threshold, improving at higher thresholds. Over the study period, patients with elevated KL-6 levels demonstrated more pronounced radiological and functional deterioration.ConclusionSerial KL-6 measurements effectively reflect disease activity and progression in CTD-ILD, with strong correlations to functional and radiological outcomes. These findings support the use of KL-6 as a valuable biomarker in the routine clinical management of these complex disorders. Our study demonstrates the significant predictive value of KL-6 for both the diagnosis and monitoring of CTD-ILD, suggesting its integration into clinical practice can enhance patient care and treatment strategies.

Diagnostic performance of specific biomarkers for interstitial lung disease: a single center study.

This study aimed to determine the clinical significance of Krebs von den Lungen-6 (KL-6), surfactant proteins A (SP-A) and D (SP-D) in the evaluation and management of interstitial lung disease (ILD). Serum KL-6, SP-A, SP-D levels were measured in122 unique consecutive patients referred for connective tissue disease (CTD) associated ILD (CTD-ILD) autoantibodies and 120"healthy" controls. Patients' charts were retrospectively reviewed and categorized as ILD and non-ILD or CTD-ILD and other ILD. All biomarkers were evaluated for diagnosis and moderate vs. severe ILD based on high-resolution computed tomography (HRCT). ILD was diagnosed in 52 % (n=64) and non-ILD in 48 % (n=58). ILD patients were categorized as other ILD (61 %, n=39) or CTD-ILD (39 %, n=25). Patients with ILD had significantly elevated levels of SP-A (p<0.02), KL-6 or SP-D (both p<0.0001) when compared to those with non-ILD. The mean levels of all biomarkers were significantly elevated levels in the ILD compared to non-ILD group (p<0.0001). No significant difference in biomarker levels between CTD-ILD and other ILD groups (p≥0.900). Biomarkers had comparable specificities (89-93 %) however; sensitivities were variable at 75 , 77 and 17 % for KL-6, SP-D and SP-A, respectively. Combination of KL-6 and SP-D yielded comparable diagnostic accuracy to all biomarkers with median levels significantly higher in patients with severe vs. mild disease. KL-6 and SP-D levels are elevated in ILD and therefore contribute to the diagnosis and risk stratification for patient management.

KL‑6, ET‑1 and S100A9 levels in patients with idiopathic pulmonary fibrosis and obstructive sleep apnea.

Obstructive sleep apnea (OSA) and idiopathic pulmonary fibrosis (IPF) frequently coexist. Elevated levels of Krebs von den Lungen-6 (KL-6), endothelin-1 (ET-1) and S100 calcium-binding protein A9 (S100A9) have been observed in patients with IPF, suggesting their potential role as biomarkers for lung fibrosis. The aim of the present study was to measure the levels of KL-6, ET-1 and S100A9 in patients with IPF-OSA and to test the potential of these biomarkers as a characteristic OSA signature with diagnostic and prognostic potential for IPF. A total of 55 subjects with newly-diagnosed IPF participated in the present cross-sectional study. In addition to performing overnight attended polysomnography and pulmonary function tests, serum and bronchoalveolar lavage (BAL) levels of KL-6, along with serum levels of ET-1 and S100A9, were also assessed. A total of 15 patients with IPF and 40 patients with IPF-OSA were included. Age, sex, comorbidities and pulmonary function tests did not differ between the groups. Although there was no significant difference between groups in the levels of KL-6, ET-1 and S100A9 (P>0.05), the serum ET-1 levels tended to be elevated in patients with OSA-IPF compared with patients with IPF (1.78 vs. 1.07 pg/ml; P=0.06). Additionally, a significant association was observed between serum KL-6 levels and the severity of IPF, and also between BAL KL-6 levels and nocturnal mean SaO2 levels, even after taking into account factors such as obesity and smoking. S100A9 levels were associated with the oxygen desaturation index, even after adjustments for obesity, smoking and the gender-age-physiology index, only in the IPF-OSA group. Conclusively, the present findings suggested significant associations between serum ET-1, S100A9 and BAL KL-6 levels and specific OSA severity parameters in the IPF-OSA group. This evidence suggested that these molecules could serve as biomarkers for the identification of patients with IPF-OSA, offering a distinct OSA signature that has diagnostic and potential treatment value. Larger studies are crucial to substantiate the present findings and reinforce this hypothesis.

Serum biomarkers in neuroendocrine cell hyperplasia of infancy.

Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified. We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI. Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured. Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane. Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI.

Correlation between CT-based phenotypes and serum biomarker in interstitial lung diseases

BackgroundThe quantitative analysis of computed tomography (CT) and Krebs von den Lungen-6 (KL-6) serum level has gained importance in the diagnosis, monitoring, and prognostication of interstitial lung disease (ILD). However, the associations between quantitative analysis of CT and serum KL-6 level remain poorly understood.MethodsIn this retrospective observational study conducted at tertiary hospital between June 2020 and March 2022, quantitative analysis of CT was performed using the deep learning-based method including reticulation, ground glass opacity (GGO), honeycombing, and consolidation. We investigated the associations between CT-based phenotypes and serum KL-6 measured within three months of the CT scan. Furthermore, we evaluated the performance of the combined CT-based phenotypes and KL-6 levels in predicting hospitalizations due to respiratory reasons of ILD patients.ResultsA total of 131 ILD patients (104 males) with a median age of 67 years were included in this study. Reticulation, GGO, honeycombing, and consolidation extents showed a positive correlation with KL-6 levels. [Reticulation, correlation coefficient (r) = 0.567, p < 0.001; GGO, r = 0.355, p < 0.001; honeycombing, r = 0.174, p = 0.046; and consolidation, r = 0.446, p < 0.001]. Additionally, the area under the ROC of the combined reticulation and KL-6 for hospitalizations due to respiratory reasons was 0.810 (p < 0.001).ConclusionsQuantitative analysis of CT features and serum KL-6 levels ascertained a positive correlation between the two. In addition, the combination of reticulation and KL-6 shows potential for predicting hospitalizations of ILD patients due to respiratory causes. The combination of reticulation, focusing on phenotypic change in lung parenchyma, and KL-6, as an indicator of lung injury extent, could be helpful for monitoring and predicting the prognosis of various types of ILD.

Combined use of serum ferritin and KL-6 levels as biomarkers for predicting COVID-19 severity

ObjectivesTo assess the value of serum ferritin and Krebs von den Lungen-6 (KL-6) levels for predicting severe COVID-19 (death or requirement for invasive mechanical ventilation [IMV]/high-flow oxygen). MethodsData were analyzed on 2495 patients with COVID-19 from February 2020 to November 2022 using data from a nationwide COVID-19 database. ResultsPatients with high KL-6 and low ferritin levels were older with more comorbidities and higher mortality rates, whereas those with high ferritin and low KL-6 levels were younger, predominantly male, and more likely to need IMV. A high level of both markers was strongly associated with critical outcomes (adjusted odds ratio: 13.6, 95% confidence interval: 8.58–21.5). The combination of both markers had higher predictive value than either marker alone (area under the curve: 0.709, 0.745, and 0.781 for KL-6, ferritin, and KL-6 + ferritin, respectively). ConclusionsThe combination of both markers accurately predicted COVID-19 severity.

CA 15 - 3 in screening for systemic autoimmune rheumatic disease associated interstitial lung disease: a single center cross-sectional study.

The natural course of interstitial lung disease (ILD) in patients with systemic autoimmune rheumatic diseases (SARD) varies significantly and is linked to considerable morbidity and mortality. Therefore, effective screening is crucial for early detection of SARD-ILD. Biomarkers associated with mucin 1, Krebs von den Lungen-6 (KL-6) and carbohydrate antigen 15-3 (CA 15-3), are increased in various ILD. This study aimed to assess the diagnostic accuracy of the serum biomarker CA 15-3 as a potential screening tool for ILD in patients newly diagnosed with SARD. Conducted as a single-center cross-sectional study, the research included newly diagnosed SARD patients consecutively examined for ILD according to the algorithm. All included patients underwent chest high-resolution CT scans (HRCT), and serum levels of CA 15-3, KL-6, and lactate dehydrogenase (LDH) were measured and correlated with other variables associated with possible ILD presence. Serum biomarker levels, specifically CA 15-3 and LDH, are significantly higher in ILD-positive patients (P<0.001 for both). An inverse relationship is observed between higher FVC values and lower CA 15-3 levels (Rho=-0.291, P=0.007). Similarly, higher DLCO values are associated with lower CA 15-3 levels (Rho=-0.317, P=0.003). Our findings revealed that elevated CA 15-3 levels are positively correlated with higher levels of KL-6 (Rho=0.268, P=0.01) and LDH (Rho=0.227, P=0.04). With a cut-off value of 24 U/mL, CA 15-3 showed the highest sensitivity and specificity (AUC=0.807, specificity=95.7%, sensitivity=71.1%). CA 15-3 emerged as the most significant predictor of a positive HRCT finding, accurately classifying 83% of cases. These results suggest that CA 15-3 shows promise as a valuable serum biomarker for screening SARD patients for ILD in routine clinical practice.

Comparative accuracy of CA-153 and KL-6 as diagnostic and prognostic biomarkers for interstitial lung disease

BackgroundsTo discern the potential of KL-6 and CA-153 as diagnostic tools for interstitial lung disease (ILD), understand their relationship with GAP (Gender, Age, and Physiology) stage, and analyze their predictive capacities alongside CT features. This research aims to enhance ILD detection and management in autoimmune patients, emphasizing the diagnostic utility of these biomarkers. MethodsFrom Mar 2017 to Mar 2024, 398 patients from Taichung Veterans General Hospital’s Division of Allergy, Immunology, and Rheumatology with autoimmune diseases were prospectively enrolled. ILD diagnoses were confirmed using High-Resolution Computed Tomography (HRCT) or lung biopsy and characterized by radiologists. GAP scores were calculated for IPF prognosis. 583 serum samples were collected and tested for KL-6, CA-153, CA-199, and CA-125 using specific assays. Statistical analyses compared patients, assessed variables, determined missingness, and predicted ILD, with tools like ROC analysis and logistic regressions. Analyses were performed with IBM SPSS and MedCalc. ResultsILD patients were older, predominantly male, and had more smokers compared to non-ILD. Both KL-6 and CA-153 were higher in ILD and showed a significant, but non-interchangeable correlation. Age, BMI, smoking, and biomarker levels influenced ILD odds, with KL-6 and CA-153 being the strongest predictors. HRCT imaging highlighted these markers’ roles, especially in detecting specific features. Both markers also strongly associated with GAP stages. Stratified analyses emphasized KL-6′s significance in predicting ILD across both AD and non-AD groups. Complete data sensitivity analysis reinforced KL-6 and CA-153 as key ILD predictors. ConclusionsThis research emphasizes CA-153 as a feasible, cost-effective alternative to KL-6 in diagnosing and monitoring ILD. Both CA-153 and KL-6 levels were notably elevated in ILD patients, displaying a strong correlation, especially at CA-153 levels of ≤100 U/ml. They both also have significant associations with CT characteristics and GAP stages. The study reinforces the potential of CA-153, particularly in settings where KL-6 testing might be inaccessible or expensive.

Correlation of serum Krebs von den Lungen-6 levels with fibrosis score on high resolution chest tomography and pulmonary function parameters in treatment naïve Idiopathic Pulmonary Fibrosis.

While serum Krebs von den Lungen-6 (KL-6) has been found to be a helpful biomarker in interstitial lung diseases for evaluating disease severity and progression, especially in connective tissue disease-associated interstitial lung disease (CTD ILD) and idiopathic non-specific interstitial pneumonia (NSIP), data on correlation of serum KL-6 levels with radiological fibrosis and pulmonary function parameters is lacking in treatment naïve Idiopathic Pulmonary Fibrosis (IPF) patients. Serum KL-6 levels were measured in thirty-nine treatment naïve newly detected IPF patients using automated immunofluorescence enzyme assay (AIA) by Tosoh Corporation, bioscience division, Tokyo, Japan. Fibrosis score was calculated by independent visual assessment of the pattern and severity of abnormalities on high resolution computed tomography (HRCT) thorax. HRCT fibrosis scores were correlated with serum KL-6 levels and pulmonary function parameters like forced vital capacity (FVC), diffusion capacity of lung for carbon monoxide (DLco). Median value of serum KL-6 levels was 1519 U/ml (range 199.41-6055 U/ml). There was positive correlation of serum KL-6 with HRCT fibrosis score (r=0.692, p<0.001) and negative correlation with FVC (r=-0.511, p=0.001) and DLco (r=-0.354, p=0.043). In the HRCT fibrosis score pattern subset analysis, the presence of reticulation revealed weak negative and statistically insignificant correlation (r=-0.116, p=0.481) while traction bronchiectasis and honeycombing exhibited statistically significant positive correlation (r=0.425, p=0.007; r=0.584, p<0.001 respectively) with serum KL-6 levels. Serum KL-6 levels showed a positive correlation with the degree of fibrotic abnormalities on HRCT thorax and pulmonary function parameters, indicating a potential use of serum KL-6 in monitoring of parenchymal fibrosis in Idiopathic Pulmonary fibrosis.

A Pilot HRCT Follow-Up Study to Test the Feasibility of Predictive Efficacy of Serum Periostin in Idiopathic Pulmonary Fibrosis.

While serum periostin and Krebs von den Lungen-6 (KL-6) have been acknowledged as independent markers in idiopathic pulmonary fibrosis (IPF) diagnosis, the clinical combinatory potential of these biomarkers combined with high-resolution computed tomography (HRCT) has yet to be fully explored. This retrospective study involved 78 participants, comprising 51 UIP-IPF patients and 27healthy controls. All subjects underwent clinical and laboratory examinations, particularly the detection of periostin and KL-6 using ELISA with innovative HRCT fibrosis score evaluations at admission and discharge during hospitalization in UIP-IPF patients. In our cohort of patients with IPF, predominantly male, over an average follow-up period of 195.27 days. Serum levels of periostin and KL-6 were significantly elevated in IPF patients compared to healthy controls (*p < 0.05). Post-treatment, KL-6 levels decreased significantly, while periostin levels increased. Notably, periostin exhibited superior prognostic accuracy over KL-6, with a higher AUC of 0.875 than 0.639 in ROC analysis. An increase in periostin levels correlated with disease progression, as evidenced by worsened HRCT fibrotic scores and decreased survival probability. These findings underscore periostin's potential as a reliable biomarker for assessing IPF severity and therapeutic response. Our findings underscore the preeminence of serum periostin over KL-6 in UIP-IPF diagnosis, particularly when conjoined with HRCT fibrosis score.