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Ann Thorac Surg 2009;87:251-254. doi:10.1016/j.athoracsur.2008.09.047
© 2009 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Soluble Triggering Receptor Expressed on Myeloid Cells-1 for Diagnosing Empyema

Jihad Bishara, MDa,*, Elad Goldberg, MDa, Shai Ashkenazi, MDd,e, Yael Yuhas, PhDd, Zmira Samra, PhDb, Milton Saute, MDc, Hila Shaked, MDa

a Infectious Diseases Unit, Tel Aviv University, Petah-Tiqwa, Israel
b Laboratory of Clinical Microbiology, Tel Aviv University, Petah-Tiqwa, Israel
c Department of Thoracic Surgery, Rabin Medical Center, Beilinson Hospital, Sackler Faculty of Medicine, Tel Aviv University, Petah-Tiqwa, Israel
d Laboratory of Infectious Diseases, Felsenstein Medical Research Center, Petah-Tiqwa, Israel
e Infectious Diseases Unit, Schneider Children's Medical Center of Israel, Petah-Tiqwa, Israel

Accepted for publication September 19, 2008.

* Address correspondence to Dr Bishara, Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tiqwa, 49100, Israel (Email: bishara{at}netvision.net.il).


   Abstract
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 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Studies have shown that soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is upregulated by microbial products in the bronchoalveolar lavage fluid, and cerebrospinal fluid of patients with pneumonia and bacterial meningitis, respectively. Our goal was to evaluate whether sTREM-1 in pleural fluid can distinguish pleural empyema from postthoracotomy-related pleural effusion and effusions of other etiologies.

Methods: Patients who presented with pleural effusion were identified through laboratory records. In addition to routine biochemical markers, differential white blood cells, cytology, Gram stain, and pleural fluid culture, pleural fluid sTREM-1 was measured by enzyme-linked immunosorbent assay using a commercial kit (R&D Systems, Minneapolis, MN).

Results: Eighty-nine patients were included in the study: 17 with empyema, 7 simple parapneumonic effusion, 18 transudate, 12 postthoracotomy pleural effusion, 22 malignancy, 1 connective tissue disease, and 12 with undetermined effusion. Mean levels of sTREM-1 were significantly higher in empyema than in postthoracotomy pleural effusion (687 ± 479 pg/mL vs 34 ± 81 pg/mL, p < 0.0001, respectively) and in effusions of other etiologies (15 ± 54 pg/mL, p < 0.0001). A cutoff value of 114 pg/mL for pleural sTREM-1achieved a sensitivity of 94% and a specificity of 93% in differentiating empyema from pleural effusions of other etiologies. The area under the receiver operating characteristic curve for pleural effusion sTREM-1 as a predictor for empyema was 0.966.

Conclusions: Our findings suggest that sTREM-1 in the pleural fluid can potentially assist clinicians in the differentiation of bacterial from nonbacterial pleural effusion, particularly in postthoracotomy pleural effusion.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Exudative pleural effusion is a common clinical condition found in hospitalized patients and might be secondary to a wide variety of infectious and noninfectious processes. Among the noninfectious causes are malignancy, lymphatic abnormalities, and various inflammatory conditions, such as FMF (familial Mediterranean fever), collagen disease, and postthoracotomy-related pleuritis.

In patients undergoing thoracotomy for coronary artery bypass grafts (CABG), the prevalence of pleural effusions during the immediate postsurgery period is high. The reported prevalence rate of pleural effusion ranges from 43% to 91% [1–3]. Most effusions are small, unilateral, asymptomatic, and resolve within a few weeks. About 10% of the patients [4, 5] will have larger effusions (those occupying more than 25% of the hemithorax) which may be manifestations of the postcardiac injury syndrome [6]. These effusions have been seen after myocardial infarction, cardiac surgery, chest trauma, pacemaker implantation, and angioplasty. These patients, similar to those with empyema, present with fever, cough, pleuritic chest pain, and dyspnea. Leukocytosis and an elevated erythrocyte sedimentation rate are common findings.

Pleural fluid parameters are compatible with exudate. Current biochemical parameters used in distinguishing empyema from postthoracotomy pleural effusion prior to outcomes of pleural fluid cultures are nonspecific. A rapid microbiologic tool is the Gram stain; however, its sensitivity is low, approximately 50%.

Triggering receptor expressed on myeloid cells (TREM-1), a 30-kDa immunoglobulin superfamily member is a recently discovered cell-surface molecule identified on both human and murine neutrophils and mature monocytes. Inflammatory responses to microbial products are amplified by a pathway mediated by TREM-1.

Studies in mice models have shown that TREM-1 may be involved in the augmentation of the inflammatory response to endotoxins and that its upregulation during sepsis is accompanied by an increased release of its soluble form [7]. Infection induces the release of a soluble form (sTREM-1) of this receptor, which can be measured in biologic fluid and may be useful as a diagnostic tool. The sTREM-1 was found in the bronchoalveolar lavage fluid of patients on mechanical ventilation, being a good indicator of infectious ventilator-associated bacterial pneumonia [8], as well as for bronchoalveolar lavage culture-positive aspiration pneumonia [9]. In a recent study [10], we found that sTREM-1 was upregulated in the cerebrospinal fluid of patients with bacterial meningitis with high specificity.

Two recent studies [11, 12] showed that the sTREM-1 levels were significantly higher in infectious pleural effusion compared with pleural effusion from other etiologies. However, in those studies, sTREM-1 in empyema versus postthoracotomy pleural effusions was not evaluated. Therefore, we endeavored to evaluate whether sTREM-1 in pleural effusion can distinguish pleural empyema from pleural effusions of other etiologies in general and from postthoracotomy-related pleural effusions, in particular.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
Patients
From November 2006 to December 2007, pleural effusion samples were obtained from consecutive patients who had undergone thoracocentesis at the Rabin Medical Center, Beilinson Hospital, and the Schneider Children's Medical Center. Patient demographics, underlying conditions, previous drug therapy, laboratory findings, and outcome were collected. The Institutional Review Board (IRB) approved the study and the IRB waived the need for patient consent after speaking to the chairperson.

Definitions
Empyema was defined as grossly purulent pleural effusion and (or) a pleural fluid associated with a pH less than7.2, a glucose level less than 40 mg/dl, and a L-lactate dehydrogenase (LDH) level greater than1,000 IU/L. Gram stain and culture results may be positive [13].

Postthoracotomy pleural effusion
Defined as pleural effusions after CABG, lung transplantation, chest trauma, or other gross medical manipulation in the cardiothoracic area, with no evidence of infection.

Transudative pleural effusion
Defined as a fluid associated with the ratio of LDH and protein in pleural fluid to plasma less than 0.6 and 0.5, respectively, and the level of LDH less than two thirds of the normal upper limit for serum.

Malignant pleural effusion
Defined as malignant cells detected on the cytology of the pleural effusion or histologic diagnosis of the neoplasm within the pleural space.

Paramalignant effusion
When a histologic diagnosis of a malignant tumor in another organ was established, the effusion did not meet the malignant criteria, and no other cause of pleural effusion was found [11].

Simple parapneumonic effusion
Defined as a fluid having a turbid appearance, with a pH greater than 7.3, a glucose level greater than 60 mg/dL, a LDH level less than 700 IU/L, and negative microbiologic test results, in a patient with a new lung infiltrate in the chest X-ray.

Collagen vascular disease-related pleural effusion
Defined as pleural effusion in a patient suffering from active collagen vascular disease with no other cause of pleural effusion.

Undetermined etiology
Exudative effusions of unknown etiology and indisputably do not fit the definition of empyema or other categories.

Pleural Effusion Laboratory Examinations
Pleural effusion samples were analyzed for the following biochemical markers: pleural fluid protein, LDH, glucose, and pH. In addition, differential cell count, cytology, and microbiologic studies including Gram stain and pleural fluid culture were performed.

For sTREM-1 analysis, 0.5 TO 5 mL of pleural effusion was collected and stored at –70°C until assayed. The sTREM-1 levels were measured by enzyme-linked immunosorbent assay (ELISA) using a commercial kit (DuoSet ELISA kit: human TREM-1 catalog no .DY 1278; R&D Systems, Minneapolis, MN) according to the manufacturer's instructions .The sTREM-1 levels were expressed as pg/mL. The decision to perform a thoracocentesis and pleural fluid analysis was at the discretion of the treating practitioner as part of routine patient management. These physicians were noninvolved in the study.

Statistical Analysis
Categoric variables were compared by the Fisher exact test or {chi}2 test. Continuous variables were compared using the Student t test or Mann-Whitney U test, as appropriate. To determine the predictive capability of the model, we calculated a receiver operating characteristic (ROC) curve and calculated the area under the curve (AUC) as a measure of discriminative ability. The SPSS version 15 software program (SPSS Inc, Chicago, IL) was used for data handling and analysis.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Eighty-nine patient-unique samples of pleural effusions were included in the study. Eighteen samples were classified as transudate, 17 as empyema, 15 as paramalignant, 12 as postthoracotomy, 7 as malignant, 7 as simple parapneumonic, and 1as collagen vascular disease-related pleural effusion. Twelve samples were defined as undetermined etiology. The group of postthoracotomy pleural effusion included 7 patients after CABG or valve replacement, 4 after lung transplantation, and one postchest trauma.

In the empyema group eight patients were children. Empyema was a complication of community-acquired pneumonia in all patients. Among the elderly patients with empyema, 3 had lung cancers: one had an infected pleural effusion, one a bronchopleural fistula, and the third a postlobectomy complication. Two patients had nursing home-acquired pneumonia; one had hospital-acquired, and one community-acquired pneumonia. Two patients had empyema of unknown origin.

Pathogens isolated from patients with empyema included Streptococcus pneumoniae (5 patients), group-A Streptococcus, Pseudomonas sp. (two patients each), Peptostreptococcus and Bacteroides sp. in one patient (polymicrobial infection), and E. coli and Streptococcus intermedius in another patient. Four patients had negative cultures and in two other patients cultures were not taken.

Comparison of patients with empyema and postthoracotomy-related pleural effusion is shown in Table 1. In the empyema group, patients were significantly younger with a higher proportion of males. Their pleural fluid LDH and leukocyte counts were significantly higher than those in the postthoracotomy group, while, as expected, glucose levels and pH were significantly lower in the empyema group. There was no difference in the pleural fluid total protein level between the two groups (Table 1).


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  		Table 1 Comparisons Between Empyema and Postthoracotomy Pleural Effusion Groups
 
Elevated levels of sTREM-1 in the pleural effusion were noted in 16 of 17 patients with empyema (94%, sTREM-1 mean value 687 pg/mL; range 0 to 1,883) compared with none (0%, sTREM-1 mean value 0 pg/mL) in the transudate group, 3 of 22 in the malignant and paramalignant group (13%, sTREM-1 mean value 14 pg/mL; range, 0 to 129), and 1 of 7 in the simple parapneumonic group (14%, sTREM-1 mean value 43 pg/mL; range, 0 to 305). Levels of sTREM-1 in the lupus patient were not elevated, but were elevated in 1 of 12 patients with undetermined effusion (8%, sTREM-1 mean value 8 pg/mL; range, 0 to 107). In the postthoracotomy group, sTREM-1 levels were elevated in only 2 of 12 patients (16%, sTREM-1 mean value 34 pg/mL; range, 0 to 246) (Table 1). True and false positive results were 94% (16 of 17) and 9% (7 of 72), while true and false negative results were 90% (65 of 72) and 6% (1 of 17), respectively. Sensitivity and specificity of the s-TREM-1 assay in predicting pleural empyema were 94% and 90%, respectively; the positive predictive value was 70%, and negative predictive value was 98% with overall accuracy of 91%. When s-TREM-1 levels were used to differentiate empyema (17 samples) from all other pleural effusion of other etiologies (82 samples), ROC analysis revealed an AUC of 0.966 (95% CI: 1.0 to 0.897) (Fig 1). Using a cutoff value of 114 pg/mL, the pleural sTREM-1 achieved a sensitivity of 94% and a specificity of 93% in differentiating empyema from pleural effusions of other etiologies. All but two of the empyema group patients required chest tube drainage and none required open drainage or thoracotomy. Two patients were treated with intrapleural fibrinolytics.


Figure 1
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  		Fig 1. Receiver-operating characteristic curve for pleural effusion levels of soluble receptor expressed on myeloid cells-1in differentiating empyema from pleural effusions of other etiologies. Sensitivity 94%, specificity 90%; area under the curve = 0.966 (95% confidence interval: 1.0 to 0.897).

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
The present study demonstrates that sTREM-1 is measurable in the pleural fluid and can also serve as an additional marker for distinguishing pleural empyema from pleural fluids of other etiologies, including exudative postthoracotomy-related pleural effusion. The assay has a high sensitivity and a good discriminatory ability, with an excellent ROC area under the curve result of 0.966.

Determining the etiology of pleural effusions is complicated, requiring thoracocentesis and several analyses of the pleural fluid sample. Definite diagnosing pleural effusion may be difficult because biochemical parameters used are often nonspecific. Pleural fluid cultures are specific, but results may take days. A rapid microbiologic tool is the Gram stain, but its sensitivity is low, approximately 50%. A greater difficulty exists in distinguishing pleural empyema from postthoracotomy-related pleural effusion. In both cases, patients usually present with fever, chest pain, dyspnea, elevated erythrocyte sedimentation rate, and characteristic exudative pleural fluid parameters. Because management of these patients varies greatly, rapid and accurate differentiation between these two syndromes is needed.

Two recent studies have shown that soluble sTREM-1 levels were significantly higher in infectious pleural effusions compared with pleural effusion of other etiologies. Chan and colleagues11] evaluated the sTREM-1 in 67 patients with pleural effusions due to transudate, malignancy, tuberculous pleuritis, parapneumonic effusion, and empyema, finding that sTREM-1 was highest in effusions of infectious etiology (parapneumonic effusion and empyema) and lowest in noninfectious effusions (transudate and malignancy). At a cutoff value of 114 pg/mL, s-TREM-1 yielded a sensitivity of 87.5% and a specificity of 89.7% in differentiating noninfectious effusion from tuberculous pleuritis. At a cutoff value of 374 pg/mL, sTREM-1 yielded a sensitivity of 93.8% and a specificity of 90.9 in differentiating tuberculous pleuritis from bacterial pleural effusion [11]. In our study, using similar cutoff values yielded even better results for differentiating empyema from pleural effusions of other etiologies, with a sensitivity and specificity of 94% and 93%, respectively.

Liu and colleagues [12] reported on significantly higher concentrations of sTREM-1 in infectious and neoplastic pleural effusions than in transudates. Among infectious effusions, the sTREM-1 levels were significantly higher in parapneumonic than in tuberculous effusions.

In another recent study, Ho and colleagues [14] measured sTREM-1 levels in 65 pleural effusions of various etiologies. The TREM-1 expression was correlated with patient survival. Increased TREM-1 positive tumor-associated macrophages in tumor tissue of non-small cell cancer patients (NSCLC) were associated with significant reduced disease-free and overall survival. Multivariate analysis indicated that TREM-1 was an independent predictor of patient survival (hazard ratio = 2.72, 95% CI = 1.33 to 5.57, p = 0.006). The authors concluded that cancer cells can directly upregulate TREM-1 expression in patients' macrophages. The TREM-1 expression in tumor-associated macrophages is associated with cancer recurrence and poor survival of NSCLC patients [14].

None of the above studies evaluated the comparison of sTREM-1 levels in pleural fluid of empyema with postthoracotomy-related pleural effusion. In our study, sTREM-1 was elevated in only 13% (3 of 22 samples) of malignant pleural fluid samples. We were unable to draw conclusions regarding the prognostic significance of sTREM-1 levels in the malignant pleural fluid due to small sample size. Whether the performance characteristics of sTREM-1 in malignant pleural fluid would be decreased comparing postthoracotomy fluid collections after lung cancer surgery versus after CABG remains unknown. Further larger scale prospective studies, including patients with malignant and postthoracotomy pleural effusions after lung cancer surgery, are needed to confirm the value of sTREM-1 measurement in the diagnosis of empyema, postthoracotomy, and malignant pleural effusions and, thereby, assessing its prognostic significance.

A major limitation of our study was the relatively small sample size in the empyema and postthoracotomy groups. However, the differences found were significant and the results provide further evidence to promote additional large scale studies. In addition, ours and others findings cannot be generalizable until proper validations of the cutoff point identified in the development test sets are performed. In conclusion, to the best of our knowledge, the present study is the first study demonstrating the ability of sTREM-1 assay to differentiate empyema from postthoracotomy-related pleural effusion.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

  1. Peng MJ, Vargas FS, Cukier A, Terra-Filho M, Teixeira LR, Light RW. Postoperative pleural changes after coronary revascularization: comparison between saphenous vein and internal mammary artery grafting Chest 1992;101:327-330.[Abstract/Free Full Text]
  2. Vargas FS, Cukier A, Hueb W, Teixeira LR, Light RW. Relationship between pleural effusion and pericardial involvement after myocardial revascularization Chest 1994;105:1748-1752.[Abstract/Free Full Text]
  3. Landymore RW, Howell F. Pulmonary complications following myocardial revascularization with the internal mammary artery graft Eur J Cardiothorac Surg 1990;4:156-162.[Abstract/Free Full Text]
  4. Light RW, Rogers JT, Moyers JP, et al. Prevalence and clinical course of pleural effusions at 30 days after coronary artery and cardiac surgery Am J Respir Crit Care Med 2002;166(12 Pt 1):1567-1571.[Abstract/Free Full Text]
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  14. Ho CC, Liao WY, Wang CY, et al. TREM-1 Expression in tumor-associated macrophages and clinical outcome in lung cancer Am J Respir Crit Care Med 2008;77:763-770.



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