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(Chest. 2003;124:2119-2125.)
© 2003 American College of Chest Physicians

Study of Clara Cell 16, KL-6, and Surfactant Protein-D in Serum as Disease Markers in Pulmonary Sarcoidosis*

Rob Janssen, MD; Hiroe Sato, MD, PhD; Jan C. Grutters, MD; Alfred Bernard, PhD; Heleen van Velzen-Blad, MS; Roland M. du Bois, MD, PhD and Jules M. M. van den Bosch, MD, PhD

* From the Heart Lung Center Utrecht (Drs. Janssen, Grutters, and van den Bosch), Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands; Interstitial Lung Disease Unit (Drs. Sato and du Bois), Imperial College, National Heart and Lung Institute and Royal Brompton Hospital, London, UK; Industrial Toxicology and Occupational Medicine Unit (Dr. Bernard), Medical School, Catholic University Louvain, Brussels, Belgium; and Department of Medical Microbiology and Immunology (Ms. van Velzen-Blad), St. Antonius Hospital, Nieuwegein, the Netherlands.

Correspondence to: Jules M. M. van den Bosch, MD, PhD, Department of Pulmonology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands; e-mail: j.vandenbosch{at}antonius.net


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To determine the discriminative value of serum Clara cell 16 (CC16), KL-6, and surfactant protein (SP)-D as markers of interstitial lung diseases, and their ability to reflect pulmonary disease severity and prognosis in sarcoidosis.

Subjects: Seventy-nine patients with sarcoidosis and 38 control subjects.

Measurements: Serum CC16, KL-6, and SP-D concentrations at disease presentation were measured. Pulmonary function tests and chest radiographs were analyzed at presentation and 2-year follow-up.

Results: All markers co-correlated, and a significant difference was found between CC16, KL-6 (Krebs von den Lungen-6), and SP-D levels in patients with sarcoidosis and control subjects (p < 0.0001). Receiver operating characteristic curve analysis revealed largest area under the curve for KL-6. Significantly higher levels of CC16 and KL-6 were found in patients with parenchymal infiltration (stage II, III) compared to patients without parenchymal infiltration (stage I). In concordance, CC16 and KL-6 levels inversely correlated with diffusion capacity and total lung capacity, and KL-6 also with inspiratory vital capacity. Moreover, higher KL-6 levels were weakly but significantly associated with persistence or progression of parenchymal infiltrates at 2-year follow-up.

Conclusion: In this study, KL-6 appears to be the best discriminative marker in differentiating patients with sarcoidosis from healthy control subjects; however, as it is not a specific marker for this condition, this quality is unlikely to be useful as a diagnostic tool. Both CC16 and KL-6 may be of value in reflecting disease severity, and KL-6 tends to associate with pulmonary disease outcome.

Key Words: Clara cell 16 • KL-6 • sarcoidosis • serum markers • surfactant protein-D


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sarcoidosis is a multiorgan granulomatous disorder of unknown etiology, affecting the lungs in up to 90%.1 Since the natural history and prognosis of sarcoidosis is highly unpredictable, and the disease tends to wax and wane, it is of the utmost importance to carefully monitor disease development.1 To date, no single laboratory marker adequately reflects pulmonary disease status.2 In addition, many of these markers add little to clinical findings, such as erythema nodosum, chest radiography, and pulmonary function tests. Moreover, none of the available markers are able to predict the outcome of sarcoidosis.

Lung epithelium-specific proteins, or pneumoproteins, offer a new perspective in assessing pulmonary involvement in interstitial lung diseases.3 The tests used to detect pneumoproteins in serum are easy to perform. Among the pneumoproteins, Clara cell 16 (CC16), KL-6 (Krebs von den Lungen-6), and surfactant protein (SP)-D have been found in serum of patients with sarcoidosis.4 5 6 Although each marker has been studied separately, their usefulness as markers in sarcoidosis has never been compared. CC16 is a protein with a molecular weight of approximately 16 kd produced by bronchiolar Clara cells.7 Increased CC16 levels have been found in serum of sarcoidosis patients, probably due to the increased lung permeability caused by disruption of the air-blood barrier.6 KL-6 is a mucin-like glycoprotein with a molecular weight of 200 kd and extensively expressed on the membrane of regenerating type II pneumocytes.8 9 Elevated KL-6 levels have also been found in serum of patients with sarcoidosis and were associated with intensity of pneumonitis.4 Further, SP-D is a member of the C-type lectin superfamily with a molecular weight of 43 kd produced by type II pneumocytes.5 This marker has been found mildly elevated in serum of patients with sarcoidosis.5

Ohnishi and colleagues10 evaluated serum KL-6, SP-A, and SP-D in patients with various interstitial lung diseases. KL-6 appeared to be best marker in the assessment of interstitial lung diseases; however, no patients with sarcoidosis were included in this study. The Potential predictive value of pneumoproteins was recently suggested in a study by Greene and colleagues.11 They found that high SP-A and SP-D levels in serum of patients with idiopathic pulmonary fibrosis were associated with decreased survival.

The present study was designed to compare the value of CC16, KL-6, and SP-D as serum markers in pulmonary sarcoidosis; therefore, we assessed the discriminative value of serum CC16, KL-6, and SP-D for patients with sarcoidosis vs healthy control subjects. Subsequently, serum levels of the pneumoproteins were evaluated in relation to clinical severity parameters in order to establish their value as marker of severity. Finally, a follow-up study was performed to analyze potential predictive value of each pneumoprotein.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
In this study, patients with sarcoidosis diagnosed at the Department of Pulmonology of the St. Antonius Hospital Nieuwegein between 1989 and 1999 were studied retrospectively. In all patients, the diagnosis of sarcoidosis was based on compatible clinical findings, histologic evidence of noncaseating epithelioid-cell granulomas, and the exclusion of known causes of granulomatous diseases. At time of presentation, none of them were receiving corticosteroids, nor had they within the previous 3 months.

Healthy subjects served as a control group in order to assess the discriminative value of the serum markers. Health was confirmed on the basis of a medical checklist.

In all patients, assessment of sarcoidosis at time of diagnosis included scoring of chest radiography, and pulmonary function testing. Serum samples were obtained at the same time and stored at – 80°C until analysis. Each serum sample was analyzed for CC16, KL-6, and SP-D. The study protocol was approved by the Ethical Committee of the St. Antonius Hospital.

CC16, KL-6, SP-D and Angiotensin-Converting Enzyme Measurements
The concentration of CC16 was determined by an immunoassay relying on the agglutination of latex particles, as described previously.6 The KL-6 level was measured by a sandwich-type enzyme-linked immunosorbent assay technique using a KL-6 antibody kit (ED046; Eisai; Tokyo, Japan) kindly provided by the manufacturer.12 The SP-D concentration was measured using enzyme-linked immunosorbent assays (Yamasa; Chiba, Japan).13 Serum angiotensin-converting enzyme (ACE) was measured using an enzymatic assay (ACE Kinetic; Buhlmann Laboratories; Schönenbuch/Basel, Switzerland) that is used for routine diagnostics in our hospital. All samples were run in duplicate, and mean values were used for subsequent analysis.

Chest Radiography
Chest radiographs were scored blind by a chest physician with > 20 years of experience in interstitial lung diseases (J.vdB.) according to standard chest radiographic staging.1 Besides this staging, patients with abnormal chest radiographic findings were also categorized as follows: without parenchymal infiltration (stage I), and with parenchymal infiltration (stage II and III).

Pulmonary Function Testing
The following pulmonary function tests were performed in agreement with the European Respiratory Society recommendations: inspiratory vital capacity (IVC) and FEV1 by using spirometry, total lung capacity (TLC) by using body plethysmography, and gas transfer measurements were performed using the carbon monoxide diffusing lung capacity single-breath technique (DLCO).14 Pulmonary function data were calculated as percentages of predicted normal values.

Follow-up Study
All patients with sarcoidosis included in this study had a follow-up of 2 years in which chest radiographs and pulmonary function tests were repeated at regular time intervals. This provided the opportunity to assess the predictive value of each pneumoprotein concerning functional and radiologic outcome. Radiologic improvement or deterioration was defined as changing of chest radiograph to a lower or higher radiographic stage, respectively. On the basis of these data, we categorized all patients into two groups: patients with deterioration or stabilization of chest radiographic stage (group 1) or patients with improvement of chest radiographic stage (group 2). Furthermore, all patients were categorized on the basis of change in parenchymal infiltrations only, ie, progression or stabilization (group A), improvement (group B), or no manifestations of parenchymal infiltrations at presentation and follow-up (group C). For this, only obvious changes of pulmonary infiltrates on follow-up chest radiograph in comparison with initial chest radiograph were scored as either "progression" or "improvement," and no or doubtful changes as "stabilization." Change in pulmonary function was expressed as change of percentage of predicted TLC (%TLC), IVC, FEV1, and DLCO per year: %TLC = (%TLC follow-up - %TLC at presentation)/%TLC at presentation x 100/years.

Finally, as treatment with corticosteroids may influence functional and radiologic outcome, patients with and without treatment were analyzed separately. The decision to treat was based on the following criteria: (1) progressive deterioration of pulmonary function, (2) progressive change on chest radiographs or extensive pulmonary involvement, (3) impairment of organs other than the lung, and (4) persistent symptoms in combination with parameters of disease activity.

Statistical Analysis
Data were expressed as median with 25 to 75% quartiles. Correlations between different variables were determined using the Spearman rank coefficient. The Mann-Whitney U test was used to compare pneumoprotein levels between two groups. The concentrations of CC16, KL-6, and SP-D were analyzed by using receiver operating characteristic (ROC) curves in order to find cut-off values for optimal discriminative accuracy. Statistical analyses were performed using the Statistical Package for Social Science for Windows (SPSS; Chicago, IL). Additionally, the Hanley test was used to compare the areas under the ROC curve. Values of p < 0.05 were considered as statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Characteristics
Seventy-nine patients with sarcoidosis (43 men and 36 women; mean age ± SD, 39 ± 12 years; 56 nonsmokers and 23 smokers), and 38 control subjects (19 men and 19 women; mean age, 37 ± 10 years; all nonsmokers) were studied.

One patient with sarcoidosis presented with radiographic stage 0, 28 patients presented with stage I, 36 patients presented with stage II, 12 patients presented with stage III, and 2 patients presented with stage IV disease. Serum CC16, KL-6, and SP-D values in patients with sarcoidosis, radiographic subgroups, and healthy control subjects are shown in Table 1 . Since smoking has an effect on pneumoprotein levels, serum values for each marker were calculated for the total group and for subgroups according to smoking habit.15 16 17


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  		Table 1.. Serum CC16, KL-6, and SP-D Levels in Patients With Sarcoidosis (Smokers and Nonsmokers) and Healthy Control Subjects*

 
ROC Curve Analysis
A significant difference was found between serum CC16, serum KL-6, and serum SP-D levels in nonsmoking patients with sarcoidosis and control subjects (p < 0.0001). We did not observe any differences in serum levels between the first and last quartile of collected samples, making bias due to bioinstability of CC16, KL-6, and SP-D epitopes over time unlikely.

ROC curves were used to evaluate the discriminative value of serum CC16, KL-6 and SP-D in sarcoidosis (nonsmokers). Serum KL-6 levels resulted in largest area under the curve: CC16, 0.83 (95% confidence interval [CI], 0.74 to 0.91); KL-6, 0.88 (95% CI, 0.81 to 0.96); SP-D, 0.75 (95% CI, 0.65 to 0.85) [Fig 1 ]. Cut-off levels were set as the closest point to 100% sensitivity and 100% specificity: 12.7 ng/mL for CC16 (sensitivity, 73%; specificity, 84%; and discriminative accuracy, 73%), 223 U/mL for KL-6 (sensitivity, 86%; specificity, 84%; and discriminative accuracy, 86%), and 91.7 ng/mL for SP-D (sensitivity, 66%; specificity, 84%; and discriminative accuracy, 66%). The difference between the area under the curve of CC16 and KL-6, and of CC16 and SP-D was not significant (p = 0.22 for both differences), but the difference between the area under the curve of KL-6 and SP-D was significant (p = 0.018).



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  		Figure 1.. ROC curve showing the sensitivity and 1-specificity of CC16 ({circ}), KL-6 (x), and SP-D ({blacksquare}) for the detection of sarcoidosis (nonsmokers).

 
Correlations Between Serum Pneumoprotein Levels
All three serum markers were significantly co-correlated in the total and nonsmoking sarcoidosis groups (CC16 and KL-6, r = 0.33, p = 0.003 [total], r = 0.43, p = 0.001 [nonsmokers]; CC16 and SP-D, r = 0.37, p = 0.001 [total], r = 0.42, p = 0.001 [nonsmokers]; KL-6 and SP-D, r = 0.40, p < 0.0001 [total], r = 0.36, p = 0.006 [nonsmokers]), but only KL-6 and SP-D were significantly correlated in the smoking sarcoidosis group (r = 0.44, p = 0.038). In the control group, a significant correlation was found between serum CC16 and serum SP-D (r = 0.32, p = 0.048). In addition, best correlations were found when combining all nonsmoking subjects (patients and control subjects; CC16 and KL-6, r = 0.58, p < 0.0001; CC16 and SP-D, r = 0.45, p < 0.0001; KL-6 and SP-D, r = 0.48, p < 0.0001). No correlation was found between serum ACE levels and any of the tested pneumoproteins.

Analysis of Serum CC16, KL-6, and SP-D as Markers of Severity
Radiography: Analysis of radiographic subgroups in relation to serum levels showed significant higher values of CC16 and KL-6 in patients presenting with stage II or III disease, ie, parenchymal infiltration, compared to stage I (p = 0.007 and p < 0.0001, respectively; Fig 2 ). Patients presenting with stage I disease had a median CC16 level of 14.7 ng/mL (range, 10.0 to 17.1 ng/mL), whereas those presenting with stage II/III disease had a median level of 18.5 ng/mL (range, 13.4 to 24.0 ng/mL). For KL-6 these values were 269 U/mL (range, 233 to 309 U/mL) and 451 U/mL (range, 313 to 577 U/mL). No significant difference was found for SP-D. Data for subgroups according to smoking habit are given in Table 1 .



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  		Figure 2.. Box plot showing the median, interquartile range, and extremes of KL-6 in all patients with stage I (n = 28), stage II (n = 36), and stage III (n = 12).

 
Pulmonary Function:
Weak associations were found between CC16 and KL-6 and pulmonary function parameters, but SP-D levels did not correlate with any of the tested parameters. CC16 in nonsmoking patients with sarcoidosis correlated with DLCO (r = - 0.42, p = 0.001; Fig 3 , top) and TLC (r = - 0.34, p = 0.011). Serum KL-6 levels correlated with DLCO in smoking and nonsmoking patients (r = - 0.65, p = 0.001 and r = - 0.30, p = 0.028, respectively; Fig 3 , bottom), and with IVC only in nonsmoking patients with sarcoidosis (r = - 0.32, p = 0.017). Further, KL-6 correlated with TLC in nonsmokers (r = - 0.35, p = 0.008).



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  		Figure 3.. Scatter diagrams showing the correlation between CC16 and DLCO in nonsmoking patients (top), and KL-6 and DLCO in the total group of patients with sarcoidosis (Bottom).

 
Analysis of Serum CC16, KL-6, and SP-D as Predictive Markers
At follow-up, 8 patients showed a higher chest radiographic stage compared to presentation of disease, and 57 patients showed unchanged radiographic stage (group 1). In 14 patients, a lower follow-up chest radiographic stage was observed (group 2). No significant difference in CC16, KL-6, or SP-D levels were found between groups 1 and 2.

Twenty-three patients with parenchymal infiltrates on their initial chest radiograph showed progression or stabilization of infiltrates, and 1 patient with no parenchymal infiltrates at presentation acquired these during follow-up (group A). Twenty-seven patients with parenchymal infiltrates at presentation showed improvement of the abnormalities during follow-up (group B). Twenty-eight patients with sarcoidosis had no parenchymal disease at presentation or follow-up (group C). Group A showed significantly higher KL-6 levels compared to group B (p = 0.045; Fig 4 ), and group B showed significantly higher KL-6 levels than C (p = 0.008). For CC16 and SP-D, no significant differences were found between groups A and B, or between groups B and C. Twenty patients were treated with corticosteroids during follow-up, and 59 patients were not treated. Subanalysis of patients with and without corticosteroid treatment showed similar results for KL-6 levels; however, p values between groups A and B dropped below significance. Further, analysis of changes in pulmonary function during follow-up showed no significant correlations between %TLC, percentage of predicted IVC, or percentage of predicted DLCO and initial levels of CC16, KL-6, and SP-D.



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  		Figure 4.. Box plot showing the median, interquartile range, and extremes of KL-6 in patients with sarcoidosis and no improvement or progression of parenchymal infiltrates on chest radiograph (group A; n = 24), patients with improvement of parenchymal infiltrates (group B; n = 27), and patients in whom no manifestations of parenchymal disease were detected either at presentation or follow-up (n = 28; group C).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we compared the value of CC16, KL-6, and SP-D as serum markers in pulmonary sarcoidosis. Although all three pneumoproteins were significantly elevated in patients with sarcoidosis compared to control subjects, ROC curve analysis revealed best sensitivity for KL-6. The results on KL-6 are in agreement with a recent study of Ohnishi and colleagues,10 who demonstrated superiority of serum KL-6 over SP-D in detecting interstitial lung disease. However, their study did not include patients with sarcoidosis, and did not evaluate CC16, which is also a potentially novel marker for interstitial lung disease. Our comparative study on three pneumoproteins now suggests that KL-6 appears to be the most useful serum marker in the assessment of sarcoidosis. However, this is not very helpful for diagnosis. It is unlikely that CC16, KL-6, and SP-D can be used in differentiating sarcoidosis from other forms of interstitial lung disease, because previous studies5 9 have shown increased levels in diseases like idiopathic pulmonary fibrosis. Therefore, we believe the value of CC16, KL-6, and SP-D in diagnosing sarcoidosis is limited.

We demonstrated, however, significantly higher levels of CC16 and KL-6 in patients with parenchymal infiltration (stage II and III) compared to patients without parenchymal infiltration (stage I). These results are in agreement with Hermans and colleagues,6 who observed increased CC16 serum levels in patients with higher radiographic stages, ie, stage II and III. Kobayashi and Kitamura4 demonstrated a similar association for KL-6: increased serum levels of KL-6 for sarcoidosis patients with parenchymal disease. Altogether, these results strongly suggest that CC16 as well as KL-6 are useful markers for determining radiologic disease severity in sarcoidosis.

Interestingly, although rather weak, associations were also found between increased serum CC16 and KL-6 levels and lung function severity, ie, lower IVC and reduced DLCO. Previous studies18 19 demonstrated similar findings for KL-6 in berylliosis and systemic sclerosis, but to our knowledge no study has yet described such a correlation for KL-6 or CC16 in sarcoidosis. Apparently, there is some contradiction when gas transfusion reduces while passage of pneumoproteins across the air-blood barrier increases. However, we postulate that DLCO and serum pneumoproteins are parameters of two distinct processes in sarcoidosis. Gas diffusion is strongly dependent on the thickness and total area of the alveolar-capillary membrane, and leakage of proteins more likely depends on the relation between molecule weight and size of pores in the total pulmonary epithelial-endothelial surface.

Besides their potential value as severity markers, we also looked at the predictive value of each pneumoprotein and found that patients with sarcoidosis and progressive or not improving parenchymal lung disease had slightly but significantly higher KL-6 levels at presentation. As standard chest radiographic staging is limited by reflecting changes in parenchymal infiltrates within stage II or III, this association could only be detected when scoring merely changes in parenchymal infiltrates. This result suggests that higher serum KL-6 levels reflect more severe forms of pulmonary sarcoidosis with higher risk of disease progression, although there was much overlap between the groups. Therefore, we propose that KL-6 levels might add to the predictive value of standard chest radiographic staging; however, further prospective studies (using sophisticated high-resolution CT scanning) are needed.

Although pneumoproteins are potentially useful as markers of inflammation they could, as some reports indicate, also play a role in mediating cellular processes in fibrosis. Hirasawa and colleagues8 found that purified KL-6 is chemotactic for human fibroblasts in vitro, comparable with platelet-derived growth factor, fibroblastic growth factor, and fibronectin. Intriguingly, for CC16 an opposite effect has been described, ie, CC16 was able to inhibit fibroblast chemotaxis in vitro.20 This suggests that KL-6 and CC16 balance might have influence on the risk of developing fibrotic disease in sarcoidosis. Therefore, studying CC16 and KL-6 levels in serum and BAL fluid in relation to long-term disease outcome could be interesting and help to elucidate the role of these markers in the evolution of sarcoidosis.

In conclusion, KL-6 appears to be best discriminative marker in differentiating patients with sarcoidosis from healthy control subjects; however, as it is not a specific marker, this quality is unlikely to be of use in clinical practice. Both CC16 and KL-6 appear to reflect some aspects of pulmonary disease severity, especially the presence of pulmonary infiltrates on chest radiograph. But further studies are needed to determine the utility of these parameters as true markers of pulmonary disease severity, and to establish if serial measurements correlate with changes in lung function or chest radiographs.


   Acknowledgements
 
The authors thank Xavier Dumont for laboratory assistance and Pieter Zanen for statistical advice.


   Footnotes
 
Abbreviations: ACE = angiotensin-converting enzyme; CC16 = Clara cell 16; CI = confidence interval; DLCO = carbon monoxide diffusing lung capacity single-breath technique; IVC = inspiratory vital capacity; ROC = receiver operating characteristic; SP = surfactant protein; TLC = total lung capacity; %TLC = percentage of predicted total lung capacity

Dr. Janssen was supported by a grant from AstraZeneca.

Received for publication January 6, 2003. Accepted for publication July 16, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  8. Hirasawa, Y, Kohno, N, Yokoyama, A, et al KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. Am J Respir Cell Mol Biol 1997;17,501-507[Abstract/Free Full Text]
  9. Kohno, N, Kyoizumi, S, Awaya, Y, et al New serum indicator of interstitial pneumonitis activity: sialylated carbohydrate antigen KL-6. Chest 1989;96,68-73[Abstract/Free Full Text]
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