Pleural SC5b-9 in Differential Diagnosis of Tuberculous, Malignant, and Other Effusions

doi:10.1378/chest.102.4.1060

Chest

Volume 102, Issue 4, October 1992, Pages 1060-1064

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A monoclonal antibody against soluble phase-terminal complement complex (SC5b-9) was used to try to differentiate pleural effusions of tuberculous vs malignant and other origin. Effusions of tuberculous origin showed a significantly higher SC5b-9 level than did plasma, suggesting activation of complement in the pleural space. All 26 patients with tuberculous effusions showed SC5b-9 levels in pleural fluid exceeding 2.0 mg/L, while 20 with malignant effusions had levels less than 2.0 mg/L. However, rheumatoid, some parapneumonic, and treated malignant effusions showed SC5b-9 levels above 2.0 mg/L. Considering a value exceeding 2.0 mg/L, the specificity and sensitivity of the SC5b-9 estimation in tuberculosis were 0.74 and 1.0, respectively. The mean values for C4d and Bb fragments of complement were significantly (p<0.05) higher in the tuberculous than in the malignant effusions. However, the values for Bb in 16 (62 percent) of the 26 patients with tuberculous or malignant effusions were in the same range. The activity of adenosine deaminase (ADA) was higher in the tuberculous than in the malignant effusions. While 1$ of 26 patients with tuberculous effusions showed an ADA value exceeding 50 mU/ml, the estimated cutoff point (sensitivity = 0.69), 35 of the 36 nontuberculous effusions showed a true negative value (specificity = 0.97). A correlation between ADA and SC5b-9 values was observed in pleural effusions. These observations suggest that the estimation of SC5b-9 in pleural fluid presents a new approach to differentiating tuberculous vs malignant effusions.

Section snippets

Patient Selection

A total of 64 patients with pleural effusions of tuberculous, malignant, parapneumonic, and immunologic origin were seen at four hospitals over a 12- month period: the Kyushu University, the Haradoi, the Sanshinkai-Hara, and the Shojuen Hospital. There were 34 men and 30 women aged 19 to 85 years (mean age, 60 years). Following their complete clinical and laboratory assessment, the patients were divided into five groups: (1) tuberculous (26 patients); (2) malignant untreated (“simple”

Comparison of Levels of SCSb-9 in Plasma and Pleural Fluid

All pleural effusions in the 64 patients examined were of an exudative nature according to one of three criteria: a ratio of pleural fluid/blood protein greater than 0.5; a ratio of pleural fluid/serum LDH greater than 0.6; more than 200 IU of LDH present in the pleural fluid.¹ When the amount of SC5b-9 in pleural fluid and in plasma was estimated in a patient with an effusion of tuberculous or malignant cause, the level of SC5b-9 was consistently higher in the pleural fluid than in plasma (Fig

DISCUSSION

Estimation of SC5b-9 in the plasma and the pleural fluid of patients with pleurisy of tuberculous or malignant origin showed a consistently higher concentration in the latter than in the former. This observation suggests that SC5b-9 in pleural fluid is generated by the activation of complement in the pleural space, not leaked from the peripheral blood. This appears to be compatible with the physicochemical characteristics of SC5b-9, a large molecular complex (> one million dalton).¹⁰

Patients

ACKNOWLEDGMENT

We thank Dr. T. Fujiki, Dr. M. Miyoshi, and Dr. J. Oomagari for providing specimens of pleural effusions.

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Tuberculous pleural effusion
2014, Archivos de Bronconeumologia
Citation Excerpt :
The quality and cost of these results do not justify routine determination in daily clinical practice.82 Determination of other biomarkers in PF for the diagnosis of TBPE had a lower yield less than that of ADA and IFN-γ (see summary in Table 1).83–94 Although differential cell count in the first 2 weeks can reveal a predominantly polymorphonuclear cell population,95 the predominant population is normally leukocytes (>50%).34
Tuberculous pleural effusion (TBPE) is the most common form of extrapulmonary tuberculosis (TB) in Spain, and is one of the most frequent causes of pleural effusion. Although the incidence has steadily declined (4.8 cases/100 000 population in 2009), the percentage of TBPE remains steady with respect to the total number of TB cases (14.3%–19.3%). Almost two thirds are men, more than 60% are aged between 15 and 44 years, and it is more common in patients with human immunodeficiency virus. The pathogenesis is usually a delayed hypersensitivity reaction. Symptoms vary depending on the population (more acute in young people and more prolonged in the elderly). The effusion is almost invariably a unilateral exudate (according to Light's criteria), more often on the right side, and the tuberculin test is negative in one third of cases.
There are limitations in making a definitive diagnosis, so various pleural fluid biomarkers have been used for this. The combination of adenosine deaminase and lymphocyte percentage may be useful in this respect. Treatment is the same as for any TB. The addition of corticosteroids is not advisable, and chest drainage could help to improve symptoms more rapidly in large effusions.
El derrame pleural tuberculoso (DPTB) es la causa más frecuente de tuberculosis (TB) extrapulmonar en nuestro país y uno de los motivos más habituales de derrame pleural. Si bien la incidencia disminuye progresivamente (4,8 casos/100.000 habitantes en el año 2009), el porcentaje de DPTB se mantiene estable con respecto al número de casos totales de TB (14,3-19,3%). Casi las dos terceras partes son hombres, más del 60% tienen edades entre los 15-44 años y es más frecuente en los pacientes infectados por el virus de la inmunodeficiencia humana. La patogenia suele ser una reacción de hipersensibilidad retardada. La clínica varía dependiendo de la población (más aguda en los jóvenes y más prolongada en los ancianos). El derrame es casi invariablemente un exudado unilateral (según los criterios de Light), más frecuentemente del lado derecho, y la prueba de la tuberculina es negativa en la tercera parte de los casos.
Los diagnósticos de certeza tienen limitaciones, por lo que para ello se han utilizado diversos biomarcadores en el líquido pleural. La asociación de la adenosina desaminasa y del porcentaje de linfocitos puede ser útil para el diagnóstico. El tratamiento es el de cualquier TB. No parece recomendable añadir corticoides y el drenaje torácico podría contribuir, en los grandes derrames, a una mejoría más rápida de los síntomas.
Soluble Fas ligand is another good diagnostic marker for tuberculous pleurisy
2010, Diagnostic Microbiology and Infectious Disease
Citation Excerpt :
Soluble FasL is more sensitive than tests based on Mycobacterium tuberculosis (MTB) nucleic acid amplification (Pai et al., 2004). Except for ADA and IFN-γ, the diagnostic accuracy of sFasL seems generally better than most recently proposed diagnostic tools (Celik et al., 2006; Chierakul et al., 2001; Cok et al., 2007; Dheda et al., 2009; Hara et al., 1992; Hooper et al., 2009; Ipcioglu et al., 2008). However, like most tests based on nonspecific inflammatory or immune response markers, sFasL could not surpass the specificities of traditional or MTB nucleic acid amplification-based tests.
Soluble Fas ligand (sFasL) is abundant in effusions of tuberculous (TB) pleurisy; however, its diagnostic value has not been scrutinized. We collected pleural effusions from 79 patients, including 23 with TB pleurisy and 56 without TB, and measured sFasL, adenosine deaminase (ADA), and interferon-γ (IFN-γ) concentrations of each specimen. The median of the sFasL concentration of the TB group was 57.3 pg/mL, which was significantly higher than that of the non-TB group (27.4 pg/mL) (P < 0.001). When cutoff value was 39.85 pg/mL, the sensitivity and specificity of sFasL were 95.7% and 80.4%, respectively. The area under the receiver operating characteristic curve for sFasL was not significantly different from those of ADA and IFN-γ. Soluble FasL concentrations of TB patients were significantly higher than those of parapneumonic effusion subgroup (P = 0.039). In conclusion, pleural effusion sFasL is another good diagnostic marker for TB pleurisy.
The use of non-routine pleural fluid analysis in the diagnosis of pleural effusion
2010, Respiratory Medicine
Citation Excerpt :
The measurement of complement activation products has also been analysed. Research on SC5b-9, a product formed by the binding of S protein to C5b-9 complexes at the C5b-7 stage of assembly in consequence of complement activation, has found that this product is elevated in the pleural fluid of patients with tuberculous effusions unlike malignant and transudative effusions.54,56 In particular Hara et al. demonstrated that all tuberculous effusions in their study had SC5b-9 levels >2 mg/L, with malignant effusions <2 mg/L.54 Using 2 mg/L as the cut-off they reported a sensitivity of 100% with a specificity of 79% (also raised in rheumatoid, parapneumonic and some treated malignant effusions) and found a positive correlation between pleural fluid ADA and SC5b-9.
The investigation of a pleural effusion is, in general, a very straight forward process with the combination of clinical history, examination, radiology and pleural fluid analysis leading to diagnosis in most cases. While most fluid samples are sent for routine analysis including protein, LDH, glucose, cytology and microbiology, there are a number of more unusual fluid analyses available which in some cases directly lead to, and in others are suggestive of the diagnosis. Moreover, other fluid markers are constantly being evaluated as a diagnostic tool. In this review, we describe these non-routine pleural fluid analyses in detail. English language publications in MEDLINE and references from relevant articles from January 1 1990 to August 1 2009 were reviewed. Keywords searched in combination were pleural fluid, effusion, analysis, transudate, exudate and diagnosis.
Diagnostic value of complement components in pleural fluid: Report of 135 cases
2008, Respiratory Medicine
Citation Excerpt :
Two found that levels of SC5b–9, a product of C3 activation, are elevated in tuberculous pleural effusions as opposed to malignant pleural effusions or transudates, and that SC5b–9 levels are highest in patients with rheumatoid diseases.8,16 Specifically, Hara et al.8 reported that all patients with tuberculous effusions had SC5b–9 levels above 2 mg/L, whereas those with malignant effusions had levels below 2 mg/L. Using this value as the cutoff, they found that the specificity of the estimated SC5b–9 level for tuberculosis-related effusion was 74%, and the sensitivity, 100%. In addition, there was a correlation between adenosine deaminase (ADA) and SC5b–9 values in the pleural effusions.
We prospectively assessed the diagnostic value of pleural fluid complement levels (total, C3, C4) in 135 patients with pleural effusion of five main etiologies, using novel markers. Complement levels correlated with pleural levels of protein, amylase, and transuded fluids. On univariate analysis, CHF-related pleural effusions were associated with significantly lower C4 levels than postsurgery or parapneumonic effusions. On multivariate analysis, pleural fluid C4 level was a significant predictor of CHF. Although the specificity, positive predictive value, and accuracy of the parameters were low in all diagnostic groups, their negative predictive value as well as the AUC ROC was high for CHF and post-LTX. We conclude that pleural fluid C4 levels can differentiate CHF-related pleural effusion from other etiologies and that normal level of C3 or C4 rule out CHF or LTX as causes of pleural effusion. Complement should be included in the assessment of pleural effusion when traditional diagnostic methods fail.
Tuberculous pleural effusions
2003, European Journal of Internal Medicine
Tuberculosis is the most frequent cause of death due to infectious diseases. In Europe, it is one of the most frequent types of pleural effusions in young patients. Tuberculosis is caused by the rupture of a pulmonary subpleural caseous focus, which releases mycobacterium into the pleural cavity, thereby triggering an immune response involving mainly macrophages, CD4+ T lymphocytes, and the cytokines released by these cells (especially interleukin 1, interleukin 2, and γ-interferon). In recent years, classical microbiological and histological methods of diagnosis have been joined by biochemical analyses of pleural fluid, which are faster and can be more sensitive. In particular, tuberculous effusions have high adenosine deaminase (ADA) activity, apparently due to high levels of the ADA isoenzyme ADA2, which is only found in monocytes and macrophages (although certain data suggest the possible involvement of activated T cells, too). It has been recommended that treatment for tuberculosis be initiated if analysis of pleural fluid shows high ADA activity, a lymphocyte/neutrophil ratio greater than 0.75, and no malignant cells. Another highly efficient marker is γ-interferon, which is released by activated CD4+ T cells, but its high price is an obstacle to its routine determination in clinical practice. Identification of mycobacterial DNA by means of the polymerase chain reaction (PCR) is less efficient, apparently because its sensitivity depends heavily on mycobacterium concentration. No other biochemical parameters currently appear to be of marked relevance for the diagnosis of tuberculous pleural effusion (TPE). TPE responds well to the standard treatment for tuberculosis. However, 50% of TPE patients have a thickened pleura as a result of the accumulation of fluid, and in 16% the quantity of effusion increases during treatment, even if corticosteroids are administered. It therefore seems reasonable for treatment with antituberculous drugs to be preceded by therapeutic thoracocentesis to remove as much fluid as possible.
Sialyl Stage-Specific Embryonic Antigen-1: A Useful Marker for Differentiating the Etiology of Pleural Effusion
1998, Chest
To assess the usefulness of sialyl stage-specific embryonic antigen-1 (SSEA-1) levels in differentiating the etiology of pleural effusion (PE).
A solid-phase immunoradiometric sandwich assay with an FH6 monoclonal antibody was used to measure sialyl SSEA-1 levels in PEs of 132 patients with various diseases. Paired serum sialyl SSEA-1 levels were measured simultaneously in 47 patients with various subtypes of lung cancer
The pleural sialyl SSEA-1 levels were significantly higher in patients who had adenocarcinoma of the lung with positive cytology than in all the other patients, including those having malignancies other than adenocarcinoma of the lung, adenocarcinoma of the lung with cytology-negative PE, and benign diseases. There were no significant differences among sialyl SSEA-1 levels in the pleural fluid containing no adenocarcinoma cells. Using the cutoff value of 265 U/mL, the sensitivity was 64% (25/39) and the specificity was 95% (88/93) for the pleural sialyl SSEA-1 level to differentiate adenocarcinoma from other effusions.
With high specificity and modest sensitivity, the pleural sialyl SSEA-1 level is a useful biochemical marker for differentiating the etiology of PEs caused by adenocarcinoma from other diseases.

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: Supported in part by a grant from the Ministry of Education, Science, and Culture in Japan.

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Chest

Pleural SC5b-9 in Differential Diagnosis of Tuberculous, Malignant, and Other Effusions

Section snippets

Patient Selection

Comparison of Levels of SCSb-9 in Plasma and Pleural Fluid

DISCUSSION

ACKNOWLEDGMENT

Diagnostic thoracentesis and pleural biopsy in pleural effusions.

Ann Intern Med

Adenosine deaminase activity in pleural effusions: an aid to differential diagnosis.

BMJ

Serum and pleural adenosine deaminase: correlation with lymphocytic populations.

Chest

Adenosine deaminase in pleural fluids: test for diagnosis of tuberculous pleural effusion.

Chest

Pleural fluid adenosine deaminase in rheumatoid arthritis and systemic lupus erythematosus.

Chest

Carcinomatous and tuberculous pleural effusions: comparison of tumor markers.

Chest