Complement Components and Their Activation Products in Pleural Fluid

doi:10.1378/chest.114.3.723

Chest

Volume 114, Issue 3, September 1998, Pages 723-730

https://doi.org/10.1378/chest.114.3.723 Get rights and content

Study objectives: The aim of this study was to determine the role of complement components in pleural effusion measured with novel markers of complement activation, to assess which pathway of activation is predominant in different diseases, and to find out whether the analysis of complement components and their activation products could help in diagnostic procedure differentiating the etiologies of pleural effusion.

Patients: The study population consisted of 71 patients who had pleural effusion secondary to tuberculosis (n=23), rheumatic disease (n=10), or malignancy (n=38).

Measurements: Complement components and their activation products, including the soluble terminal complex SC5b-9, were measured in plasma and pleural fluid.

Results: In all patients with rheumatic pleurisy, pleural fluid SC5b-9 was higher than 2 AU/mL and in all patients with malignant pleural fluid it was lower than 2 AU/mL. The mean level of SC5b-9 in rheumatic pleural effusion was also significantly higher than in tuberculosis. In addition, the concentrations of pleural fluid C3 and C4 were significantly lower and the ratio C4d/C4 was significantly higher in rheumatic compared with tuberculous or malignant pleurisy. In plasma, both SC5b-9 and C1s-C1r-ClINH-complexes were significantly higher in rheumatic subjects than in other patients. In stepwise multinominal logistic regression analyses, the most significant predictors for rheumatic pleural fluid were high pleural fluid SC5b-9 and low C4.

Conclusions: These observations indicate that the complement cascade is activated through both the classic and the alternative pathways in rheumatic pleurisy. Determinations of SC5b-9 and C4d/C4 in pleural fluid were the best variables differentiating rheumatic, tuberculous, and malignant effusions.

(CHEST 1998; 114:723–730)

Abbreviations: Bb=activation product of factor B; BSA=bovine serum albumin; C1s-C1r-C1INH = soluble C1/C1-esterase inhibitor complex; C3=complement component C3; C3d=activation product of C3; C4=complement component C4; C4d=activation product of C4; EIA=enzyme immunoassay; FB=factor B; PBS = phosphate-buffered saline solution; SC5b-9=soluble terminal complex

Section snippets

Patients

The study population consisted of 71 patients who had pleural effusion secondary to tuberculosis (n=23), rheumatic disease (n=10), or malignancy (n=38), diagnosed at the Department of Pulmonary Diseases of Turku University Hospital during 1990 to 1992. In the group of patients with tuberculosis, there were 16 men and 7 women, and their mean age was 56 years (range, 26 to 88 years); in the group of patients with rheumatic pleurisy, there were 8 men and 2 women, and their mean age was 54 years

RESULTS

The mean concentrations of plasma complement components and their activation products were within the normal range in all disease groups except that the patients with rheumatic pleural effusion had higher values of C4d and C1s-C1r-C1INH (Table 1). In patients with rheumatoid arthritis, the mean concentrations of plasma C1s-C1r-C1INH and SC5b-9 were significantly higher than in patients with tuberculosis or malignancy (p <0.001).

In the pleural fluid, the mean values of complement components C3,

DISCUSSION

In clinical practice, we often face difficulties in differentiating between the several etiologies of pleural effusion. Earlier studies of complement components and their activation products in pleural fluid have shown activation in autoimmune diseases and infections.4, 5, 6,8, 9, 10,²² Higher activation of the alternative pathway (C3, FB) has been observed in tuberculous and other infectious pleural effusions when compared with malignant effusions.⁹,²³ Recently, using novel markers of

CONCLUSION

In all patients with rheumatic pleurisy, pleural fluid SC5b-9 was higher than 2 AU/mL, and in all patients with malignant pleural fluid, it was lower than 2 AU/mL. The mean level of SC5b-9 in rheumatic pleural effusions was also significantly higher than in tuberculous pleurisy, but some patients with tuberculous pleurisy had values of higher than 2 AU/mL. The concentrations of pleural fluid C3 and C4 were significantly lower in patients with rheumatic disease compared with patients with

ACKNOWLEDGMENT

We thank Seija Laanti for skillful technical assistance in performing the complement assays and Hans Helenius for statistical advice.

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C5aR contributes to the weak Th1 profile induced by an outbreak strain of Mycobacterium tuberculosis
2017, Tuberculosis
Citation Excerpt :
Widening the focus of investigation to explore components of immunity that are usually overlooked might open new perspectives to approach the subject. In this regard, little attention has been paid to the contribution of the complement system, even though its activation products are elevated in tuberculous pleural effusions [2,3] and in sera from patients with active pulmonary TB [4]. The complement system, a crucial component of humoral innate immunity, has been recently found to be involved in the regulation of the adaptive immune response through the action of the anaphylatoxins produced as part of the proteolytic cascade of complement activation [5].
C5a anaphylatoxin is a component of the complement system involved in the modulation of T-cell polarization. Herein we investigated whether C5a receptors, C5aR and C5L2, modulate the cytokine profiles induced by Mycobacterium tuberculosis (Mtb). We analyzed the impact of both receptors on T helper cell polarization induced by the multidrug resistant outbreak strain named M, which is a poor IFN-γ inducer compared with the laboratory strain H37Rv. To this aim, we first blocked C5aR or C5L2 of peripheral blood monocytes (Mo) from patients with tuberculosis and healthy donors, then we stimulated the Mo either with H37Rv or the M strain, and finally we analyzed cytokine profiles of Mo/macrophages (MΦ) and CD4⁺ T-cells. We found that: (i) Mtb modulated the expression of both C5a receptors, (ii) C5aR inhibited the expansion of CD4⁺IFN-γ⁺ lymphocytes stimulated by the M strain but not by H37Rv, (iii) both receptors modulated the Mo/MΦ cytokine expression induced by Mtb. We conclude that C5aR, but not C5L2, plays a role in T helper cell polarization induced by Mtb and that this effect is strain- and donor-dependent. We speculate that the epidemiologically successful M strain takes advantage of this C5aR-mediated inhibition of Th1 polarization to survive within the host.
Systemic Diseases and the Pleura
2011, Archivos de Bronconeumologia
La afectación pleural en las enfermedades sistémicas suele ser un reflejo de las lesiones que se producen a otros niveles. A pesar de la baja incidencia de derrame pleural causado por enfermedades sistémicas (alrededor del 1%), las conectivopatías más frecuentes como la artritis reumatoide o el lupus eritematoso sistémico pueden presentarlo. De la misma forma, vasculitis como la granulomatosis de Wegener, el síndrome de Churg-Strauss, enfermedades menos prevalentes como la enfermedad de Still de inicio en el adulto, o la enfermedad adyuvante humana, también pueden tener la pleura afectada. Aunque su incidencia es baja, es importante tenerlas en cuenta a la hora de realizar el diagnóstico diferencial del derrame pleural. En este artículo se revisan las enfermedades sistémicas que cursan con afectación pleural, así como las características del derrame y la evolución del mismo.
Pleural involvement in systemic diseases is usually a sign of lesions occurring at other levels. Despite the low incidence (around 1%) of pleural effusions caused by systemic diseases, more often connective tissue diseases, such as rheumatoid arthritis or systemic lupus erythematosus, may present with this. Similarly, vasculitis, such as Wegener's granulomatosis, Churg-Strauss syndrome, or less prevalent diseases, such as adult onset Still's disease, or human adjuvant disease, can also have pleural involvement. Although their incidence is low, it is important to take them into account when making a differential diagnosis of a pleural effusion. In this article, the systemic diseases that include pleural involvement are reviewed, as well as the characteristics of the effusions and their outcome.
The lung in rheumatoid arthritis
2011, Presse Medicale
Citation Excerpt :
Chyliform effusion may result from rupture of a necrotic subpleural rheumatoid nodule. Whole complement activity and C3 and C4 levels are lower in RA pleural fluid than in non-rheumatoid effusions, however, diagnostic and prognostic accuracy of complement measurements in rheumatoid pleural effusions is of limited clinical value [155,162,165]. On cytological examination, characteristic findings include slender or elongated multinucleated macrophages, round giant multinucleated macrophages, and necrotic background material in the absence of mesothelial cells, although their specificity has not been evaluated in large series of unselected patients [162,166,167].
Rheumatoid arthritis (RA) is a common inflammatory disease, affecting about 1% of the population. Although a major portion of the disease burden including excess mortality is due to its extra-articular manifestations, the prevalence of RA-associated lung disease is increasing. RA can affect the lung parenchyma, airways, and the pleura; and pulmonary complications are directly responsible for 10 to 20% of all mortality. Even though pulmonary infection and drug toxicity are frequent complications of RA, lung disease directly associated with the underlying RA is more common. The prevalence of a particular complication varies based on the characteristics of the population studied, the definition of lung disease used, and the sensitivity of the clinical investigations employed. An overview of lung disease associated with RA is presented here with an emphasis on parenchymal lung disease, pleural effusion, and airway involvement.
The use of non-routine pleural fluid analysis in the diagnosis of pleural effusion
2010, Respiratory Medicine
Citation Excerpt :
Salomaa et al. (1998) found that SC5b-9 levels were >2 AU/L in rheumatoid arthritis related effusion and were <2 AU/L in malignant effusions. Fluid C3 and C4 levels were also significantly lower along with an increased C4d/C4 ratio in the rheumatoid patients when compared with malignant and tuberculous effusions.56 The use of SC5b-9 is hampered by the superior diagnostic accuracy of ADA in tuberculous effusions and the fact that rheumatoid related effusions are extremely rare with serum rheumatoid factor analysis being preferred.56
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 :
In addition, there was a correlation between adenosine deaminase (ADA) and SC5b–9 values in the pleural effusions. In the second study, Salomaa et al.16 found that the SC5b–9 level in the pleural fluid was higher than 2 AU/ml in all their patients with rheumatic disease and lower than 2 AU/ml in all their patients with malignancy. Furthermore, the concentrations of pleural fluid C3 and C4 were significantly lower, and the ratio of C4d/C4 significantly higher, in the patients with rheumatic pleurisy than in those with tuberculous or malignant pleurisy.
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.
Rheumatoid Pleural Effusion
2006, Seminars in Arthritis and Rheumatism
To describe the clinical and laboratory features of rheumatoid pleural effusion (RPE) and the diagnostic and therapeutic approaches to this condition.
The review is based on a MEDLINE (PubMed) search of the English literature from 1964 to 2005, using the keywords “rheumatoid arthritis” (RA), “pulmonary complication”, “pleural effusion”, and “empyema”.
Pleural effusion is common in middle-aged men with RA and positive rheumatoid factor (RF). It has features of an exudate and a high RF titer. Underlying lung pathology is common. Generally RPE is small and resolves spontaneously but symptomatic RPE may require thoracocentesis. Rarely, RPE has features of a sterile empyematous exudate with high lipids and lactate dehydrogenase, and very low glucose and pH levels. This type of effusion eventually leads to fibrothorax and lung restriction. Superimposed infective empyema often complicates RPE. Oral, parenteral, and intrapleural corticosteroids, pleurodesis and decortication, have been used for the treatment of sterile RPE. Infected empyema is treated with drainage and antibiotics.
RPE may evolve into a sterile empyematous exudate with the development of fibrothorax. Symptomatic effusions or suspicion of other causes of exudate (infection, malignancy) require thoracocentesis. The “rheumatoid” nature of the pleural exudate in patients without arthritis mandates a pleural biopsy to exclude tuberculosis or malignancy. The optimal therapy of RPE has yet to be established. The role of cytokines in the course of RPE and the possible usefulness of cytokine blockade in the treatment of this RA complication require further evaluation.

View all citing articles on Scopus

: Manuscript received November 11, 1997; revision accepted March 30, 1998.

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Chest

Complement Components and Their Activation Products in Pleural Fluid

Section snippets

Patients

RESULTS

DISCUSSION

CONCLUSION

ACKNOWLEDGMENT

Chest

Chest

J Immunol Methods

Clin Immunol Immunopathol

Synovial fluid levels of complement SC5b-9 and fragment Bb are elevated in patients with rheumatoid arthritis.

Arthritis Rheum

Crofton and Douglas's respiratory diseases.

Pleural fluid complement, complement conversion and immune complexes in immunologic and nonimmunologic diseases.

J Lab Clin Med

Immune complexes and other laboratory features of pleural effusions: a comparison of rheumatoid arthritis, systemic lupus erythematosus, and other diseases.

Ann Intern Med

Chemical and immunological features of pleural effusions: comparison between rheumatoid arthritis and other diseases.

Thorax

Pleural fluid soluble interleukin 2 receptor in rheumatoid arthritis and systemic lupus erythematosus.

J Rheumatol

High levels of complement breakdown products in tuberculous pleural effusions.

Clin Exp Immunol