Tuberculous pleural effusions

doi:10.1016/S0953-6205(03)00018-9

European Journal of Internal Medicine

Volume 14, Issue 2, March 2003, Pages 77-88

https://doi.org/10.1016/S0953-6205(03)00018-9 Get rights and content

Abstract

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.

Introduction

Worldwide, tuberculosis is the most frequent cause of death due to infectious disease [1]. Tuberculous pleural effusion (TPE) is the second most frequent extrapulmonary form of presentation [2]. TPE is induced when the mycobacterium releases antigenic protein into the pleural cavity, thus triggering an imperfectly understood delayed hypersensitivity reaction and the accumulation of fluid in the cavity.

The diagnosis of TPE can be difficult. One-third of TPE patients have a negative tuberculin test [3], only about 5% are detected by Ziehl-Neelsen stain (which requires bacillus concentrations of at least 10 000 per ml) [4], and only 25–37% are identified by culture of Mycobacterium tuberculosis in pleural fluid samples, which furthermore takes 2–6 weeks [4], [5]. Even culture and histological analysis of pleural biopsy samples give negative results in 10–20% of cases. Because of this, in recent years a large number of biological parameters have been evaluated as possible diagnostic markers of TPE.

In this paper we review the current situation of TPE with emphasis on its pathogenesis and recent diagnostic developments.

Section snippets

Incidence

In Europe, TPE is one of the most frequent types of pleural effusions in young patients. Its incidence is variable and depends on the region studied. In Spain, the pleura is affected in 23.3% of tuberculosis patients and tuberculous pleurisy is a major health problem [6]. In the authors’ institution, TPE is the most common form of pleural effusion among patients admitted to the Departments of Pneumology and Internal Medicine, accounting for 25% of all cases [7]. A similar figure has been

Pathogenesis

Tuberculous pleurisy was once considered always to be a primary form of tuberculosis, firstly because it generally affected children and young adults, and secondly because the reactivity of these patients to tuberculin was not longstanding. This still seems to be true in most cases in our region [4]. However, in recent decades, the average age of presentation has increased progressively [16], [17], [18], at least in developed countries, as the result of tuberculous pleurisy becoming

Diagnosis

A definitive diagnosis of tuberculous pleurisy requires either identification of the bacillus in cultures of pleural fluid or pleural biopsy tissue, or observation of granulomas in the latter. Table 1 lists the sensitivity of the various procedures employed to these ends, according to our experience [4].

Most TPE patients present no TPE-specific signs; fever, chest pain, and weight loss can also accompany pleural exudates in other diseases. Also, the possibility that a pleural effusion is due to

Treatment

Most TPE cases tend to resolve spontaneously, since the intensity of mycobacterial infection is generally relatively low [109]. TPE patients should, nevertheless, receive treatment because 65% of untreated patients develop pulmonary tuberculosis within 5 years [109]. It is currently recommended that the first stage of treatment of both pulmonary and non-pulmonary tuberculosis should consist of 2 months of rifampicin, isoniazid, and pyrazinamide. This should be followed in a second stage by a

References (116)

J.B. Mehta et al.
Epidemiology of extrapulmonary tuberculosis. A comparative analysis with pre-AIDS era
Chest
(1991)
H.W. Berger et al.
Tuberculous pleurisy
Chest
(1973)
L. Valdés et al.
The etiology of pleural effusions in an area with high incidence of tuberculosis
Chest
(1996)
M. Marel et al.
The incidence of pleural effusion in a well-defined region: epidemiologic study in Central Bohemia
Chest
(1993)
D.M. Epstein et al.
Tuberculous pleural effusions
Chest
(1987)
A.F. Seibert et al.
Tuberculous pleural effusions. Twenty-year experience
Chest
(1991)
H. Moudgil et al.
Reactivation disease: the commonest form of tuberculous pleural effusion in Edinburgh, 1980–1991
Respir Med
(1994)
T. Pettersson et al.
T and B lymphocytes in pleural effusions
Chest
(1978)
V. Bergroth et al.
Lymphocyte subpopulations, activation phenotypes and spontaneous proliferation in tuberculous pleural effusions
Chest
(1987)
L. Valdés et al.
Cholesterol: a useful parameter for distinguishing between pleural exudates and transudates
Chest
(1991)

K.Y. Lau

Numerous mesothelial cells in tuberculous pleural effusions

Chest

(1989)

I. Ocaña et al.

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

Chest

(1983)

W.F.M. Strankinga et al.

Adenosine deaminase activity in tuberculous pleural effusions: a diagnostic test

Tubercle

(1987)

L. Valdés et al.

Diagnosis of tuberculous pleurisy using the biologic parameters adenosine deaminase, lysozyme, and interferon gamma

Chest

(1993)

L.J. Burgess et al.

Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio. Increased specificity for the diagnosis of tuberculosis pleuritis

Chest

(1996)

P. Riantawan et al.

Diagnostic value of pleural fluid adenosine deaminase in tuberculous pleuritis with reference to HIV coinfection and a Bayesian analysis

Chest

(1999)

M.V. Villegas et al.

Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-γ in pleural fluid for the differential diagnosis of pleural tuberculosis

Chest

(2000)

Y. Yamada et al.

Cytokines in pleural fluid for diagnosis of tuberculous pleurisy

Respir Med

(2001)

J.S. Ferrer et al.

Evolution of idiopathic pleural effusion. A prospective, long-term follow-up study

Chest

(1996)

R. Orriols et al.

High adenosine deaminase activity in pleural effusion due to psittacosis

Chest

(1992)

S.H. Zuckerman et al.

Adenosine deaminase activity during in vitro culture of human peripheral blood monocytes and pulmonary alveolar macrophages

Exp Cell Res

(1980)

J.P.J. Ungerer et al.

Significance of adenosine deaminase activity and its isoenzymes in tuberculous effusions

Chest

(1994)

I. Ocaña et al.

Adenosine deaminase activity in the diagnosis of lymphocytic pleural effusions of tuberculous, neoplastic and lymphomatous origin

Tubercle

(1986)

C. Gakis et al.

Serum and pleural adenosine deaminase activity. Correct interpretation of the findings

Chest

(1991)

E. Ribera et al.

High level of interferon gamma in tuberculous pleural effusion

Chest

(1988)

K. Shimokata et al.

Cytokine content in pleural effusion: comparison between tuberculous and carcinomatous pleurisy

Chest

(1991)

D. de Wit et al.

A comparative study of the polymerase chain reaction and conventional procedures for the diagnosis of tuberculous pleural effusion

Tuber Lung Dis

(1992)

B.S. Nagesh et al.

Evaluation of polymerase chain reaction for detection of mycobacterium tuberculosis in pleural fluid

Chest

(2001)

D. Orphanidou et al.

Tumor necrosis factor, interleukin-1 and adenosine deaminase in tuberculous pleural effusion

Respir Med

(1996)

M. Ito et al.

Elevated levels of soluble interleukin-2 receptors in tuberculous pleural effusions

Chest

(1990)

A. Yokoyama et al.

Soluble interleukin-6 receptor levels in pleural effusions

Respir Med

(1996)

N. Hara et al.

Pleural SC5b-9 in differential diagnosis of tuberculous, malignant and other effusions

Chest

(1992)

R.J. Anderson et al.

The chemistry of the lipoids of tubercle bacilli: VI Concerning tuberculostearic acid and phthioic acid from the acetone-soluble fat

J Biol Chem

(1929)

L. Larsson et al.

Detection of tuberculostearic acid in mycobacteria and nocardiae by gas chromatography and mass spectrometry using selected ion monitoring

J Chromatogr

(1979)

M. Raviglione et al.

Update on the global epidemiology of TB

Curr Issues Public Health

(1996)

L. Valdés et al.

Tuberculous pleurisy: a study of 254 casos

Arch Intern Med

(1998)

L. Scharer et al.

Isolation of tubercle bacilli from needle biopsy specimens of parietal pleura

Am Rev Respir Dis

(1968)

R. Vidal et al.

Estudio controlado de 637 pacientes con tuberculosis: diagnóstico y resultados terapéuticos con esquemas de 9 y 6 meses

Med Clin (Barc)

(1986)

J. Fontán Bueso et al.

Diagnostic value of simultaneous determination of pleural adenosine deaminase and pleural lysozyme/serum lysozyme ratio in pleural effusions

Chest

(1988)

J. Chretien et al.

Diagnostic aspects

J. Batungwanayo et al.

Pleural effusion, tuberculosis and HIV-1 infection in Kigali, Rwanda

AIDS

(1993)

A.M. Saks et al.

Tuberculosis in HIV-positive patients in South Africa: a comparative radiological study with HIV-negative patients

Clin Radiol

(1982)

N. Mlika-Cabanne et al.

Radiographic abnormalities in tuberculosis and risk of coexisting human immunodeficiency virus infection: results from Dar-es-Salaam, Tanzania, and scoring system

Am J Respir Crit Care Med

(1995)

N. Mlika-Cabanne et al.

Radiographic abnormalities in tuberculosis and risk of coexisting human immunodeficiency virus infection: methods and preliminary results from Bujumbura, Burundi

Am J Respir Crit Care Med

(1995)

D.E. Jones et al.

Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection

Am Rev Respir Dis

(1993)

C.E. Bueno et al.

Cytologic and bacteriologic analysis of fluid and pleural biopsy specimens with Cope’s needle

Arch Intern Med

(1990)

O. Winsdrow et al.

Pleurisy induced by intrapleural BCG in immunized guinea-pigs

Eur J Respir Dis

(1982)

J.C. Allen et al.

Experimental pleural effusion as a manifestation of delayed hypersensitivity to tuberculin PPD

J Immunol

(1968)

S. Leibowitz et al.

The tuberculin reaction in the pleural cavity and its suppression by antilymphocyte serum

Br J Exp Pathol

(1973)

S. Yamamoto et al.

Studies on delayed hypersensitivity pleural exudates in guinea pigs

Immunology

(1976)

Cited by (125)

Evaluation of Mycobacterium tuberculosis derived cell-free DNA using pleural fluid and paired plasma samples for the diagnosis of pleural tuberculosis
2023, Tuberculosis
Pleural tuberculosis (pTB) is a grave clinical challenge. A novel cell-free M. tuberculosis DNA (cfM.tb-DNA) probe-based-qPCR assay was developed for the diagnosis of pTB. Total cell-free DNA was extracted from pleural fluid (PF) and paired plasma samples and cfM.tb-DNA was quantified by probe-based qPCR targeting devR (109-bp) gene of M. tuberculosis in patients with pleural effusion. Patient categorization was done using ‘Composite-Reference-Standard’ formulated for the study. Assay cut-offs were determined from samples in the ‘Development set’ (n = 17; ‘Definite & Probable’ pTB; n = 9 and ‘Non-TB’; n = 8) by ROC-curve analysis and applied to ‘Validation set’ (n = 112; ‘Definite’ pTB; n = 8, ‘Probable’ pTB; n = 34, ‘Possible’ pTB; n = 28 and ‘Non-TB’; n = 42). cfM.tb-DNA qPCR had a sensitivity of 62.5% (95%CI; 24.4,91.4) in ‘Definite’ pTB category and 59.5% (95%CI; 43.2,74.3) in ‘Definite & Probable’ pTB category with 95.2% (95%CI; 83.8,99.4) specificity using PF. In plasma (n = 85), the assay had a sub-optimal sensitivity of 7.6% (95%CI; 0.95,25.1) with 88.2% (95%CI; 72.5,96.7) specificity in ‘Definite & Probable’ pTB group. Xpert MTB/RIF assay detected only six-samples in the ‘Validation set’. Logistic regression analysis indicated that PF-cfM.tb-DNA qPCR provided incremental advantage over existing pTB diagnostic algorithms. To the best of our knowledge, this is the first report describing the utility of cfM.tb-DNA for pTB diagnosis in India.
Pleural tuberculosis: experiences from two centers in Brazil
2022, Jornal de Pediatria
Citation Excerpt :
Pleural tuberculosis may be a manifestation of primary or reactivated infection.9,10 It is speculated that tuberculous pleural effusion is a result of the rupture of a subpleural caseous focus into the pleural space,9-13 causing type IV delayed hypersensitivity reaction, in which different cytokines stimulate the antimycobacterial activity of macrophages, resulting in pleural exudates.9-11,13 There are usually very few bacilli in pleural fluid, where they induce a granulomatous reaction.4
This study aimed to describe the clinical and laboratory findings of patients diagnosed with pleural tuberculosis at two hospitals in southern Brazil.
Patients aged < 18 years were evaluated retrospectively. The patients’ medical and epidemiological history, tuberculin skin test results, radiological and pathological findings, and pleural fluid analysis results were retrieved.
Ninety-two patients with pleural tuberculosis were identified. The mean age was 10.9 years old. Twenty-one percent were children aged six years or less. The most common symptoms were fever (88%), cough (72%), and chest pain (70%). Unilateral pleural effusion was observed in 96% of the cases. Lymphocyte predominance was found in 90% of the pleural fluid samples. The adenosine deaminase activity of the pleural fluid was greater than 40 U/L in 85% of patients. A diagnosis of community-acquired pneumonia with antibiotic prescriptions was observed in 76% of the study population.
Tuberculosis etiology must be considered in unilateral pleural effusion in a child with contact with a case of tuberculosis. Pleural fluid biomarkers contribute to the diagnosis of pleural tuberculosis in children and adolescents.
Diagnosis of tuberculous pleural effusions: A review
2021, Respiratory Medicine
Tuberculous pleural effusion (TPE) is the second most common presentation of extrapulmonary tuberculosis. The paucibacillary nature of the effusion poses diagnostic challenges. Biomarkers like adenosine deaminase and interferon-γ have some utility for diagnosing TPEs, as do cartridge-based polymerase chain reaction (PCR) methods. When these fluid studies remain indeterminate, pleural biopsies must be performed to confirm the diagnosis. This review article elaborates on the scientific evidence available for various diagnostic tests and presents a practical approach to the diagnosis of TPEs.
Biomarkers of Distinguishing Neutrophil-Predominant Tuberculous Pleural Effusion from Parapneumonic Pleural Effusion
2021, American Journal of the Medical Sciences
Tuberculous pleural effusion (TPE) is usually characterized by lymphocytic predominance and high pleural fluid adenosine deaminase (pfADA), while parapneumonic pleural effusion (PPE) is usually characterized by neutrophilic predominance. However, in some cases, neutrophils can be predominant in TPE. In such cases, the differential diagnosis between TPE and PPE is challenging and has been rarely investigated. The aim of this study was to evaluate the accuracy of pfADA, pleural fluid lactate dehydrogenase (pfLDH) and other parameters, such as age/pfADA in the differential diagnosis of neutrophil-predominant TPE (NP-TPE) and PPE.
Between January 2003 and August 2018, 19 patients with NP-TPE and 54 patients with PPE at Shanghai Jiao Tong University Affiliated Sixth People's Hospital were retrospectively reviewed. Age, blood and pleural fluid findings, and eight ratios that consisted of routine biomarkers were compared between the two groups in ≤50 and >50 years old groups. ROC curve analysis was used to evaluate diagnostic performance.
The three parameters with the largest AUC were age/pfADA, pfADA and pfLDH in ≤ 50 years old group, and pfADA, age/pfADA and the percentage of neutrophils in pleural fluid (pfN%) in >50 years old group. For patients ≤ 50 years old, pfADA combined with pfLDH or age/pfADA combined with pfLDH could increase the specificity to 100%, while the sensitivity of the former was high (84.6% vs 76.9%). For patients >50 years old, both pfADA combined with pfN% and age/pfADA combined with pfN% could increase the specificity to 90.3% with the same sensitivity.
Although pfADA played an important role in the discrimination of NP-TPE from PPE, combining pfADA with pfLDH for patients ≤50 years old or combining pfADA with pfN% for patients >50 years old might improve diagnostic performance.
Role of cancer ratio and other new parameters in the differential diagnosis of malignant pleural effusion
2021, Clinics
We compared the diagnostic potential of cancer ratio (CR, serum lactate dehydrogenase [LDH]/pleural fluid adenosine deaminase [pfADA]), cancer ratio plus (CR plus, cancer ratio/pleural lymphocyte percentage), and age/pfADA ratio with pfADA in malignant pleural effusion.
Data from 100 patients with malignant pleural effusion (MPE) and 119 patients with tuberculous pleural effusion (TPE) were retrospectively collected. PfADA, age/pfADA ratio, CR, and CR plus were compared between patients with MPE and those with TPE in two age groups (≤50 and >50 years). The best cut-off value was determined, and the diagnostic performance was evaluated according to the receiver operating characteristic curve.
PfADA was statistically significantly lower while age/pfADA ratio, CR, and CR plus were significantly higher in the MPE group than in the TPE group in both age groups (p<0.05). For patients aged ≤50 years, the differential diagnostic value of pfADA for MPE was better than those of age/pfADA ratio, CR, and CR plus. At a cut-off value of 13.0 U/L, the sensitivity, specificity, and accuracy were 88.9%, 100.0%, and 98.9%, respectively. For patients aged >50 years, the diagnostic performance of CR plus was superior to those of pfADA, age/pfADA ratio, and CR. At a cut-off value of 22.6, the sensitivity, specificity, and accuracy of CR plus for the diagnosis of MPE were 86.8%, 84.6%, and 86.2%, respectively.
The best parameter for diagnosing MPE was different for patients aged ≤50 years and >50 years. For patients aged >50 years, CR plus was a good parameter for the differential diagnosis of MPE. For patients aged ≤50 years, pfADA was better.
Developing a new intelligent system for the diagnosis of tuberculous pleural effusion
2018, Computer Methods and Programs in Biomedicine
Citation Excerpt :
In those endemic areas with high TB prevalence, the combination of increased lymphocyte counts, exudative pleural fluid and a high adenosine deaminase (ADA) titer is of substantial value in the diagnosis of TB. However, the likelihood of false positives or false negatives still poses an inconvenience, especially in early TPE cases, where the PE mainly shows increased neutrophils and a low ADA titer [11,15]. Pleural biopsy is also considered to be an invasive procedure, with blind biopsies not only yields lower sensitivity for the detection of TB, but also carries the potential risk of iatrogenic pneumothorax.
Background and Objective: In countries with high prevalence of tuberculosis (TB), clinicians often diagnose tuberculous pleural effusion (TPE) by using diagnostic tests, which have not only poor sensitivity, but poor availability as well. The aim of our study is to develop a new artificial intelligence based diagnostic model that is accurate, fast, non-invasive and cost effective to diagnose TPE. It is expected that a tool derived based on the model be installed on simple computer devices (such as smart phones and tablets) and be used by clinicians widely.
Methods: For this study, data of 140 patients whose clinical signs, routine blood test results, blood biochemistry markers, pleural fluid cell type and count, and pleural fluid biochemical tests’ results were prospectively collected into a database. An Artificial intelligence based diagnostic model, which employs moth flame optimization based support vector machine with feature selection (FS-MFO-SVM), is constructed to predict the diagnosis of TPE.
Results: The optimal model results in an average of 95% accuracy (ACC), 0.9564 the area under the receiver operating characteristic curve (AUC), 93.35% sensitivity, and 97.57% specificity for FS-MFO-SVM.
Conclusions: The proposed artificial intelligence based diagnostic model is found to be highly reliable for diagnosing TPE based on simple clinical signs, blood samples and pleural effusion samples. Therefore, the proposed model can be widely used in clinical practice and further evaluated for use as a substitute of invasive pleural biopsies.

View all citing articles on Scopus

View full text

ReviewTuberculous pleural effusions

Abstract

Introduction

Section snippets

Incidence

Pathogenesis

Diagnosis

Treatment

Chest

Chest

Chest

Chest

Chest

Chest

Respir Med

Chest

Chest

Chest

Chest

Chest

Tubercle

Chest

Chest

Chest

Chest

Respir Med

Chest

Chest

Exp Cell Res

Chest

Tubercle

Chest

Chest

Chest

Tuber Lung Dis

Chest

Respir Med

Chest

Respir Med

Chest

J Biol Chem

J Chromatogr

Update on the global epidemiology of TB

Curr Issues Public Health

Tuberculous pleurisy: a study of 254 casos

Arch Intern Med

Isolation of tubercle bacilli from needle biopsy specimens of parietal pleura

Am Rev Respir Dis

Estudio controlado de 637 pacientes con tuberculosis: diagnóstico y resultados terapéuticos con esquemas de 9 y 6 meses

Med Clin (Barc)

Diagnostic value of simultaneous determination of pleural adenosine deaminase and pleural lysozyme/serum lysozyme ratio in pleural effusions

Chest

Diagnostic aspects

Pleural effusion, tuberculosis and HIV-1 infection in Kigali, Rwanda

AIDS

Tuberculosis in HIV-positive patients in South Africa: a comparative radiological study with HIV-negative patients

Clin Radiol

Radiographic abnormalities in tuberculosis and risk of coexisting human immunodeficiency virus infection: results from Dar-es-Salaam, Tanzania, and scoring system

Am J Respir Crit Care Med

Radiographic abnormalities in tuberculosis and risk of coexisting human immunodeficiency virus infection: methods and preliminary results from Bujumbura, Burundi

Am J Respir Crit Care Med

Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection

Am Rev Respir Dis

Cytologic and bacteriologic analysis of fluid and pleural biopsy specimens with Cope’s needle

Arch Intern Med

Pleurisy induced by intrapleural BCG in immunized guinea-pigs

Eur J Respir Dis

Experimental pleural effusion as a manifestation of delayed hypersensitivity to tuberculin PPD

J Immunol

The tuberculin reaction in the pleural cavity and its suppression by antilymphocyte serum

Br J Exp Pathol

Studies on delayed hypersensitivity pleural exudates in guinea pigs

Immunology

Review
Tuberculous pleural effusions