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Official reprint from UpToDate www.uptodate.com ©2015 UpToDate

AuthorMichael D Frye, MD

Section EditorC Fordham von Reyn, MD

Deputy EditorElinor L Baron, MD, DTMH

Tuberculous pleural effusions in HIV-negative patients

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: Feb 19, 2015.

INTRODUCTION — Tuberculous pleural effusion accounts for approximately 5 percent of disease due to Mycobacterium tuberculosis and is the second

most common form of extrapulmonary tuberculosis (TB) after lymphatic involvement [1,2].

Issues related to the diagnosis and treatment of tuberculous pleural effusions in HIV-negative patients will be reviewed here. Issues related to tuberculous

pleural effusions in HIV-infected patients are discussed separately. (See "Tuberculous pleural effusions in HIV-infected patients".)

PATHOGENESIS — Tuberculous pleural effusions are thought to result from a delayed hypersensitivity reaction to mycobacteria and mycobacterial

antigens in the pleural space [3]. These organisms and/or their antigens probably enter the pleural space due to leakage or rupture of a subpleural focus of

disease. In one study of 24 patients with tuberculous pleural effusions who underwent thoracotomy, for example, a caseous focus in the lung contiguous

with the diseased pleura was found in half of cases [4]. Development of pleural effusion occurs largely as a result of hypersensitivity reaction, but

tuberculous pleurisy must be considered to be due to infection since culture of the fluid grows mycobacteria in some cases and culture of the pleural

tissue usually grows mycobacteria. Tuberculous pleural effusions are usually self-limited and resolve spontaneously with or without treatment in most

cases. However, the condition can potentially progress and worsen and become a tuberculous empyema.

A tuberculous empyema represents chronic active infection of the pleural space and can occur in the setting of a large pleural effusion that progresses,

usually leading to an unexpandable lung [5]. Simple tuberculous pleural effusion and tuberculous empyema can be considered a continuum of the same

process. Tuberculous empyema can also develop via extension of infection from thoracic lymph nodes or subdiaphragmatic focus, via hematogenous

spread, or in the setting of therapeutic pneumothorax therapy leading to an unexpandable lung.

In an experimental model of tuberculous effusion in which Bacille Calmette-Guérin (BCG) was injected into the pleural space of rabbits that had been

previously sensitized with intradermal BCG, a sequential influx of cells into the pleural space was observed [6]. An initial neutrophilic response is

necessary for the subsequent mononuclear influx [7]. Macrophages are the predominant mononuclear cells until day four, with lymphocytes predominating

thereafter [6]. The local release of cytokines probably induces the sequential expression of specific cell adhesion molecules in vascular endothelium that

direct the influx of the different inflammatory cells.

In patients with tuberculous pleural effusion, the proportion of T lymphocytes is higher in pleural fluid than in blood. This is due to selective enrichment of

cells with the helper/inducer (CD4) phenotype via local proliferation and probable selective influx. Those pleural helper T cells with a "memory" phenotype

(CD4+, CDw29+) are the cells that proliferate and produce gamma interferon when stimulated with purified protein derivative (PPD) [8].

CLINICAL MANIFESTATIONS — Tuberculous pleural effusions can occur in association with either reactivation disease or primary tuberculosis (TB) [9-

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12]. Most often they are due to reactivation disease in adults [10,11] and to primary disease in children [12]. Tuberculous pleural effusions are typically

unilateral and small to moderate in size [9].

Patients with tuberculous pleural effusion usually have acute febrile illness with nonproductive cough (94 percent) and pleuritic chest pain (78 percent),

without an elevation in the peripheral white blood cell count [13]. Night sweats, chills, weakness, dyspnea, and weight loss can also occur. The average

age in one series from the United States was 47 years [1].

In some cases, pleural scarring can lead to a "trapped lung" and pleural fluid fills the void created by the nonexpandable lung. Less commonly, tuberculous

pleural effusion can develop when a cavity ruptures into the pleural space, resulting in a chronic suppurative effusion, called a chronic tuberculous

empyema [5,14]. Chronic tuberculous empyema is characterized by purulent fluid containing numerous tuberculous organisms and results in thickened,

scarred, and calcified pleura.

Radiographic imaging — Tuberculous pleural effusions are unilateral in almost all cases and occur slightly more frequently on the right side than the left

(55 versus 45 percent) [15,16]. The effusions are typically small to moderate in size; they occupy less than one-third of the hemithorax in 82 percent of

cases [15]. The size or side of the effusion has no bearing on prognosis [17].

Parenchymal disease has been observed in association with pleural effusion on chest radiography in up to 50 percent of patients [1]. These findings are

located in the upper lobe in approximately three-fourths of cases, suggestive of reactivation TB. In the remaining patients, parenchymal disease is located

in the lower lobe and resembles primary disease. The effusion virtually always occurs on the same side as the parenchymal infiltrate [13]. Computed

tomography (CT) is more sensitive than chest radiography; it demonstrates parenchymal disease in over 80 percent of cases, supporting the theory of

spread to the pleura from a subpleural focus of infection (image 1) [18]. In patients without apparent parenchymal involvement, pleural disease may develop

via hematogenous spread following primary infection.

DIAGNOSIS — Diagnostic evaluation of pleural effusion in the setting of suspected tuberculosis (TB) begins with thoracentesis; fluid should be sent for

routine studies and additional assays as discussed below. In the setting of moderate to high suspicion for tuberculosis with nondiagnostic pleural fluid

evaluation, pleural biopsy is warranted.

In addition to pleural evaluation, routine laboratory diagnostic evaluation for TB should also be pursued; this is discussed in detail separately. Evaluation for

concurrent HIV infection should also be performed. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected patients" and "Epidemiology, clinical

manifestations, and diagnosis of tuberculosis in HIV-infected patients".)

Pleural fluid — Evaluation of pleural fluid consists of routine studies, as outlined below. The additional assays described are not required for routine

evaluation but can be helpful in some cases if the diagnosis is difficult to establish based on routine pleural studies and pleural biopsy.

Routine studies — The pleural fluid in tuberculous pleural effusion is straw colored in more than 80 percent of cases [19]. It is uniformly exudative [15];

the protein concentration is invariably >3.0 g/dL (30 g/L), and >5.0 g/dL (50 g/L) in 50 to 77 percent of cases [13,20]. The pleural fluid lactate

dehydrogenase (LDH) level is elevated in approximately 75 percent of cases, with levels commonly exceeding 500 IU/L [1,13,15,20].

Low pH and low glucose concentration may be observed; these findings are more characteristic of chronic tuberculous empyema than tuberculous pleural

effusion. The pleural fluid pH is virtually always <7.40; pH <7.30 is observed in about 20 percent of cases. The pleural fluid glucose concentration in

tuberculous pleural effusion is usually between 60 and 100 mg/dL (3.3 and 5.6 mmol/L). Glucose levels below 50 mg/dL (2.8 mmol/L) are observed in 7 to

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20 percent of effusions. Extremely low glucose concentrations (<30 mg/dL [1.7 mmol/L]) can occur occasionally [13,20]. (See 'Pathogenesis' above.)

The pleural fluid nucleated cell count is usually between 1000 and 6000 cells/mm [15]. It is lymphocyte predominant in 60 to 90 percent of cases; the

remaining cases have neutrophil predominance [1,13,20]. Timing is important in the type of nucleated cells that are seen; neutrophils predominate in the

first few days of a tuberculous pleural effusion and lymphocytes predominate thereafter [6,7,19]. The pleural fluid rarely contains more than 5 percent

mesothelial cells. Eosinophil infiltration is uncommon. The presence of more than 10 percent eosinophils usually excludes the diagnosis of tuberculous

pleuritis unless the patient has had a pneumothorax or hemothorax near the time of pleural analysis [21]. (See "Pleural fluid eosinophilia".)

Pleural fluid cultures are positive in 12 to 80 percent of patients; most series note positive cultures in less than 20 to 30 percent of cases [9]. The addition

of pleural biopsy culture may increase the yield to >90 percent [9,19]. (See 'Pleural biopsy' below.)

Nucleic acid amplification techniques for evaluation of tuberculous pleural effusion in HIV-negative patients appear to have high specificity but relatively low

sensitivity [22,23]. In one systemic review and meta-analysis including 18 studies, the sensitivity and specificity for the Xpert MTB/RIF assay (compared

with culture) in pleural fluid were 46 and 99 percent, respectively [23]. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected patients", section on

'Nucleic acid amplification'.)

Additional assays — Additional assays for evaluation of pleural fluid in the setting of suspected TB include measurement of pleural fluid adenosine

deaminase (ADA) level, lysozyme concentration, and interferon-gamma (IFN-gamma) concentration. Of these tests, the pleural fluid ADA level is most

clinically useful and accessible. An ADA level should be sent along with the routine pleural fluid studies whenever TB is the suspected cause of the

effusion. Even when the acid-fast bacilli (AFB) smear and culture are negative, compatible routine studies along with an elevated ADA level may establish

a presumptive diagnosis of tuberculous pleuritis in the right clinical setting.

ADA levels are most useful in patients with moderate to high suspicion for TB with negative pleural histology and culture [24]. Some large series suggest

that a value >45 to 60 U/L is 100 percent sensitive and up to 97 percent specific for tuberculous pleural effusion [15,24-27]. However, one report of 87

cases found levels >43 U/L in only 78 percent of cases [28]; other series have documented specificities of 85 to 89 percent [29,30]. Pleural effusions with

an ADA level <40 U/L are rarely caused by TB [31]. Specificity is diminished by elevated ADA levels that can occur in other conditions, including

rheumatoid effusion, empyema, mesothelioma, lung cancer, parapneumonic effusion, and hematologic malignancies. These findings in part reflect failure to

distinguish between the two principal isoenzymes, ADA-1 and ADA-2; most assays report the total level only. ADA-2 is increased in tuberculous effusions,

while ADA-1 is increased in empyemas [32].

Pleural fluid lysozyme concentrations are >15 mg/dL in over 80 percent of tuberculous pleural effusions [27,33]. The highest concentrations are found in

empyemas, which can be tuberculous or bacterial. Lysozyme concentrations can also be elevated in the setting of malignant effusions. The pleural fluid-to-

serum lysozyme ratio may be more useful than the absolute value. Excluding empyemas, a ratio above 1.2 has been reported to have 100 percent

sensitivity for tuberculous effusions and 95 percent specificity [33]. In a heterogeneous group of 276 effusions, however, a threshold ratio of 1.1 was

associated with a sensitivity of only 67 percent; the specificity was 90 percent [27].

Measurement of pleural fluid interferon-gamma concentration by commercially available enzyme-linked immunosorbent assay kits may be a useful

diagnostic tool [34,35]. In one study including 145 patients with tuberculous pleural effusion, an IFN-gamma concentration >140 pg/mL had sensitivity and

specificity of 94 percent and 92 percent, respectively [27]. Another study including 66 patients with exudative, lymphocytic pleural effusions with cut-off

value of 240 pg/mL noted sensitivity and specificity of 95 and 96 percent (figure 1) [36]. A meta-analysis including 22 studies to estimate the accuracy of

interferon-gamma in the diagnosis of tuberculous pleural effusion were 89 and 97 percent, respectively [37]; other series have described lower sensitivity

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[30].

Pleural fluid tuberculous antigens and antituberculous antibodies have also been studied and appear to be elevated in tuberculous pleuritis. However, these

immunologic tests are not useful diagnostically due to lack of specificity for TB.

Pleural biopsy — Pleural biopsy is warranted in the setting of moderate to high suspicion for TB when pleural fluid evaluation is not diagnostic. A

definitive diagnosis should be pursued in most cases when tuberculous pleurisy is suspected. Pleural biopsy offers the highest likelihood of a certain

diagnosis, and a positive culture also provides information pertaining to drug sensitivities of the organism. Pleural biopsy for confirmation of the diagnosis

may also be necessary when use of antituberculous medications poses a particularly high risk of complications, such as in patients with preexisting liver

disease.

Histologic examination and culture of pleural tissue is the most sensitive evaluation for pleural TB; this approach yields a diagnosis in 60 to 95 percent of

cases [9,19,38,39]. Pleural biopsy demonstrates granulomas in 50 to 97 percent of cases and culture of biopsy material is positive in 40 to 80 percent of

cases [9]. Sensitivity generally increases with the number of biopsies taken.

The presence of pleural caseating granulomas on histologic examination is virtually diagnostic of TB pleural effusion. Caseation and demonstration of acid-

fast bacilli are not required. Noncaseating pleural granulomas can occasionally be seen in other disorders, such as sarcoidosis, fungal disease, and

rheumatoid pleuritis.

Pleural tissue can be obtained via thoracoscopy or closed percutaneous needle biopsy. Sensitivities are comparable; needle biopsy is generally preferred

in areas where tuberculous pleuritis is common [40,41].

Other evaluation — In addition to pleural evaluation, routine laboratory diagnostic evaluation for TB should also be pursued; this is discussed in detail

separately. Evaluation for concurrent HIV infection should also be performed. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected patients" and

"Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients".)

Sputum culture is positive in 20 to 50 percent of patients with pleural effusion; positive sputum culture is more likely in the setting of concomitant

parenchymal disease [1,4,13,20,42]. In one report of 70 patients with tuberculous pleural effusions, sputum culture was positive in 89 percent of patients

with parenchymal changes but only 11 percent of patients without parenchymal changes [42]. The yields for induced sputum and pleural biopsy were 52

and 62 percent, respectively [42].

Tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) can be useful components of the evaluation of suspected tuberculous pleural

effusions, although neither can distinguish between latent tuberculosis infection and active tuberculosis disease. Older series reported almost uniformly

positive TST results in patients with tuberculous pleural effusions; subsequent reports have observed false-negative tests in 7 to 30 percent of patients

[1,13]. Almost all patients with tuberculous pleural effusion and an initially negative TST have a positive TST if retested two months later. One possible

explanation for the initial negative TST is suppression of sensitized T cells in the peripheral circulation and skin by circulating adherent mononuclear cells

(chiefly monocytes, not classic CD8 suppressor cells). These monocytes are known to suppress antigen-induced lymphocyte blastogenesis and the

production of interleukin-2.

Interferon-gamma release assays can be used in place of TST and are discussed further separately. The use of IGRAs on pleural fluid for the diagnosis of

tuberculous pleuritis has been investigated and thus far appears to lack sufficient sensitivity and specificity for clinical use. A meta-analysis reported that

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IGRAs used on pleural fluid in patients with tuberculous pleuritis has a sensitivity and specificity of 75 and 82 percent, respectively [43]. (See "Interferon-

gamma release assays for diagnosis of latent tuberculosis infection".)

MANAGEMENT AND OUTCOME — Treatment of tuberculous pleural effusion is similar to treatment of pulmonary tuberculosis (TB). This is discussed in

detail separately. (See "Treatment of pulmonary tuberculosis in HIV-uninfected patients" and "Treatment of pulmonary tuberculosis in the HIV-infected

patient".)

In some cases, the diagnosis rests on clinical rather than microbiologic or histologic criteria. Presumptive therapy is warranted for patients with

lymphocytic exudate and a positive tuberculin skin test or interferon-gamma release assay, even in the absence of definitive diagnosis [44]. In the absence

of treatment for tuberculous pleuritis, patients have a 65 percent risk of developing pulmonary or extrapulmonary TB within five years [45]. (See "Diagnosis

of pulmonary tuberculosis in HIV-uninfected patients" and "Epidemiology, clinical manifestations, and diagnosis of tuberculosis in HIV-infected patients".)

Routine complete drainage of pleural fluid at the time of diagnosis does not appear to improve long-term outcomes. This was demonstrated in a

randomized trial including 61 patients with newly diagnosed tuberculous pleural effusion treated with anti-TB therapy with or without pigtail drainage [46].

Drainage was associated with significantly more rapid resolution of dyspnea (four versus eight days), although after the first week there were no differences

in symptoms between groups during the 24-week follow-up period. Pulmonary function and the degree of residual pleural thickening on chest radiography

were the same in both groups at the conclusion of the trial.

With appropriate therapy, most patients defervesce within two weeks; in most cases, pleural fluid is resorbed within six weeks. However, some patients

take up to two months to defervesce, and fluid resorption may take up to four months. In selected patients, administration of corticosteroids can shorten

the duration of fever and time to fluid resorption, although the precise risks and benefits of corticosteroids in this setting have not been well defined [47,48].

Data are insufficient to support routine adjunctive use of corticosteroids for tuberculous pleuritis [49,50].

Residual pleural thickening can occur in 50 percent of patients [51]. Among 56 patients with 10 mm of residual pleural thickening following completion of

medical therapy, the pleural fluid had a significantly lower pH, lower glucose concentration, higher lysozyme concentration, and higher tumor necrosis

factor-alpha levels; the adenosine deaminase level was elevated to a similar degree in both groups [52].

SUMMARY

Tuberculous pleural effusions can occur in association with either primary tuberculosis (TB) or reactivation disease. Patients with tuberculous pleural

effusion usually have acute febrile illness with nonproductive cough and pleuritic chest pain. Night sweats, chills, weakness, dyspnea, and weight

loss can also occur. (See 'Clinical manifestations' above.)

●

Tuberculous pleural effusions are usually small to moderate in size, unilateral, and occur slightly more frequently on the right side than the left.

Parenchymal disease may be observed in association with pleural effusion. Most often, parenchymal disease is in the upper lobe, suggestive of

reactivation TB; in some cases, parenchymal disease is in the lower lobe and resembles primary disease. (See 'Radiographic imaging' above.)

●

Diagnostic evaluation of pleural effusion in the setting of suspected tuberculous pleuritis begins with thoracentesis. The pleural fluid is generally

exudative with protein concentration >3.0 g/dL and lactate dehydrogenase level commonly exceeding 500 IU/L. Low pH and low glucose

concentration may be observed; these findings are more characteristic of chronic tuberculous empyema than tuberculous pleural effusion. The pleural

fluid nucleated cell count is usually lymphocyte predominant. Cultures are positive in <30 percent of cases. (See 'Routine studies' above.)

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ACKNOWLEDGMENT — The editorial staff at UpToDate, Inc. would like to acknowledge Steven Sahn, MD, who contributed to an earlier version of this

topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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●

Additional assays for evaluation of pleural fluid in the setting of suspected TB (such as pleural fluid adenosine deaminase level, lysozyme

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●

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50. Engel ME, Matchaba PT, Volmink J. Corticosteroids for tuberculous pleurisy. Cochrane Database Syst Rev 2007; :CD001876.

51. Barbas CS, Cukier A, de Varvalho CR, et al. The relationship between pleural fluid findings and the development of pleural thickening in patients withpleural tuberculosis. Chest 1991; 100:1264.

52. de Pablo A, Villena V, Echave-Sustaeta J, Encuentra AL. Are pleural fluid parameters related to the development of residual pleural thickening intuberculosis? Chest 1997; 112:1293.

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GRAPHICS

Tuberculous pleural effusion

Computed tomography (CT) scan showing a parenchymal focus of

tuberculosis close to the pleura and an ipsilateral pleural effusion.

Courtesy of Paul Stark, MD.

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Interferon-gamma in tuberculous pleural effusions

One study in 66 patients with exudative, lymphocytic pleural effusions found a

sensitivity of 95 percent and a specificity of 96 percent for pleural fluid

interferon-gamma concentrations when a cut-off value of 240 pg/mL was

employed.

Data from Wongtim S, Silachamroon U, Ruxrungtham K, et al. Thorax 1999; 54:921.

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Disclosures: Michael D Frye, MD Nothing to disclose. C Fordham von Reyn, MD Nothing to disclose. Elinor L Baron, MD, DTMH Nothingto disclose.

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