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(Chest. 2001;120:362-368.)
© 2001 American College of Chest Physicians

Soluble Leukocyte Selectin in the Analysis of Pleural Effusions*

Lynn Longmore Horvath, CPT, MC, USA; Roger A. Gallup, MAJ, MC, USA; Brian D. Worley, MD, FCCP; Gerald A. Merrill, PhD and Michael J. Morris, LTC, MC, USA

* From the Pulmonary Disease/Critical Care Service (Drs. Gallup, Worley, and Morris) and Internal Medicine Service (Dr. Horvath), Department of Medicine, and Department of Clinical Investigation (Dr. Merrill), Brooke Army Medical Center, Fort Sam Houston, TX.

Correspondence to: CPT Lynn Longmore Horvath, MC, USA, Department of Internal Medicine Infectious Disease Service, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX 78234-6200; e-mail: Lynn.Horvath{at}cen.amedd.army.mil


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To determine if soluble leukocyte selectin (sL-selectin) levels in serum and pleural fluid (PF) are an inflammatory marker that differentiates pleural effusion transudates from exudates.

Design: sL-selectin PF and serum levels were measured in consecutive patients and compared to established criteria.

Setting: A tertiary-care military medical center.

Patients: One hundred twenty patients undergoing diagnostic or therapeutic thoracentesis.

Interventions: PF and serum samples were collected during thoracentesis and analyzed separately for sL-selectin levels. Results were compared with clinical diagnosis and established PF criteria including the criteria of Light et al, cholesterol ratio, total bilirubin ratio, and albumin gradient.

Measurements and results: sL-selectin levels in PF and serum were determined in 109 patients. By clinical diagnosis, mean ± SD PF sL-selectin levels were 200.2 ± 124.3 ng/mL in transudates and 496.8 ± 379.2 ng/mL in exudates (p < 0.001). By the criteria of Light et al, mean PF sL-selectin levels were 195.7 ± 105.2 ng/mL in transudates and 448.2 ± 367.6 ng/mL in exudates (p < 0.001). Mean sL-selectin PF to serum ratios were 0.31 ± 0.17 in transudates and 0.72 ± 0.31 in exudates (p < 0.001) by clinical criteria, and 0.31 ± 0.18 in transudates and 0.64 ± 0.33 in exudates (p < 0.001) by the criteria of Light et al. No significant difference was noted with serum sL-selectin levels between groups.

Conclusions: sL-selectin is an inflammatory marker that differentiates transudates from exudates in pleural effusions and is a sensitive indicator for PF analysis.

Key Words: exudate • inflammatory markers • pleural effusion • sL-selectin • transudate


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Analysis of pleural fluid (PF) is an important initial step in determining the underlying cause of pleural effusions. The extent of further evaluation to include repeat thoracentesis and pleural biopsy is predicated on whether the effusion is classified as a transudate or exudate. Light et al1 established a PF to serum total protein (TP) ratio of > 0.5, a PF to serum lactate dehydrogenase (LDH) ratio of > 0.6, and an LDH level greater than two thirds the upper limit of normal as the initial diagnostic criteria. The article established the criteria of Light et al1 as an effective method of separating transudates and exudates. Since the publication of this article in the early 1970s, analysis of PF has greatly expanded and further research2 3 4 has described the utility of other laboratory parameters in the analysis of PF. These include a PF to serum cholesterol ratio > 0.3, a PF to serum total bilirubin (Tbili) ratio > 0.6, and a serum to PF albumin gradient < 1.2 as predictive of exudative effusions. A meta-analysis5 of all these parameters has demonstrated that the criteria of Light et al1 remain the most sensitive and specific parameters for PF analysis.

Relatively little data have been published on the use of inflammatory markers in the analysis of PF. Many of the cytokines have been previously studied. Interleukin-2, interleukin-6, and monocyte chemotactic peptide-1 have all shown higher levels with exudates, but there is substantial overlap between groups.6 7 8 Since transudates are due to alterations in hydrostatic or osmotic pressures and many etiologies of exudative pleural effusions are inflammatory in origin, a substance directly involved in the inflammatory response may differentiate transudates from exudates.

Soluble leukocyte selectin (sL-selectin), a member of the selectin family, is a cell adhesion molecule expressed on all WBCs. Its role is integral in the attachment of leukocytes to endothelial cells, allowing migration of WBCs into sites of inflammation.9 After activation of leukocytes, it is rapidly shed from the cell surface and released into the bloodstream. sL-selectin continues to be functionally active and is measurable in human serum.10 Elevated serum levels have been measured in acute inflammatory states such as trauma and myocardial injury.11 12 However, studies on rheumatic diseases do not always show a correlation between sL-selectin serum levels and disease activity.13 14 15

Several studies investigated localized concentrations of sL-selectins in other body fluids. Two studies16 17 of sL-selectin in cerebrospinal fluid (CSF) demonstrated that levels are elevated in those patients with meningeal leukemia when compared to acute leukemia patients without meningeal involvement. To our knowledge, no studies to date have been published that have investigated sL-selectin levels in PF. The purpose of this study was to measure sL-selectin levels in the serum and PF of patients with pleural effusions. We hypothesized that sL-selectin levels should be elevated in exudative effusions due to inflammation of the pleura as compared to transudative effusions.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Any patient undergoing diagnostic or therapeutic thoracentesis was eligible for inclusion in the study. The primary physician was asked to obtain two 5-mL aliquots of both blood and PF in standard chemistry test tubes from the patient at the time of thoracentesis. One sample of blood and one sample of PF were sent to the hospital laboratory for the following chemistries: TP, LDH, albumin, cholesterol, and TBili. Other laboratory tests such as cell count, cultures, pH, and cytology were sent at the discretion of the primary physician. The other sample of blood and PF was collected by one of the investigators and taken immediately to the clinical investigation laboratory where it was centrifuged at 1,000 revolutions per minute for 15 min. The PF supernatant and the blood serum samples were collected, placed in cryotubes, and frozen at - 80°C.

Pleural effusions were classified as either a transudate or exudate based on established criteria using PF and serum chemistries. The classic criteria of Light et al1 used were a PF to serum TP ratio of > 0.5, a PF to serum LDH ratio of > 0.6, and an LDH value greater than two thirds of the normal laboratory value. An exudate had one or more positive criteria, and a transudate had none of the positive criteria. For the other criteria, exudates were defined in the following manner: a cholesterol PF to serum ratio of > 0.3, a TBili PF to serum ratio of > 0.6, and a serum minus PF albumin gradient < 1.2. Both the combined criteria of Light et al1 and the individual values were compared to sL-selectin values.

A review of charts and chest radiographs was conducted on each patient enrolled in the study using the specified clinical criteria to determine the etiology of the effusion. Collected laboratory data were not used to determine transudates or exudates. Exudates were defined for the following processes. Malignant effusions were diagnosed on the basis of a positive PF cytology or pleural biopsy finding. The presence of primary lung carcinoma or metastatic disease to the lung with a persistent effusion was also considered diagnostic. A parapneumonic effusion was diagnosed in patients with an effusion associated with a pulmonary infiltrate, clinical signs of infection (fever, elevated WBC count) and clinical treatment as a pneumonic process. Evidence of infection such as positive culture results, Gram’s stains, or purulent material was also considered diagnostic. A hemothorax was diagnosed in those patients with evidence of gross blood who were treated with tube thoracostomy. Other exudative effusions such as pulmonary embolism and pancreatitis were based on direct association between the effusion and the underlying process.

Transudates were defined for the following processes. An effusion due to congestive heart failure was diagnosed by the presence of bilateral effusions with decreased left ventricular function. The use of diuretics at the time of thoracentesis was likewise noted. A unilateral effusion associated with congestive heart failure was not diagnostic unless other etiologies were excluded. Volume overload was diagnosed in those ICU patients with bilateral effusions who had no evidence of left ventricular failure but received large volumes of fluid. Other specific transudative diagnoses, such as nephrosis and cirrhosis with ascites, were based on documented presence of these diseases.

Once all the samples were collected, both serum and PF were analyzed for sL-selectin levels. The frozen samples were thawed to room temperature, and the sL-selectin levels were determined by a quantitative sandwich enzyme immunoassay (R&D Systems; Minneapolis, MN). Appropriately diluted samples and standards were pipetted into 96-well microplates precoated with murine monoclonal antibody specific for human sL-selectin. An enzyme-linked horseradish peroxidase sheep polyclonal antibody was added to the wells and incubated for 1 h. The wells were washed with phosphate-buffered saline solution to remove unbound sample. A substrate (tetramethylbenzidine) was added to each well; the reaction was stopped after 30 min, and the plate was read at 450 nm. A mean absorbance standard curve was determined from the control samples, and the concentration of unknown samples was calculated.

Standard curves for the sL-selectin assay were generated using commercial software (TableCurve 2D, v2.03; Jandel Scientific; San Rafael, CA). Statistical analysis was performed using a standard t test. A Mann-Whitney rank sum test was used when the normality test failed. The analysis was performed using commercial software (SigmaStat, version 2.0; Jandel Scientific). All p values < 0.05 were considered significant. Receiver operating characteristic curves were generated using commercial software (SPSS for Windows, release 9.0; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
One hundred twenty patients had PF and serum samples collected for the protocol. Only 109 samples were analyzed for sL-selectin levels. Two of the patients were excluded, as samples were submitted from two different thoracenteses; the remaining were excluded because more than one of the required laboratory chemistries was not submitted by the primary physician. The mean ± SD age of patients was 70.2 ± 14.2 years. After review of the patient’s records as outlined in the "Materials and Methods" section, a clinical diagnosis for the etiology of the pleural effusion was established. There were 40 patients with transudative diagnoses and 69 patients with exudative diagnoses. The list of diagnoses is shown in Table 1 .


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  		Table 1. A Listing of Clinical Diagnoses and No. of Patients for Each Transudate and Exudate Diagnosis

 
The serum and PF chemistries were compared to classify the pleural effusions as either transudate or exudate. The results are listed in Table 2 with reference to established TP, LDH, cholesterol, albumin, and TBili criteria. The combined criteria of Light et al1 (TP ratio, LDH ratio, absolute LDH value) most closely matched the classification using clinical diagnoses with 83.5% of effusions classified identically. Forty percent of the clinical transudates were classified as exudates using the criteria of Light et al.1 The cholesterol ratio was in agreement for 83% of the effusions. The separate LDH and TP criteria were identical for 76 to 81% of the effusions, while the TBili and albumin criteria were in agreement 70% and 54%, respectively.


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  		Table 2. Classification of Effusions Based on Established Criteria

 
The results of the selectin assay for PF were first compared to all diagnostic criteria for transudate or exudate (Table 3 ). The most significant findings were demonstrated for clinical, Light et al,1 and cholesterol criteria all with p values < 0.001. Less significance is noted for the albumin gradient, and none was demonstrated with the TBili ratio. The comparison of sL-selectin serum values for these criteria showed no significant difference in any of the serum values. For the listed criteria, sL-selectin serum values for exudates and transudates were the following, respectively: clinical criteria, 762.8 ± 592.5 ng/mL vs 710.9 ± 345.4 ng/mL; Light et al1 criteria, 728.2 ± 566.5 ng/mL vs 697.8 ± 300.2 ng/mL; cholesterol ratio, 749.6 ± 588.8 ng/mL vs 650.9 ± 325.5 ng/mL; albumin gradient, 709.6 ± 442.8 ng/mL vs 727.3 ± 552.2 ng/mL; and TBili ratio, 698.7 ± 564.1 ng/mL vs 791.3 ± 395.0 ng/mL. Finally, PF to serum sL-selectin ratios were compared as shown in Table 3 . Similar findings are noted in the sL-selectin PF values with the most statistical significance (p < 0.001) seen with clinical criteria, Light et al1 criteria, and the cholesterol ratio.


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  		Table 3. Mean PF sL-selectin Levels and PF to Serum sL-selectin Ratios for Both Transudates and Exudates Based on Established Laboratory Values as Compared to Clinical Criteria *

 
PF sL-selectin levels were compared to pleural fluid WBC counts when these results were available. WBC counts were recorded in 32 of 40 transudates (mean value of 616.9 ± 998.4 x 109/L) and 49 of 69 exudates (mean value of 2,444.8 ± 3,737.9 x 109/L). There was no correlation between pleural sL-selectin levels and WBC counts, with an r value of 0.15.

Receiver operating characteristic curves were generated, and the optimal cutoff point was determined based on the prevalence of disease and the cost of an incorrect classification. As outlined in the meta-analysis by Heffner and colleagues,5 the prevalence was set at 0.5 and the ratio of false-positive cost to false-negative cost was also set at 0.5. The resulting slope of the prevalence-cost equation line is 0.5. Using the clinical criteria as the standard, a cutoff value for PF sL-selectin was 240 ng/mL and the sL-selectin ratio was 0.40. Sensitivity, specificity, positive and negative predictive values to confirm the presence of an exudate for clinical criteria, Light et al1 criteria, and cholesterol ratio are shown in Table 4 . For all three criteria, the sL-selectin ratio had slightly better values than the absolute sL-selectin PF value. Combining these two values slightly improved the sensitivity and positive predictive value for all three criteria but decreased both the specificity and negative predictive value. PF sL-selectin values (Fig 1) and sL-selectin ratios (Fig 2 ) show distribution of the values for each criteria. It is notable there is significant overlap between transudates and exudates at the cutoff point for each criterion.


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  		Table 4. Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value of PF sL-selectin, PF to Serum sL-selectin Ratios, and a Combination of These Two Indexes to Confirm the Presence of an Exudate *

 


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  		Figure 1. Plot depicting individual values for each PF sL-selectin level. Columns for each category (clinical criteria, Light et al1 criteria, and cholesterol [Chol] ratio) are separated based on classification into exudate (EX) and transudate (TR). The cutoff line is drawn at 240 ng/mL.

 


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  		Figure 2. Plot depicting individual values for each PF to serum sL-selectin ratio. Columns for each category (clinical criteria, Light et al1 criteria, and cholesterol ratio) are separated based on classification into exudate and transudate. The cutoff line is drawn at 0.40. See Figure 1 legend for expansion of abbreviations.

 
Receiver operating characteristic curves were generated for PF sL-selectin values and the PF to serum sL-selectin ratio for clinical, Light et al,1 and cholesterol ratio criteria. Area under the curve was calculated for each criterion. For PF sL-selectin values, area under the curve results were as follows: clinical criteria, 0.81; Light et al1 criteria, 0.76; and cholesterol ratio, 0.86. For sL-selectin PF to serum ratios, area under the curve results were as follows: clinical criteria, 0.90; Light et al1 criteria, 0.83; and cholesterol ratio, 0.86. The sL-selectin ratio was a better diagnostic test based on these criteria.

The final analysis evaluated sL-selectin levels in patients with specific exudative diagnoses. The two most common exudative effusions were due to malignant (n = 31) and parapneumonic effusions (n = 21). The mean sL-selectin PF value for malignant effusions was 502.5 ± 421.5 ng/mL and for parapneumonic effusions was 523.7 ± 362.7 ng/mL (p = 0.85). When the sL-selectin PF to serum ratios were compared, malignant effusions were 0.68 ± 0.23 and parapneumonic effusions were 0.79 ± 0.43 (p = 0.85). No significant difference is demonstrated for these two groups, and higher sL-selectin levels do not predict a specific type of exudative effusion.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Accurate and rapid analysis of PF is necessary for the proper management of patients with pleural effusions. The ability to correctly determine whether an effusion is an exudate or transudate with the initial thoracentesis is important. An incorrect analysis can significantly increase the number of additional diagnostic procedures and the cost to evaluate patients. This analysis is more difficult in those complex patients who may have multiple possible etiologies for the effusion. The established criteria currently available to the clinician measure the permeability of the pleural space to proteins and are not a direct measure of inflammation. Measurement of the sL-selectin level in PF is a marker of the inflammatory process in exudative pleural effusions and helps to differentiate these from transudative effusions.

An inflammatory reaction is characterized by the movement of leukocytes from the circulation into the affected tissues. This process is mediated by a family of adhesion molecules (leukocyte selectin [L-selectin], platelet-selectin, and endothelial-selectin) referred to as selectins. They mediate the initial attachment of leukocytes to vascular endothelium prior to leukocyte migration into inflamed tissue. L-selectin is expressed on the surface of most leukocytes and is rapidly cleaved from the cell surface after cellular activation. The soluble form of L-selectin can be easily measured in the serum of normal patients with a mean level of 1.6 ± 0.8 µg/mL and maintains functional activity.10

The majority of clinical research into sL-selectin has focused on systemic inflammatory disorders. Several studies have focused on autoimmune rheumatic diseases with variable findings. In a study of 42 patients with systemic lupus erythematosus and 33 normal control subjects, Font et al13 noted serum sL-selectin levels were higher in lupus patients and significantly elevated in those with active disease. Patients with primary Sjögren’s syndrome had lower serum sL-selectin levels than control subjects but significantly higher levels in those Sjögren’s patients with Raynaud’s or autoimmune thyroiditis.14 In two other studies,15 18 patients with systemic sclerosis were shown to have lower levels than normal control subjects, whereas patients with systemic lupus erythematosus and vasculitis had significantly elevated levels. A study19 of sL-selectin serum levels in patients with inflammatory bowel disease showed a correlation with disease activity in ulcerative colitis but not in Crohn’s disease. Type I diabetics but not type II diabetics also showed correlation with disease activity.20 Other studies21 22 have investigated atopic dermatitis and diffuse panbronchiolitis and found elevated sL-selectin serum activity associated with increased disease activity.

CNS disease has been extensively investigated to correlate disease activity with sL-selectin levels in the CSF. In patients with acute subarachnoid hemorrhage, levels of other adhesion molecules but not sL-selectin were elevated when compared to control subjects and patients with old subarachnoid hemorrhage.23 However, two studies of malignancy in the CSF have noted increased sL-selectin levels. Dagdemir et al16 studied children with CNS leukemia with the presence of blasts and noted elevated sL-selectin levels (12.41 ± 2.14 ng/mL) compared to leukemic patients without CSF involvement (1.34 ± 0.21 ng/mL) and normal control subjects (1.46 ± 0.18 ng/mL). Stucki et al17 found similar results with higher CSF sL-selectin levels in 15 patients with meningeal leukemia (median of 60 ng/mL) than 20 leukemia patients without meningeal involvement (median of 12 ng/mL).

This study demonstrated several important points about the use of sL-selectin in the analysis of PF. There is clearly a significant difference with higher sL-selectin PF levels and PF to serum sL-selectin ratios in exudates when compared to transudates. This is most pronounced when comparisons are made using the clinical diagnosis but also retains significance when the criteria of Light et al1 or the cholesterol ratio is used. The significance of these levels is not as pronounced when the TBili ratio or albumin gradient is used. Furthermore, by measuring serum levels in addition to PF levels, the possibility that sL-selectin PF levels are simply a reflection of serum levels is excluded.

The analysis of pleural effusions has been well defined. This was originally defined by Light et al1 using TP ratio, LDH ratio, and absolute LDH value, and has been confirmed by numerous other studies.5 These criteria have been expanded with the use of albumin gradient, cholesterol ratio, and TBili ratio. However, none of the criteria are absolute, and the parameters only offer a probability about the etiology of the effusion. Most recently, a meta-analysis by Heffner et al5 helped to better define the best cutoff values using receiver operating characteristic curves. For the criteria of Light et al,1 they were defined as follows: an LDH ratio of > 0.6 is 88% sensitive and 81.8% specific, TP ratio > 0.5 is 89.5% sensitive and 90.9% specific, and LDH greater than two thirds of the normal value is 91.4% sensitive and 85.0% specific. For the other criteria, a cholesterol ratio of > 0.3 is 92% sensitive and 81.4% specific, an albumin gradient < 1.2 is 86.8% sensitive and 91.8% specific, and a TBili ratio of > 0.6 is 84.3% sensitive and 61.1% specific.5

The most important information to the clinician is the ability to accurately diagnose a pleural effusion. As a measure of inflammation, sL-selectin should be a more sensitive and specific indicator of exudative effusions. While the sensitivity and specificity of sL-selectin in this study approach the established criteria, neither the PF value, the PF to serum ratio or combination are a better diagnostic indicator. There may be several reasons for these findings. First there is no established "gold standard" with which to compare the sL-selectin values. We used the clinical diagnosis as the standard and found large discrepancies in comparisons to laboratory criteria. While clinicians do not have the ability to review all data retrospectively, we were able to extensively review charts and follow chest radiograph findings. The criteria of Light et al1 tended to overdiagnose transudates as exudates, especially in those patients receiving diuretics. It cannot be determined clinically which chronic transudative effusions will become exudates with diuretic use. While the cholesterol ratio had an equal percentage (83.0%) of correlation as Light et al1 criteria (83.5%) with the clinical diagnosis, TBili showed less correlation. The albumin gradient only correlated with clinical diagnosis just over 50% of the time. This made any analysis of sL-selectin levels insignificant. The reason for this factor is unclear, but this may be related to the ability of our laboratory to accurately identify low albumin levels and consequently overestimate the number of transudates.

The chronicity of the pleural effusion may also play a definite role in sL-selectin level measurement. Acute inflammatory processes such as trauma have shown an initial increase in sL-selectin followed by a gradual decrease over time.11 Furthermore, sL-selectin levels in the CSF show an increase with the onset of meningeal leukemia.16 Thus, the onset of an effusion and the timing of the thoracentesis may make a significant difference in the sL-selectin levels. Exudates may actually have a low sL-selectin level if there is little or no active inflammation in the pleural space. Few of our patients had transudates caused by inflammatory or vascular disorders, and these situations may also limit the applicability of sL-selectin levels.

This study investigated the role of sL-selectin in the analysis of pleural effusion to determine if the measurement of this inflammatory marker improves clinical diagnostic ability. Our data show that sL-selectin levels differentiate transudates and exudates nearly as well as established criteria. The specificity of sL-selectin is most useful when the PF to serum ratio is measured. sL-selectin measurements may be an adjunct to current PF analysis methods. More research is needed to investigate whether other inflammatory markers can further improve the diagnostic accuracy of pleural effusions.


   Footnotes
 
Abbreviations: CSF = cerebrospinal fluid; LDH = lactate dehydrogenase; L-selectin = leukocyte selectin; PF = pleural fluid; sL-selectin = soluble leukocyte selectin; TBili = total bilirubin; TP = total protein

The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the opinion of the Department of the Army or the Department of Defense.

Received for publication August 15, 2000. Accepted for publication February 16, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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