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[This corrects the article DOI: 10.3389/fmed.2025.1579209.].

Background Biomarkers have been actively investigated to supplement functional and imaging modalities to predict the severity, therapeutic responsiveness, and progression of connective tissue disease-associated interstitial lung disease (CTD-ILD). This study aimed to evaluate Krebs von den Lungen 6 (KL-6) as a potential biomarker reflecting the severity of CTD-ILD as assessed through computed tomography (CT) and pulmonary function test (PFT) parameters. Methods This retrospective study included 549 Korean patients with rheumatoid arthritis, systemic sclerosis, inflammatory myositis, and other CTDs with or without concurrent ILD. Serum KL-6 concentration (U/mL) was measured using the latex-enhanced immunoturbidimetric assay method. CT and PFT results were collected within 1 year of serum collection. A semiquantitative grade of ILD extent was evaluated through CT scan (grade 1, 0–25%; grade 2, 26–50%; grade 3, 51–75%; grade 4, 76–100%). Results CTD-ILD patients ( n  = 165) had elevated serum KL-6 levels compared to CTD patients without ILD ( n  = 384) ( p  < 0.001), and those findings were preserved after adjusting for age, sex, and CTD type. The semiquantitative grade of ILD on CT scan was significantly proportional to the KL-6 level, and the optimal cut-off KL-6 value effectively differentiated each ILD grade. The percent diffusing capacity of the lung for carbon monoxide (DLCO) ( p  < 0.001) and forced vital capacity (FVC) ( p  < 0.001) parameters had a moderate, negative correlation with the KL-6 level. Conclusion Serum KL-6 levels were increased in CTD-ILD patients and had a positive correlation with CT grade and a negative correlation with FVC and DLCO. Serum KL-6 levels may reflect CTD-ILD severity.

Screening and follow-up of interstitial lung disease associated with rheumatoid arthritis (RA-ILD) is a challenge in clinical practice. In fact, the majority of RA-ILD patients are asymptomatic and optimal tools for early screening and regular follow-up are lacking. Furthermore, some patients may remain oligosymptomatic despite significant radiological abnormalities. In RA-ILD, usual interstitial pneumonia (UIP) is the most frequent radiological and pathological pattern, associated with a poor prognosis and a high risk to develop acute exacerbations and infections. If RA-ILD can be identified early, there may be an opportunity for an early treatment and close follow-up that might delay ILD progression and improve the long-term outcome. In connective tissue disease–associated interstitial lung disease (CTD-ILD), lung ultrasound (LUS) with the assessment of B-lines and serum Krebs von den Lungen-6 antigen (KL-6) has been recognized as sensitive biomarkers for the early detection of ILD. B-line number and serum KL-6 level were found to correlate with high-resolution computed tomography (HRCT), pulmonary function tests (PFTs), and other clinical parameters in systemic sclerosis–associated ILD (SSc-ILD). Recently, the significant correlation between B-lines and KL-6, two non-ionizing and non-invasive biomarkers, was demonstrated. Hence, the combined use of LUS and KL-6 to screen and follow up ILD in RA patients might be useful in clinical practice in addition to existing tools. Herein, we review relevant literature to support this concept, propose a preliminary screening algorithm, and present 2 cases where the algorithm was used.

IntroductionRheumatoid arthritis (RA)–associated interstitial lung disease (ILD) (RA-ILD) is a serious systemic RA manifestation with high mortality that needs proper, accurate, and sensitive assessment tools.ObjectivesFirstly, evaluate serum Krebs von den Lungen-6 (KL-6) levels and lung ultrasound B lines (LUS B lines) score in RA-ILD correlating them with the severity of ILD assessed by high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). Secondly, determine cut-off values for LUS and KL-6 in RA-ILD assessment and outcome prediction.MethodsA case-control study included seventy-five RA-ILD patients with an equal number of matched RA patients without ILD. Clinical assessment includes DAS-28 and PFTs, laboratory assessment of serum KL-6 by latex-enhanced immunoturbidimetric assay, and radiological evaluation of ILD using semiquantitative CT grade and LUS B lines.ResultsRA-ILD patients had significantly higher serum KL6 compared to those without ILD (1025.5 ± 419.6 vs. 237.5 ± 51.9, p ≤ 0.001). Serum KL6 was positively correlated with HRCT and LUS scores (r = 0.93, r = 0.97, respectively) with negative correlation with FVC% and FEV1% (r = − 0.93, r = − 0.91, respectively). LUS was positively correlated with KL6 and HRCT (r = 0.97, r = 0.944, respectively) while, negatively correlated with PFTs. Cut-off values of KL6 and LUS were 277.5 U/ml and < 5.5, with AUC 0.878 and 1, sensitivity 86.7% and 100%, and specificity 88% and 100%, respectively.ConclusionsThe non-invasive, radiation-free LUS with a score < 5.5 combined with serum KL6 could be helpful for RA-ILD assessment correlating with HRCT and disease severity. Serum KL6 combined with LUS is important new and potential prognostic factor predicting poor outcomes in RA-ILD. Further large-scale, multi-center, and prospective studies are needed to confirm these findings.Key Points• Combination of the non-invasive, radiation-free LUS with a score < 5.5 and serum KL6 levels of 277.5 U/ml is recommended as prognostic tools for RA-ILD.• Easily obtainable tests such as serum KL-6, inflammatory markers, and LUS are sensitive for assessing RA-ILD and the risk of poor outcomes in patients with RA-ILD.• RA-ILD patients with higher KL6 levels, higher LUS scores had a poor prognosis with short survival.• LUS B lines could be used as the first imaging tool for the evaluation of RA-ILD decreasing the risk of HRCT radiation exposure in asymptomatic or mild RA-ILD patients.

Background: Krebs von den Lungen 6 (KL-6) is a novel biomarker for interstitial lung disease, and it reflects acute lung injury. We explored the usefulness of KL-6 to predict clinical outcomes in hospitalized coronavirus disease 2019 (COVID-19) patients. Methods: In a total of 48 hospitalized COVID-19 patients, KL-6 levels were measured using the HISCL KL-6 assay (Sysmex, Kobe, Japan) with the HISCL 5000 automated analyzer (Sysmex). Clinical outcomes (intensive care unit [ICU] admission, ventilator use, extracorporeal membrane oxygenation [ECMO] use, and 30-day mortality) were analyzed according to KL-6 percentiles. Age, initial KL-6 level, Charlson comorbidity index (CCI), and critical disease were compared using the receiver operating characteristic (ROC) curve and Kaplan-Meier methods for clinical outcomes. Results: KL-6 quartiles were associated with ICU admission, ventilator use, and ECMO use (all p < 0.05), except 30-day mortality (p = 0.187). On ROC curve analysis, initial KL-6 level predicted ICU admission, ventilator use, and ECMO use significantly better than age, CCI, and critical disease (all p < 0.05); age, initial KL-6 level, CCI, and critical disease predicted 30-day mortality comparably. On Kaplan–Meier survival analysis, hazard ratios (95% confidence interval) were 4.8 (1.2–19.3) for age, 4.7 (1.1–21.6) for initial KL-6 level, 3.9 (0.9–16.2) for CCI, and 2.1 (0.5–10.3) for critical disease. Conclusions: This study demonstrated that KL-6 could be a useful biomarker to predict clinical outcomes in hospitalized COVID-19 patients. KL-6 may contribute to identifying COVID-19 patients requiring critical care, including ICU admission and ventilator and/or ECMO use.

[This corrects the article DOI: 10.3389/fmed.2023.1282757.].

Krebs von den Lungen-6 (KL-6) has been described as a promising biomarker in the diagnosis and determining the severity of interstitial lung disease in adults with connective tissue disease. This study was performed to determine whether the serum KL-6 level is useful as a biomarker for detecting the interstitial lung disease (ILD) in pediatric cases of connective tissue disease (CTD). In total, 88 patients [36 patients with systemic juvenile idiopathic arthritis (sJIA), 27 patients with juvenile systemic lupus erythematosus (JSLE), 14 patients with juvenile dermatomyositis (JDM), and 11 patients with juvenile systemic sclerosis (JSSc)] and 68 healthy controls were included in this study. Age, sex, and duration of CTD and ILD (if any) were recorded. Blood samples from all the patients and controls were examined by ELISA. Eleven of the 88 patients with CTD (12.5%) had ILD and all of them were symptomatic. Subgroup analysis indicated that eight patients had JSSc, two had JSLE, and one had systemic JIA. The median serum KL-6 level was 1450.5 U/mL (interquartile range (IQR) 742.9–2603.2) in the CTD with ILD group, 415.9 U/mL (IQR 233.4–748.4) in the CTD without ILD group, and 465.9 U/mL (IQR 273.6–1036) in the control group. KL-6 levels were significantly higher in the CTD with ILD group than the CTD without ILD group and the control group (p = 0.003). At a cut-off of 712.5 U/ml identified by ROC curve, serum KL-6 yielded a sensitivity of 81% and specificity of 72% for CTD with ILD group. There was no significant difference in serum KL-6 level among the disease subgroups (sJIA, JSLE, JSSc, JDM), in either the CTD with ILD group or the CTD without ILD group (p > 0.05). In conclusion, KL-6 is a useful biomarker of CTD with ILD in pediatric patients.

SARS-CoV2-induced direct cytopathic effects against type II pneumocytes are suspected to play a role in mediating and perpetuating lung damage. The aim of this study was to evaluate serum KL-6 behavior in COVID-19 patients to investigate its potential role in predicting clinical course. Sixty patients (median age IQR, 65 (52–69), 43 males), hospitalized for COVID-19 at Siena COVID Unit University Hospital, were prospectively enrolled. Twenty-six patients were selected (median age IQR, 63 (55–71), 16 males); all of them underwent follow-up evaluations, including clinical, radiological, functional, and serum KL-6 assessments, after 6 (t1) and 9 (t2) months from hospital discharge. At t0, KL-6 concentrations were significantly higher than those at t1 (760 (311–1218) vs. 309 (210–408) p = 0.0208) and t2 (760 (311–1218) vs 324 (279–458), p = 0.0365). At t0, KL-6 concentrations were increased in patients with fibrotic lung alterations than in non-fibrotic group (755 (370–1023) vs. 305 (225–608), p = 0.0225). Area under the receiver operating curve (AUROC) analysis showed that basal KL-6 levels showed good accuracy in discriminating patients with fibrotic sequelae radiologically documented (AUC 85%, p = 0.0404). KL-6 concentrations in patients with fibrotic involvement were significantly reduced at t1 (755 (370–1023) vs. 290 (197–521), p = 0.0366) and t2 (755 (370–1023) vs. 318 (173–435), p = 0.0490). Serum concentrations of KL-6 in hospitalized COVID-19 patients may contribute to identify severe patients requiring mechanical ventilation and to predict those who will develop pulmonary fibrotic sequelae in the follow-up.

About one third of non-IPF ILD patients progresses over time. Serum KL-6, a lung epithelial mucin type 1, is an established marker to assess disease severity in ILD but its ability to predict progression needs to be further explored. To investigate whether serum KL-6 is of additional value to stratify the patients for the risk of developing clinical or functional progression at one year. ILD patients from 6 European centers were retrospectively enrolled. Disease progression was defined as relative decline ⩾10% in FVC or ⩾15% in DLco from baseline. Serum KL-6 was measured using a full-automated chemiluminescent immunoassay (Fujirebio). Comparative logistic regression was used to identify predictors of progression at one year. 303 patients were included. 37% developed progression after one year from KL-6 measurement. A stepwise selection was used to identify and include five predictors of progression in a risk score: age, gender, BMI, FVC, and KL-6. The final model was superior to KL-6 alone to predict progression at one year, with 55% sensitivity, 73% specificity and 67% accuracy at a cut-off of 5. Patients were stratified in low and high risk of progression at one year based on the cut-off of 5, with a similar accuracy for IIP 0.687 and CTD-ILD 0.720 but not for HP. Serum KL-6 levels, included in a risk score with other clinical and functional variables, may help to better stratify patients for the risk of disease progression at one year, compared to any individual predictor.

KL-6 is a sialoglycoprotein antigen which proved elevated in the serum of patients with different interstitial lung diseases, especially in those with a poorer outcome. Given that interstitial pneumonia is the most common presentation of SARS-CoV2 infection, we evaluated the prognostic role of KL-6 in patients with COVID-19 pneumonia. Patients with COVID-19 pneumonia were prospectively enrolled. Blood samples were collected at the time of enrolment (TOE) and on day 7 (T1). Serum KL-6 concentrations were measured by chemiluminescence enzyme immunoassay using a KL-6 antibody kit (LUMIPULSE G1200, Fujirebio) and the cut-off value was set at >1000 U/mL. Fifteen out of 34 enrolled patients (44.1%) died. Patients with unfavourable outcome showed significantly lower P/F ratio and higher IL-6 values and plasmatic concentrations of KL-6 at TOE compared with those who survived (median KL-6: 1188 U/mL vs. 260 U/mL, p < 0.001). KL-6 > 1000 U/mL resulted independently associated with death (aOR: 11.29, p < 0.05) with a positive predictive value of 83.3%. Our results suggest that KL-6 is a reliable indicator of pulmonary function and unfavourable outcome in patients with COVID-19 pneumonia. A KL-6 value > 1000 U/mL resulted independently associated with death and showed good accuracy in predicting a poorer outcome. KL-6 may thus represent a quick, inexpensive, and sensitive parameter to stratify the risk of severe respiratory failure and death.