Correlation between CT Score and KL-6: A Severity Assessing in Juvenile Dermatomyositis Associated Interstitial Lung Disease

Background There is no radiological measurement to estimate the severity of pediatrics juvenile dermatomyositis (JDM) with interstitial lung disease (ILD). We validated the effectiveness of CT scoring assessment in JDM patients with ILD. Aim To establish a CT scoring system and calculate CT scores in JDM patients with ILD and to determine its reliability and the correlation with Krebs von den Lungen-6 (KL-6). Methods The study totally enrolled 46 JDM-ILD patients and 16 JDM without ILD (non-ILD, NILD) patients. The chest CT images (7.0 ± 3.6 years; 32 male and 30 female) were all analyzed. CT scores of six lung zones were retrospectively calculated, included image pattern score and distribution range score. Image pattern score was defined as follows: increased broncho-vascular bundle (1 point); ground glass opacity (GGO) (2 points); consolidation (3 points); GGO with bronchiectasis (4 points); consolidation with bronchiectasis (5 points); and honeycomb lung (6 points). Distribution range score was defined as no infiltrate (0 point); <30% (1 point); 30%–60% (2 points); and ≥60% (3 points). Two pediatric radiologists reviewed all CT images independently. The ROC curve was established, and the optimal cutoff score for severity discrimination was set. Results The agreement between two observers was excellent, and the ICC was 0.930 (95% CI 0.882–0.959, p < 0.01). CT score and KL-6 level had a positive linear correlation (r = 0.784, p < 0.01). However, the correlation between CT scores of different lung zone and KL-6 level was different. The KL-6 cut off level suggested for JDM with ILD was 209.0 U/ml, with 73.9% sensitivity and 87.5% specificity, and the area under curve was (AUC) 0.864 (p < 0.01). Conclusion The CT scoring system we established, as a semiquantitative method, can effectively evaluate ILD in JDM-PM patients and provide reliable evidence for treatment.


Introduction
Juvenile dermatomyositis (JDM) is one of the autoimmune diseases in pediatrics, characterized by skin and muscle involvement, which can also afect lung tissue, resulting in interstitial lung disease [1]. Te annual incidence of JDM ranges from 2/1,000,000 to 4/1,000,000 [2]. Te peak incidence age is from 5 to 10 years, and girls are more susceptible than boys (2-5 : 1) [3][4][5]. JDM is often associated with interstitial lung disease (ILD), which is difcult to identify early due to its insidious onset. Some of these children can develop severe ILD, which is extremely difcult to treat and has a very high mortality rate. Clinically, serum Krebs von den Lungen-6 (KL-6) and high-resolution CT (HRCT) are often used to evaluate the pulmonary involvement of JDM patients.
KL-6 is an efective biomarker in diagnosing and determining the severity of ILD with connective tissue disease [6]. KL-6 is a high molecular weight mucin-like protein produced by type 2 alveolar lung cells. Te increased expression of KL-6 in serum is often associated with damage to alveolar cells. Terefore, the level of KL-6 has a positive correlation with the ILD severity. However, KL-6 has signifcant limitations in some cases, including its low diagnostic sensitivity. Several factors besides ILD infuence KL-6 concentrations, including prolonged smoking, aging [7], renal function [8], and gene (rs4072037) [9].
HRCT is an important supplement for evaluating the degree of ILD. It can ofer the possibility of measuring disease severity more accurately and sensitively. However, the ILD lesions of patients were constantly changing. CT could not well evaluate the changes of the patient's condition before and after. Furthermore, diferent radiologists will give diferent interpretations for the same signs, particularly in lung imaging. Many scholars have developed multiple systems to standardize the interpretation of CT signs. Evaluating the severity of lung parenchymal involvement based on the common representation in JDMassociated ILD, we reviewed fve scoring systems that could quantify the extent of the abnormalities [10][11][12][13][14]. Considering the convenience and feasibility, we designed a 3-grade chest CT severity scoring system to verify the efectiveness of the CT score system and the correlation between KL-6 concentrations. By constructing such a CT scoring system, the lung involvement of patients with JDM can be more accurately evaluated and reliable basis can be provided for follow-up.

Study Population.
Te Ethics Review Committee of Capital Institute of Pediatric approved this single-center study. Tis was a retrospective observational study in nature, and the informed consent was exempt. Te study was carried out from January 2017 to March 2021 in our institution. Forty six JDM-associated ILD (excluding pulmonary interstitial caused by other diseases) patients underwent 62 HRCT scans. Te control group of 16 patients for JDM with non-ILD (NILD) underwent 32 HRCT scans. Te cohort of JDM-associated ILD patients in our study had a mean age of (7.0 ± 3.6) years, ranging from 1.5 to 16.0 years, with a nearly equal sex ratio (Table 1). Te median follow-up time of CT scan was 6 months. Te KL-6 values were measured simultaneously on the day of each CT examination.

CT Protocol.
All CT scans were performed on Discovery CT 750 HD (GE Healthcare), from the apex to the base of the lung, with the parameters as followed: pitch 1.375, tube voltages 80 kVp/100 kVp (based on body weights), and rotate time 0.6 s, and the automatic dose modulation technique was used. All the images were reconstructed of 0.625 mm in both thickness and interval space with lung windows (width, 1200 HU; level, −600 HU).

CT Scoring.
Te severity and extent of lung involvement were assessed as superimposed in three levels: (1) 1 cm above the carina (upper level), (2) the superior margin of the inferior pulmonary vein (middle level), and (3) inferior pulmonary vein (lower level). Te two lungs were divided into six regions. Te right lung was marked from top to bottom as Zone A to C. Te left lung was marked from top to bottom as Zone D to F (Figure 1).

Statistics.
All statistical analyses were performed with Jefrey's Amazing Statistics Program (JASP, version 0.14.1). Te mean ± standard deviation (x ± s) is used for all continuous variables that conform to the normal distribution. Te anomalous distribution was described by median. Te intraclass correlation coefcient (ICC) was used to estimate the agreement of two reviewers. Te ROC was used to calculate the sensitivity and specifcity. Pearson's correlation analysis was employed to assess the relationship between CT scores and KL-6. A statistical signifcance was accepted at p < 0.05.

Discussion
HRCT is the gold standard for the diagnosis of ILD, especially for early diagnosis and activity evaluation. Routine chest HRCT fndings in DMJ patients are usually warranted due to their relatively high-risk of death. Te nonspecifc interstitial pneumonia (NSIP) is the main pathological type of JDM-associated ILD patients [15]. NSIP abnormalities on chest CT are mainly located in the lower lung, with difuse or peripheral distribution in the axial direction. Commonest HRCT signs in NISP are reticular abnormalities, traction bronchiectasis, GGO, and honeycombing [16]. CT scores include an assessment of the extent and severity of lung disease. We selected 3-level chest severity score because it is more intuitive. In our study, there was an excellent agreement among observers which revealed that the 3-level chest severity score was highly reproducible (ICC � 0.930, p < 0.01). CT scores were positively correlated with the level of KL-6 (r � 0.784, p < 0.01). Terefore, CT scores could well refect the course of ILD in patients. Te highest correlation zone we found was the right lower lobe (Zone C) and left lower lobe (Zone F) (r � 0.762, p < 0.01; r � 0.769, p < 0.01 retrospectively). In ILD induced by JDM, the lower lobe of the right lung was most seriously involved.
KL-6 is mainly found on the surface of type II alveolar epithelium, especially in the tissue sections of ILD. In ILD patients, the proliferation of type II alveolar epithelium increased the KL-6 expression. KL-6 fows into the bloodstream due to increased permeability following destruction of the alveolar-blood interface. ROC analysis showed the KL-6 level, which can suggest the occurrence of ILD, and the cut of value was higher than 209.0 U/ml (AUC = 0.848, p � 0.03). Tis was lower than the results among connective tissue disease (CTD) patients [6,14,17], suggested that JDM may have lower KL-6 levels in the presence of ILD. Figure 1: A 9-year-old girl of JDM-ILD. Te KL-6 value was 3949 U/ml. Te level of pulmonary vein and 1 cm above carina divide the lungs into upper, middle, and lower parts. Te right lung was marked from top to bottom as Zone A to C. Te left lung was marked from top to bottom as Zone D to F. Te score of each zone was equal to image pattern points multiplied by distribution range points. Zone A score � 3 × 2, Zone B score � 3 × 3, Zone C score � 3 × 3, Zone D score � 3 × 2, Zone E score � 3 × 2, and Zone F score � 3 × 2. Total CT score � 42.  Terefore, the level of KL-6 is more likely to be afected by other factors, which further reduces its sensitivity. Tus, CT can be an efective supplement to KL-6 in the diagnosis of ILD. Te chest CT signs of ILD showed variability, and the half-quantitative method of CT score could efectively evaluate the progression of the disease and provide a reliable basis for treatment.
Inevitably, there are some limitations to this study. Te sample size of negative CT fndings in this study was small. Moreover, because CT scores are established among experienced radiologists, it needs to be tested in younger radiologists and clinicians. Spirometry is very important for the assessment of lung function [18]; however, young children could not cooperate well, so it was not collected in the study.

Conclusion
Te CT scoring system we established, as a semiquantitative method, can efectively evaluate ILD in JDM-PM patients and provide reliable evidence for treatment.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.