Abstract
Background/Aim
Serum KL-6 is widely used to monitor interstitial lung disease (ILD), but its short-term behavior around acute exacerbation (AE) and its prognostic value at AE onset remain unclear. This study evaluated serial KL-6 changes before AE and their association with survival.
Patients and Methods
We retrospectively reviewed patients with idiopathic pulmonary fibrosis or progressive pulmonary fibrosis who underwent KL-6 measurement at two hospitals between May 2015 and June 2025. KL-6 at AE onset was compared with values one month earlier, the highest value during the preceding year, and maximum values in patients without AE. Associations with post-AE survival were assessed.
Results
Among 409 patients with ILD, KL-6 was measured at onset in 109 AE episodes among 97 patients; 142 patients without AE had at least one measurement. Median KL-6 at AE onset was higher than the median maximum value in patients without AE (1,100 vs. 690 U/ml, p=0.0001). However, paired analyses showed no significant difference between KL-6 at AE onset and the value one month earlier (n=32, p=0.092) or the highest value during the preceding year (n=58, p=0.145). KL-6 at AE onset did not differ among patients who died within 30 days, died between 30 and 90 days, or survived beyond 90 days (p=0.4307). A high KL-6 level (≥1,100 U/ml) was not associated with survival.
Conclusion
Although KL-6 levels were higher in patients with interstitial lung disease experiencing AE compared to patients without AE, they did not consistently increase immediately before AE and had limited prognostic value at AE onset.
Keywords: KL-6, acute exacerbation, interstitial lung disease
Introduction
Krebs von den Lungen-6 (KL-6) is a monoclonal antibody that was originally developed as a tumor marker for non-small cell lung cancer (NSCLC) (1). However, serum KL-6 levels are now recognized as a useful marker for the diagnosis and management of interstitial lung disease (ILD), and are very much used in the clinical practice of ILD patients, including not only idiopathic pulmonary fibrosis (IPF) but also progressive pulmonary fibrosis (PPF) (2, 3). IPF is the most common type of ILD and is a progressive, intractable disease of unknown causes (4). The term PPF was introduced in the 2022 official clinical practice guideline jointly issued by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Asociación Latinoamericana de Tórax (ALAT) to describe progressive fibrotic ILDs other than IPF (4). Many patients with ILD develop acute exacerbations (AEs) during the course of their disease, and their prognosis is extremely poor. AEs are understood as disease entities that cause widespread, rapidly progressing, and exacerbating alveolar damage in patients with ILD (5). In clinical practice, AEs should be suspected when there are rapidly worsening dyspnea and widespread, worsening ground-glass opacities or infiltrations on imaging. However, diagnosing acute exacerbation can be challenging because other conditions, including heart failure, bacterial pneumonia, and fluid overload, may cause similar clinical and radiological findings and must therefore be excluded (5).
KL-6 levels are useful the diagnosis and monitoring of relatively slow-progressing interstitial lung disease (ILD) (6, 7), and may play a role during AEs (3, 8-11). In addition, these studies showed a long-term upward trend in KL-6 levels leading up to the onset of AEs in patients ILD (3, 6-11). However, to our knowledge, there have been no reports that have thoroughly investigated KL-6 levels in individual patients with ILD before and at the onset of AEs. In addition, we could not find any studies that investigated the relationship between KL-6 levels at the time of AE onset and the prognosis after AE onset.
Therefore, we conducted this retrospective study with the aim of clarifying the following two objectives. First. evaluate whether there was an increase in KL-6 levels at the onset of AE and determine whether these KL-6 levels were higher than those before the onset of AE. Second, obtain information on whether KL-6 levels at the onset of AE provide useful information for predicting prognosis after the onset of AE. Through these objectives, we discuss the clinical significance of measuring KL-6 levels at the time of AE onset.
Patients and Methods
Study design. We retrospectively reviewed the medical records and chest CT scans of all consecutive patients with IPF and PPF who underwent measurements for serum KL-6 levels between May 2015 and June 2025 at Ryugasaki Saiseikai Hospital and Mito Medical Center, Tsukuba University Hospital-Mito Kyodo General Hospital. The diagnostic criteria for IPF and PPF were based on the ATS/ERS/JRS/ALAT guidelines (4). The official guideline defines PPF as the presence of at least two of three domains: worsening respiratory symptoms, physiological progression, and radiological progression. Physiological progression is defined as either an absolute decline in FVC of ≥5% or an absolute decline in DLCO of ≥10% within one year (4). In this study, patients who met two of the three domains within one year – worsening of respiratory symptoms, radiological progression, and an absolute decrease of 5% or more in FVC during physiological progression – were treated as patients with PPF. Patients with occupational ILDs, iatrogenic ILDs (e.g., drug-induced ILDs), sarcoidosis, pulmonary alveolar proteinosis, or lymphangioleiomyomatosis were excluded from this study. Additionally, patients with acute interstitial pneumonia (AIP) who did not show a clinical course of ILD for more than one year were excluded due to the importance of evaluating the ILD course. In this study, disease severity was assessed using the Japanese Respiratory Society staging system (12, 13): Stage I, resting PaO₂ ≥80 Torr; Stage II, 70≤ PaO₂ <80 Torr; Stage III, 60≤ PaO₂ <70 Torr; and Stage IV, PaO₂ <60 Torr. Patients classified as Stage I or II based on resting PaO₂ were reclassified as Stage III if their minimum SpO₂ during the 6-minute walk test was <90%. Patients classified as Stage III were reclassified as Stage IV if their minimum SpO₂ during the 6-minute walk test was <90%.
Definition of AEs. The diagnostic criteria for AE were based on those proposed by the American Thoracic Society (5). AE was defined as acute worsening of dyspnea within the preceding month, accompanied by new bilateral ground-glass opacities and/or consolidations on high-resolution CT superimposed on a background pattern consistent with usual interstitial pneumonia (UIP), with clinical deterioration not fully explained by heart failure, infection, or fluid overload (5). Chest physicians reviewed the medical records and chest images to confirm each diagnosis of AE.
Measurement of serum KL-6 levels. In both hospitals, serum KL-6 levels were measured by a sandwich-type enzyme-linked immunosorbent assay technique using a KL-6 antibody kit (Eisai Co., Ltd., Tokyo, Japan). According to the regulations of health insurance system in our country, serum KL-6 measurement is limited to once a month; therefore, measurements were taken at intervals of one month or longer. The timing of KL-6 measurements was determined by the chest physicians involved in the treatment according to health insurance regulations. Considering the relationship between serum KL-6 levels and the onset of AE, KL-6 levels within one year from the onset of AE or the last follow-up were evaluated. If the same patient experienced more than one AE, each episode of AE was evaluated separately. Each AE episode, including recurrent episodes in the same patient, was treated as a separate case.
Statistical analysis. For statistical analysis, the Mann-Whitney U test, a nonparametric test, was used to compare demographics, such as age, and clinical test values, between two groups. The time when the presence of ILD was confirmed using chest CT was defined as the starting point, and the survival status at the end of the study period was examined. For patients who were alive at the end of the study period, the observation period was the period from the starting point. For patients who died during the study period or who stopped visiting our hospitals due to transfer to another hospital, the observation period was the period from the starting point to the last follow-up. In examining survival after AE onset, we first reviewed 30-day and 90-day survival, as previously reported (14-16). Additionally, we performed univariate analysis using the log-rank test. If significant factors were identified in the univariate analysis, a multivariate analysis was scheduled. Comparisons between groups were made using chi-squared test, Mann-Whitney U test, Kruskal-Wallis test, and Wilcoxon signed-rank test. A p-value of <0.05 was considered to indicate a significant difference.
Ethical approval. This retrospective study was approved by the ethics committees of Mito Medical Center, Tsukuba University Hospital-Mito Kyodo General Hospital (approval number: NO 25-47, Approval Date: July 2, 2025), and by the participating medical institutions, and was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.
Results
ILD patients who developed AEs and those who did not. Figure 1 shows the study flow chart of patients with ILD. During the study period, 409 patients were diagnosed with ILD. One hundred and twenty-four patients developed an acute exacerbation, while KL-6 measurements at AE onset were available for 109 episodes occurring in 97 patients. During the study period, 64 patients died of AE. However, in 142 of the 285 patients who did not develop AEs, serum KL-6 levels were measured at least once during the study period. Of the 142 patients, 28 died of causes other than AE.
Figure 1.
Study flow chart. ILD: Interstitial lung disease; AE: acute exacerbation.
KL-6 levels at the time of AE onset. The clinical backgrounds of cases who developed AE and cases who did not develop AE did not differ significantly (Table I). Median (range) KL-6 level at the time of AE in 56 IPF cases and 53 PPF cases was 1,120 (335-3,660) U/ml and 1,190 (233-2,980) U/ml, respectively. There was no significant difference in KL-6 levels at the time of AE in IPF and PPF cases (p=0.3505, Mann-Whitney U test).
Table I. Comparison of clinical characteristics between cases with and without acute exacerbation.
AE: Acute exacerbation; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; PPF: progressive pulmonary fibrosis; JRS: Japanese Respiratory Society.
The median (range) level of KL-6 at the time of AE in 109 cases who developed AE was 1,100 (233-3,660) U/ml. However, the median (range) of the maximum KL-6 level during the course of ILD in 142 patients who did not develop AE was 690 (208-4,760) U/ml. There was a significant difference between them (p=0.0001, Figure 2).
Figure 2.
Comparison between serum KL-6 levels at the time of acute exacerbation (AE) onset in cases developing AE and maximum KL-6 levels during the course of interstitial lung disease in cases not developing AE.
Among the cases who developed an AE, some patients had two or more AEs. Specifically, nine patients had two AEs and survived the first, while one patient had four AEs and survived three. The KL-6 levels at the time of AE onset were 1,400 (490-2,750) U/ml for cases with two or more AEs and 1,010 (233-3,660) U/ml for cases with a single AE. Cases with two or more AEs tended to have higher KL-6 levels at the time, but the difference was not statistically significant (p=0.0666).
Changes in KL-6 over time in ILD cases with AE. Figure 3 shows the overall time courses of serum KL-6 levels in 109 cases who developed AE. As observed, KL-6 appeared to be a serum indicator showing considerable individual variation. In the clinical courses shown in Figure 3, we first focused on the changes in KL-6 levels one month before the onset of an AE and at the time of AE onset and compared the KL-6 levels in these courses. In 32 out of 109 cases, KL-6 levels were measured one month before and at the time of AE onset. There was no significant difference between the KL-6 level at the time of AE onset and the level one month before AE onset (p=0.092, Wilcoxon signed-rank test), and in 12 cases, the level at the time of AE onset was lower than the level one month before AE onset (Figure 4A).
Figure 3.
The time course of KL-6 measurements in 109 cases of interstitial lung disease who developed acute exacerbation.
Figure 4.
Comparison of serum KL-6 levels during the clinical course and at the onset of acute exacerbation. (A) Comparison of KL-6 levels measured one month before and at the time of acute exacerbation (AE) onset in 32 cases who had complete datasets. Of them, 12 cases had lower KL-6 levels at the time of AE onset, but the increase over time in each case was not significant (p=0.092, Wilcoxon signed-rank test). (B) Comparison of the highest KL-6 levels measured between 1 and 12 months before the onset of AE and the levels at the time of AE onset in 58 cases who had complete datasets. Thirty-six cases had higher KL-6 levels at the time of AE onset, but the increase over time in each case was not significant (p=0.145, Wilcoxon signed-rank test).
Next, we compared KL-6 levels at the time of AE onset and the highest KL-6 levels in the year before the onset of AE. In 58 of the 109 cases who developed AE, KL-6 was measured at least once in the year before the onset of AE. KL-6 levels at the time of AE onset were not higher than the highest KL-6 levels in the year before the onset of AE (p=0.145, Wilcoxon signed-rank test; Figure 4B).
KL-6 levels at the time of AE onset and prognosis after AE. Median (range) KL-6 levels for the 44 cases who died within 30 days of AE onset, the 39 cases who died between 30 and 90 days of AE onset, and the 26 cases who survived for more than 90 days of AE onset were 1,400 (233-2,980) U/ml, 1,120 (409-3,660) U/ml, and 1,190 (317-2,300) U/ml, respectively. There were no significant differences in KL-6 levels at the time of AE among them (p=0.4307, Kruskal-Wallis test).
Univariate analysis was performed on prognostic factors in 109 cases who developed AE. The results are shown in Table II. The patients were divided into two based on the median KL-6 level of 1,100 U/ml at the time of AE onset and compared. No significant prognostic factors, including KL-6 levels, were found. Therefore, multivariate analysis could not be performed.
Table II. Univariate analysis results on prognostic factors in 109 cases who developed acute exacerbation (AE).
ILD: Interstitial lung disease; IPF: idiopathic pulmonary fibrosis; PPF: progressive pulmonary fibrosis.
Discussion
KL-6 levels at the time of AE onset were higher than the maximum KL-6 levels during the clinical courses of patients with ILD who did not develop AE. Although the results were limited to the cases whose KL-6 levels were measured, no significant difference was found between the KL-6 levels at the time of AE onset and KL-6 levels one month prior to AE onset. In addition, KL-6 levels at the time of AE onset were not higher than the highest KL-6 levels in the year prior to AE onset. We compared KL-6 levels at the time of AE onset in three groups: those who died within 30 days of AE onset, those who died between 30 and 90 days, and those who survived for 90 days or more. However, there were no significant differences in KL-6 levels among these three groups. A median KL-6 level (1,100 U/ml) or higher at the time of AE onset was defined as ‘high KL-6 levels’. The association between patient characteristics such as age at the time of AE onset, sex and ‘high KL-6 levels’ with poor prognosis after AE onset were examined but no significant factors were found.
KL-6 is a convenient serum marker that is considered useful in the diagnosis and treatment of ILD and is used in many countries (3). However, as could be seen from the history of its development as a tumor marker for NSCLC (1), it is important to note that some ILD patients with NSCLC might exhibit extraordinarily high KL-6 levels (17, 18). Several studies have reported that KL-6 levels increase over time in patients who ultimately die from ILD, with significant longitudinal elevations observed during extended follow-up (3, 6-11). However, to our knowledge, there have been no studies reporting consecutive serial measurements of KL-6 immediately before the onset of AE. In recent years, clinical studies have been conducted on drugs for treating ILD, and some reports have shown that the reduction of KL-6 indicates a therapeutic effect (19, 20). These studies appeared to assume that KL-6 levels increase over time, but is this a correct assessment? Conversely, there have been reports suggesting that KL-6 cutoff values of 800 U/ml or 3,000 U/ml indicate poor prognosis (15, 21, 22). However, previous studies have not provided clear answers to questions such as whether KL-6 levels were high at the time of AE onset, and whether they elevated further within one year of AE onset, and whether KL-6 levels at the time of AE onset could predict the prognosis after AE onset. This research was conducted to answer these unresolved questions.
It is still unclear whether high KL-6 levels are a result of extensive epithelial cell damage (2) or reflect extensive lung tissue repair (23). ILD is considered a condition accompanied by “temporal and spatial heterogeneity” (24), and it has been presumed that relatively slow tissue destruction and gradual fibrosis occur simultaneously (4). However, AE is understood as a condition in which the deterioration of the respiratory condition progresses rapidly, and rapid tissue destruction outpaces tissue repair (5). KL-6 has been widely used clinically as a marker for ILD (3). If high KL-6 levels are a marker that reflects tissue repair, then measuring KL-6 at the time of AE would mean performing the test with the expectation of understanding the degree of repair. However, at the onset of an AE, the urgent issue is how to overcome respiratory failure caused by rapidly progressing tissue destruction rather than slowly progressing fibrosis. Therefore, measuring KL-6 to assess the degree of fibrosis will not provide clinically significant information. However, if KL-6 is a marker that reflects rapid destruction of lung tissue, then it is presumed that levels will be significantly higher at the onset of an AE than before the onset. Overall, KL-6 levels at the time of AE onset were significantly higher than before AE onset in our study, as observed in previous studies (3, 8-11). But this was not necessarily true for all individual cases. In addition, if KL-6 levels at the time of AE onset indicated extensive epithelial cell damage, it might be useful in predicting the prognosis after AE onset. However, our results did not necessarily support this hypothesis. Therefore, we concluded that careful consideration should be given to the fact that measuring KL-6 at the time of AE might not provide insight into the disease state or prognosis in some cases, and that it might not be possible to predict the prognosis after the onset of AE in some cases. In understanding the progression of AEs, the significance of measuring KL-6 at the time of AE might be limited, both biologically and clinically, and therefore, its implementation should be approached with caution.
Study limitations. First, KL-6 is a serum biomarker characterized by substantial interindividual variability, as demonstrated by the longitudinal measurements presented in Figure 3. These findings should therefore be interpreted with caution. Second, although this was a multicenter study, the small sample size, the adequacy of the study and follow-up periods, and the absence of standardized measurement intervals were important limitations. There is a concern about potential bias, as missing data might be closely related to the results. The use of the JRS staging classification, which had limited evidence for PPF, is also a limitation. Therefore, caution is necessary when interpreting statistical significance directly as clinical significance. Despite these limitations, our findings may inform future studies investigating the biological and clinical significance of serum KL-6 levels at the onset of acute exacerbation.
Conclusion
Among patients with ILD, there were some patients whose KL-6 levels at the onset of AE were not significantly higher than those before the onset of AE. Additionally, in some patients, KL-6 levels at the time of AE onset did not reflect poor prognosis after AE onset. In other words, in some patients, KL-6 levels at the onset of AE did not seem to necessarily provide useful information to accurately understand the rapidly deteriorating disease state or to understand subsequent prognosis. Large prospective studies are warranted to validate these results.
Conflicts of Interest
The Authors declare that they have no competing interests in relation to this study.
Authors’ Contributions
MU, KM, and HS designed the study. MU, KM, YM, SO, NK and HS collected the data. MU, KM and HS analyzed the data. MU and HS prepared the manuscript. HS and RH supervised this study. All authors approved the final manuscript version for submission.
Acknowledgements
Not applicable.
Funding
No funding was received.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
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