Lung (2009) 187:263–270
DOI 10.1007/s00408-009-9165-3
STATE OF THE ART REVIEW
Tuberculous Pleural Effusion
José M. Porcel
Received: 19 February 2009 / Accepted: 26 July 2009 / Published online: 13 August 2009
Ó Springer Science+Business Media, LLC 2009
Abstract Tuberculous pleural effusion is one of the most
common forms of extrapulmonary tuberculosis (TB). The
immediate cause of the effusion is a delayed hypersensi-
tivity response to mycobacterial antigens in the pleural
space. For this reason microbiological analyses are often
negative and limited by the lengthy delay in obtaining
results. In areas with high TB prevalence, pleural fluid
adenosine deaminase (ADA) levels greater than 40 U/l
argue strongly for TB; in contrast, low levels of pleural
ADA have high negative predictive value in low-preva-
lence countries. The specificity of this enzyme increases if
only lymphocytic exudates are considered. The shortcom-
ing of the ADA test is its inability to provide culture and
drug sensitivity information, which is paramount in coun-
tries with a high degree of resistance to anti-TB drugs.
Sputum induction (in addition to pleural fluid) for acid-fast
bacilli and culture is a recommended procedure in all
patients with TB pleurisy. The microscopic-observation
drug-susceptibility assay performed on pleural fluid or
pleural tissue increases by two to three times the detection
of TB over conventional cultures, and it allows for the
identification of multidrug-resistant TB. A reasonable
management strategy for pleural TB would be to initiate a
four-drug regimen and perform a therapeutic thoracentesis
in patients with large, symptomatic effusions.
J. M. Porcel (&)
Department of Internal Medicine, Pleural Diseases Unit,
Arnau de Vilanova University Hospital, Institut de Recerca
Biomèdica de Lleida (IRBLLEIDA), Avda Alcalde Rovira
Roure 80, 25198 Lleida, Spain
e-mail: jporcelp@yahoo.es
Keywords Pleural effusion
Tuberculosis

Adenosine deaminase
Introduction
Tuberculosis (TB) is a major public health problem in
developing countries. There were an estimated 9.2 million
new cases of TB in 2006, of which 8% were in human
immunodeficiency virus (HIV)-positive patients [1]. In that
year, the overall annual incidence of TB in Europe was
reported to be 49 cases per 100,000 people, ranging from 2
to 141 cases depending on the country (e.g., Spain 30/
100,000). These figures were 4.6/100,000 people in the
United States and 363/100,000 people in Africa. The
country with the highest TB incidence rate was Swaziland
(southern Africa), with 1,155 cases/100,000 people; that
with the lowest was Monaco (Europe), with 2/100,000 [1].
Overall, the African, southeast Asian, and western Pacific
regions account for more than 80% of the total case noti-
fications of TB in the world. In developed nations like the
United States, TB is primarily a disease of immigrants
from high-prevalence countries (who comprise over half of
all reported TB cases) as well as the socially and eco-
nomically disadvantaged.
Although pulmonary disease is the most common form
of TB, extrapulmonary TB affecting mainly the lymph
nodes and pleura serves as the initial presentation in about
25% of adults. Pleural TB accounts for 4% of all TB cases
in the United States [2]; in Spain, however, this percentage
is greater than 10% [3]. TB is one of the most common
causes of pleural effusion in some geographical areas [4].
At the author’s institution, the leading etiologies of pleural
effusion in the 2000 patients who underwent diagnostic
thoracentesis during the last 12 years were cancer (30%),
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pneumonia (20%), heart failure (17%), and TB (10%)
(unpublished data).
Pathogenesis
Tuberculous pleural effusion (TPE) may be a manifestation
of either primary or reactivated infection, the latter of
which is predominant in the adult population of developed
countries. TPEs are thought to result from the breakdown
of a small subpleural focus that releases its content into the
pleural space. This release is followed by acute inflam-
mation from a CD4? T-cell-mediated hypersensitivity
reaction [5]. Activated T lymphocytes interact through
different cytokines (e.g., interferon-c, interleukin-2) with
macrophages in order to stimulate maximally the antimy-
cobacterial actions. Although neutrophils may be the pre-
dominant cells in the pleural cavity in the initial stage, T
lymphocytes predominate thereafter. The compartmental-
ized inflammatory process increases the permeability of
pleural capillaries. Along with impaired lymphatic clear-
ance due to parietal pleural involvement, this leads to
pleural fluid formation and accumulation [5].
In contrast, tuberculous empyema, which represents an
uncommon chronic, active infection of the pleural space,
arises when a bronchopleural fistula spills the content of a
cavity or other parenchymal focus into the pleural space.
Finally, a remote tuberculous pleurisy may cause a fibrous
peel over the visceral pleura that prevents lung expansion
(‘‘trapped lung’’), thereby creating a high negative pleural
space pressure that favors the development of chronic
pleural effusion.
Clinical Manifestations
In an epidemiological analysis from the United States, the
mean age of 7549 patients with pleural TB was 49 years:
about 50% were younger than 45 years and 30% were over
65 years of age [2]. In contrast, pleural TB affects mainly
younger adults (mean age = 34 years) in countries with a
higher incidence of TB [6–8], where cases may still be
from the primary form of the disease. Pleural TB pre-
dominates in men, with an overall male-to-female ratio of
2:1 [2, 9].
TPE most commonly manifests as an acute or subacute
illness causing fever, cough, and pleuritic chest pain in
more than 70% of patients [9]. Other symptoms include
night sweats, weight loss, malaise, and dyspnea varying in
severity according to the effusion’s size. As a general rule,
an acute illness is more likely to occur in younger patients
who are more immunocompetent. In contrast, bacterial
pneumonia occasionally mimics the disease, but there is
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Lung (2009) 187:263–270
generally no elevation of the peripheral leukocyte count in
pleural TB.
TPEs are typically unilateral ([95%), small to moderate
in size, and, in nearly 30% of cases, loculated [10]. In one
series of 254 patients with TB pleurisy, the effusions
occupied more than two-thirds of the hemithorax in 18%,
between one-third and two-thirds of the hemithorax in
46%, and less than one-third of the hemithorax in 34% of
patients [6]. In another series, pleural TB represented the
third leading cause of large or massive pleural effusion
(12%) after malignancy (55%) and pneumonia (22%) [11].
Coexisting parenchymal disease, mostly localized to the
ipsilateral upper lobe, may be seen in approximately 20%
of chest radiographs [6, 12]. However, this percentage
depends on whether TPE occurs as a primary infection or
reactivation. Computed tomography (CT) scanning offers a
more sensitive method and can demonstrate parenchymal
disease in 40-85% of cases [13, 14].
A negative tuberculin skin test does not rule out TB
pleurisy. Such a test is negative in about 20–30% of cases
[6, 15], yet the results usually become positive if repeated
1–2 months later [9]. Patients with HIV infection, partic-
ularly those with CD4 counts less than 200 cells/mm3, are
more likely to have a negative skin test.
Diagnosis
The definitive diagnosis of TPE depends on the demon-
stration of M. tuberculosis in the sputum, pleural fluid, or
pleural biopsy specimens [16]. The diagnosis can also be
established with reasonable certainty by demonstrating
granuloma in the parietal pleura or an elevated adenosine
deaminase (ADA) level in pleural fluid in the adequate
clinical context.
Analysis of the pleural fluid permits the presumptive
diagnosis of TB pleurisy in most cases. The fluid is
invariably an exudate, with lymphocytic predominance in
about 90% of cases [17]. Occasionally, an initial poly-
morphonuclear cell predominance with a subsequent
change to a lymphocytic predominance within 1 week is
seen [17]. A pleural fluid protein concentration greater than
5 g/dl, a low pleural fluid glucose level (\60 mg/dl), and a
low pH (\7.2) are found in more than 70, 25, and 10% of
patients, respectively [18]. The pleural fluid rarely contains
more than 5% of mesothelial cells or is eosinophilic [5].
Adenosine Deaminase
Testing for pleural fluid ADA levels is an easy and inex-
pensive method for establishing the diagnosis of TB
pleuritis. ADA, a predominant T-lymphocyte enzyme,
Lung (2009) 187:263–270
catalyzes the conversion of adenosine and deoxyadeno-
sine to inosine and deoxyinosine, respectively. A meta-
analysis of 63 studies, including 2796 patients with TPE
and 5297 with nontuberculous effusions, found that the
summary receiver operating characteristic curves for the
sensitivity and specificity of pleural ADA in the diagnosis
of pleural TB were 92 and 90%, respectively. The posi-
tive likelihood ratio was 9.03, the negative likelihood
ratio was 0.10, and the diagnostic odds ratio was 110.08
[19]. ADA analysis is a sensitive marker of TPE, even in
HIV patients with very low CD4 cell counts [20]. The
most widely accepted cutoff value for pleural fluid ADA
is 40 U/l. Higher levels are associated with a greater
chance of a patient having TB. Persistent low pleural fluid
ADA activity observed upon repeated thoracentesis argues
strongly against TB [4, 15].
The main disease that causes an elevated ADA in
addition to TB is empyema. Roughly one-third of para-
pneumonic effusions and two-thirds of empyemas have
ADA levels above 40 U/l [21], but these conditions are
easily distinguished from pleural TB in terms of both
clinical picture and the fact that they exhibit pleural fluid
with predominantly polymorphonuclear leukocytes instead
of the typical pleural lymphocytosis of TB. Less com-
monly, high pleural fluid ADA has also been reported in
malignancies (5%, particularly lymphomas), infectious
diseases (e.g., brucellosis, Q fever), and connective tissue
diseases (e.g., rheumatoid arthritis, systemic lupus erythe-
matosus) [5, 9, 16].
Nontuberculous lymphocytic pleural effusions seldom
exceed the ADA cutoff set for TPE. Three series measured
the pleural ADA levels in a total of 630 patients with
lymphocytic exudative effusions not due to TB [22–24].
Only 18 patients (2.8%) had ADA levels above 40 U/l. The
diagnoses in the 18 patients included 6 cases of lymphoma,
5 parapneumonic effusions, 3 lung carcinomas, and 1 each
of colorectal carcinoma, acute lymphoid leukemia, meso-
thelioma, and idiopathic pleural effusion.
The ADA2 isoenzyme is primarily responsible for the
increased total ADA activity in TPE, whereas high ADA in
nontuberculous pleural effusions (e.g., empyemas or cer-
tain malignancies) is due to an increase in the ADA1 iso-
enzyme. Nevertheless, although the determination of the
ADA2 isoenzyme is at least as sensitive and more specific
than that of total ADA activity for diagnosing TPE (cutoff
[40 U/l) [25], this procedure is infrequently performed.
Currently, pleural fluid ADA is routinely employed in
the diagnostic workup of pleural effusions in countries
where TB is endemic. In areas where the prevalence of TB
is low, however, the negative predictive value remains high
even though the positive predictive value of pleural ADA
declines. Therefore, this test can still be considered a
valuable screening tool for TPE.
265
Interferon-c
Nonstimulated pleural fluid interferon-c levels are also
very efficient for differentiating TB from nontuberculous
pleural effusions [26]. Interferon-c is a cytokine released
by activated CD4? T lymphocytes that increases the my-
cobactericidal activity of macrophages. A meta-analysis of
22 studies that included 782 patients with TB and 1319
patients with nontuberculous pleural effusions has shown
that the mean sensitivity of the interferon-c assay was 89%,
the mean specificity was 97%, and the maximum joint
sensitivity and specificity was 95% [27]. Establishing a
precise discriminating cutoff value is not possible because
the methods of estimation and units differ between studies.
A previous meta-analysis that reviewed 31 studies on ADA
(4738 patients) and 13 studies on interferon-c (1189
patients) concluded that both ADA and interferon-c are
reasonably accurate in diagnosing TB pleuritis [28]. The
results revealed a maximum joint sensitivity and specificity
of 93% for ADA and 96% for interferon-c [28]. The long
historical success of the simple ADA test in countries with
a high prevalence of TB makes it the preferred test. As in
the ADA assays, hematologic malignancies and empyemas
can cause elevated interferon-c levels in pleural fluid [29].
On the other hand, interferon-c-release assays (IGRAs)
that have emerged as attractive alternatives to the tuber-
culin skin test for detecting latent TB infections might also
contribute to the diagnosis of TPE [30]. The IGRAs are T-
cell-based in vitro assays that measure interferon-c release
by sensitized T cells from peripheral blood or pleural fluid
in response to highly M. tuberculosis-specific antigens such
as early secretory antigen (ESAT)-6 and culture filtrate
protein (CRP)-10. Two IGRAs, QuantiFERON-TB Gold
and T-SPOT.TB, are now commercially available. The
latter may be more sensitive but less specific than the
former, and both are affected far less by immunosuppres-
sion than the tuberculin skin test [31]. A few preliminary
investigations have shown that the sensitivity of IGRAs
performed on pleural fluid mononuclear cells for the
diagnosis of pleural TB ranges from 45% [32] to 95% [33].
The specificity in one study was 76% [34], most likely
because of coincidental latent or coexisting TB in patients
with nontuberculous effusions. Due to the limited evidence
available, the use of these tests in patients with pleural
effusion cannot yet be recommended for diagnostic pur-
poses [30, 35].
Mycobacterial Stain and Culture
In patients with suspected pleural TB, it is important to
obtain sputum in addition to pleural fluid for the acid-fast
bacilli smear and mycobacterial culture, even in the
absence of parenchymal involvement. In one study of 84
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patients with TB pleuritis, induced sputum was smear-
positive in 12% and culture-positive in 52% of cases [36].
Contrary to that described previously, the yield of induced-
sputum cultures for M. tuberculosis was not influenced by
the radiographic evidence of pulmonary involvement [36].
Direct examination of pleural fluid by Ziehl-Neelsen
staining detects acid-fast bacilli in only 5% of TB effusions
[6], unless the patient has a tuberculous empyema or HIV
infection [16]. In a series of 254 patients with TB pleurisy
from a single center, 93 patients (36.6%) had positive
cultures of pleural fluid in the Löwenstein-Jensen medium
[6]. Pleural fluid and sputum cultures have a higher yield in
HIV-positive patients than in patients without HIV infec-
tion. In addition, the use of a BACTEC system with bed-
side inoculation provides higher yields and faster results
than conventional methods. These points were addressed in
a study of 109 HIV-positive and 33 HIV-negative patients
with TB pleurisy [37]. The pleural fluid cultures were
positive according to the BACTEC system in 24% of HIV-
negative and 75% of HIV-positive individuals, whereas the
cultures were positive according to the Löwenstein-Jensen
medium in 12% of HIV-negative patients and 43% of HIV-
positive patients. In the same study, the mean time before
the identification of positive cultures was significantly
lower using BACTEC than Löwenstein-Jensen medium
(3.5 vs. 4.7 weeks) [37]. In another study, the use of a
BACTEC system reduced the average detection time of M.
tuberculosis in pleural fluid and pleural biopsy specimens
by 50% compared to that of Löwenstein-Jensen medium
(13 vs. 28 days) [38].
With regard to pleural tissue specimens, the largest pub-
lished series (including 248 patients with pleural TB who
underwent needle biopsy of the pleura) reported that Ziehl-
Nielsen staining and culture of the biopsy were positive in 64
(26%) and 140 (56%) subjects, respectively [6].
The recently developed microscopic-observation drug-
susceptibility (MODS) assay is a low-cost ($3 per test),
low-tech, highly sensitive, and relatively rapid liquid cul-
ture method for M. tuberculosis that provides simultaneous
drug-susceptibility data [39]. In a recent study of 70
patients with confirmed pleural TB, MODS culture was
significantly more sensitive than Löwenstein-Jensen cul-
ture of either biopsy (81% vs. 51%) or pleural fluid (20%
vs. 7%) specimens [40]. In addition, MODS culture
shortened the median time to diagnosis compared with that
of conventional culture (i.e., 11 days vs. 24 days for the
culture of biopsy specimens) [40].
Nucleic Acid Amplification Tests
The conventional bacteriological methods used for diag-
nosing pleural TB (a paucibacillary disease) lack sensitiv-
ity and are time-consuming. Nucleic acid amplification
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Lung (2009) 187:263–270
(NAA) assays amplify M. tuberculosis-specific nucleic
acid sequences with a nucleic acid probe, enabling direct
detection of M. tuberculosis in clinical specimens like
pleural fluid within hours of their receipt. Two assays, the
AMPLICOR MTB and the AMTD, are widely available for
commercial use. The pooled analysis of the data from 20
studies related to the use of pleural fluid NAA tests con-
cluded that these tests demonstrated reasonably high
specificity (97% for commercial and 91% for in-house
tests) but generally poor and variable sensitivity (62% for
commercial and 76.5% for in-house tests) for diagnosing
TB pleurisy [41]. Almost identical results were obtained in
another systematic review and meta-analysis of 40 studies
[42]. It is believed that the disappointingly low sensitivities
of NAA techniques might be due to the presence of
inhibitors in the pleural fluid or to intracellular sequestra-
tion of mycobacteria. Thus, the inconsistent results of
different studies and the high cost of the NAA tests (US
$25-50 per test) limit their use to investigational settings.
Pleural Biopsy
Obtaining pleural tissue through closed-needle biopsy or
medical thoracoscopy is still considered a reference pro-
cedure in the evaluation of suspected pleural TB. Closed
pleural biopsy performed by experienced physicians dem-
onstrates granulomas, with or without caseous necrosis, in
approximately 80% of the cases. However, its diagnostic
yield rises to 90% if the pleural tissue is sent for culture [6].
Even when granulomas are not visualized, the biopsy
specimen should be examined for acid-fast bacilli and
culture [5, 16].
Taking into account the high diagnostic accuracy of both
the pleural ADA test and the closed-needle biopsy, thora-
coscopy is usually unnecessary to establish the diagnosis of
a tuberculous effusion. However, it may be useful in
exceptional circumstances such as when ADA is not
available and closed pleural biopsy fails to confirm the
diagnosis because of sampling error. In this case, thora-
coscopy permits biopsies to be taken under direct vision
and has a diagnostic accuracy of virtually 100% [43].
Thoracoscopy is also useful when lysis of adhesions is
indicated for more effective drainage of loculated effusions
or when larger quantities of tissue are required for culture
in suspected drug-resistance cases. Helpful diagnostic tests
for pleural TB are summarized in Table 1.
Combination of Tests
Combinations of tests, especially combinations that include
ADA, seem to perform better than any single test [8, 15,
26, 44]. A decision tree analysis that contained simple
Lung (2009) 187:263–270 267

Table 1 Studies for diagnosing pleural tuberculosis

Test Notes

Chest X-ray Lung infiltrates with or without cavitation in apical lobes or apical segments of the lower lobes
(reactivation TB) may be seen on 20% of chest X-rays
Tuberculin skin test False negative results occur in up to 25% of cases
Sputum induction Induced sputum should be obtained in all patients with suspected pleural TB. Sensitivity improves with
multiple specimens. In one study, sputum cultures were positive in 52% of patients with tuberculous
pleuritis [36]
Pleural fluid ADA The most valuable test for establishing the diagnosis of pleural TB in moderate-to-high TB incidence
settings. Pleural ADA levels greater than 35–40 U/l argue strongly for TB in patients with a
lymphocytic exudate (sensitivity and specificity [90%)
Pleural fluid IF-c Accuracy similar to ADA test but more expensive
Interferon-c release assays applied to Unable to distinguish between latent or active TB. False-positive results are common in endemic
pleural fluid regions
Pleural fluid culture (LJ media) Positive in 25–35% of TB cases but higher yield in HIV coinfected patients
BACTEC (liquid culture media) on Higher yield and faster results than LJ media
pleural specimensa
MODS (liquid culture media) on Low-cost, low-tech tool which is faster and more sensitive than LJ media. It allows drug-susceptibility
pleural specimensa testing for multidrug-resistant TB
Nucleic acid probes on pleural fluid Results available in a few hours but the test is expensive and generally has low sensitivity
Pleural biopsy Necrotizing granulomas and/or cultures of those biopsies are positive in more than 90% of TB cases
ADA adenosine deaminase, IF interferon, LJ Löwenstein-Jensen, MODS microscopic-observation drug-susceptibility, TB tuberculosis
a
Pleural fluid or pleural biopsy specimens

clinical (age, fever) and laboratory (pleural fluid ADA)
data allowed differentiation between TB and malignant
effusions with high accuracy (area under the
curve = 0.976) [8]. In brief, a young patient (\35 years)
with fever, a lymphocytic pleural exudates with high ADA
activity ([38 U/l), and negative cytological studies is
assumed to have a TB pleurisy until proven otherwise [8].
In another study, the combination in pleural fluid of high
ADA ([45 U/l) and low C-reactive protein (\4 mg/dl)
levels resulted in the correct classification of 92% of TB
effusions [44]. These models can be highly relevant to
practicing clinicians, particularly in areas with a high or
moderate incidence of TB.
diagnosing TB unless a high clinical probability of TPE
remains (i.e., febrile young patient from an endemic area of
TB with a negative pleural fluid cytological examination).
Alternatively, if pleural ADA levels exceed 40 U/l, the
physician can assume the diagnosis of pleural TB. Anti-TB
chemotherapy should be initiated, provided that the diag-
nosis occurs in a country with a high or moderate incidence
of TB and low drug-resistance rates. A tissue diagnosis by
pleural biopsy with accompanying culture and sensitivity
data should be pursued only if a patient demonstrating a
lymphocytic exudate and high ADA concentration belongs
Clinical suspicion of pleural TB

Biochemistries,
Thoracentesis
Recommended Diagnostic Approach MT cultures & cytology

Lymphocytic exudate
According to the preceding text, epidemiological infor- & negative cytology
mation should influence physician diagnostic habits for
normal Consider non-TB
suspected pleural TB. The first diagnostic step always ADA?
AFB and MT cultures effusions
includes the processing of pleural fluid for biochemical and >35-40 U/L
of sputum & TST
microbiological studies as well as examination of the
sputum for mycobacteria. If the physician is then con- Low Incidence of TB? Moderate-high
fronted with an exudative pleural effusion of lymphocytic High MT resistance? Low
predominance, pleural fluid ADA can be used as a
screening test regardless of the prevalence of TB in the Pleural biopsy Treat as TB
specific geographical area [45]. An ADA activity less than
Fig. 1 Algorithmic approach to pleural tuberculosis. ADA adenosine
40 U/l virtually rules out TB and no further diagnostic deaminase, AFB acid-fast bacilli, MT M. tuberculosis, TB tubercu-
procedures (pleural biopsy) should be necessary for losis, TST tuberculin skin test

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to a region with either a low epidemiological burden of TB
(e.g., annual incidence of less than 25 cases/100,000) or
high levels of mycobacterial resistance (e.g., eastern Eur-
ope). Figure 1 suggests an algorithmic approach for diag-
nosing pleural TB.
Treatment
In many cases, pleural TB is a self-limited disease; how-
ever, about half of untreated patients would subsequently
develop some form of the active disease [5, 9]. Treatment
of TPE does not differ from that used for pulmonary TB
(Table 2). The recommended treatment involves a 6-month
multidrug regimen (2HRZE/4HR). Although it is likely
that the standardized regimen without ethambutol would be
a valid treatment option, this drug should be included
whenever primary resistance to at least one first-line drug is
greater than 4% [46]. For example, primary resistance rates
to isoniazid and rifampin in Catalonia (Spain) were
reported to be 7.2 and 2.8%, whereas the rate of multidrug
resistance (MDR) to isoniazid and rifampin ranged from
0.7% (autochthons) to 1.8% (immigrants) in 2007 [47]. In a
comprehensive epidemiological analysis of pleural TB in
the United States, 9.9% of patients had isolates resistant to
at least one first-line drug. Furthermore, MDR TB was
detected in 1% of cases [2]. The drug-resistant pattern of
pleural TB broadly reflects that of pulmonary TB. Overall,
MDR TB represents about 5% of all TB cases in the world
[48]. China, India, and the Russian Federation are esti-
mated to have the highest number of MDR TB cases.
Extensively drug-resistant TB (XDR TB) refers to MDR
TB isolates with further resistance to a second-line,
injectable agent and a fluoroquinolone. Surveillance data
on XDR TB is limited, but it represents 1.9% of MDR TB
cases in the United States [48].
The treatment of pleural TB in patients with HIV
infection should follow the same principles as that for
people without HIV infection. However, drug interactions
of rifampin with antiretroviral drugs are a significant con-
cern. Rifampin is a potent inducer of the cytochrome P-450
enzyme and should not be used with protease inhibitors and
most non-nucleoside reverse transcriptase inhibitors, with
the exception of efavirenz [49]. Adjusted doses of rifabutin
are an alternative. Even so, rifampin-containing regimens
can be prescribed if the selected antiretroviral drugs
include efavirenz and two nucleoside transcriptase inhibi-
tors (e.g., tenofovir and emtricitabine) (Table 2). One-third
of patients with HIV receiving treatment for TB at the time
of antiretroviral treatment develop a clinical deterioration
due to an immune reconstitution inflammatory syndrome
[50]. Therefore, unless the patient exhibits profound
immunosuppression (CD4 \100 cells/mm3), delaying the
initiation of antiretroviral therapy until at least 2 months
after the beginning anti-TB therapy is preferred.
The response of TPE to therapy is generally good, with
resolution of fever within 2 weeks and pleural fluid
resorption within 6 weeks [51]. During the initial weeks of
therapy, effusions may paradoxically enlarge in a small
minority (10-15%) of patients, without implying treatment
failure [5].
Routine complete drainage of pleural fluid at the time of
diagnosis does not appear to improve mid- and long-term
outcomes [52]. If the patient is dyspneic from a large
pleural effusion, however, a therapeutic thoracentesis
should be performed. Two small series suggest that pigtail

Table 2 Drug treatment of pleural tuberculosis

Condition Suggested regimena Notes

HIV-negative patients 2 HRZE/4 HR If the patient has cavitary disease and the sputum remains culture-positive after
2 months of therapy, the continuation phase should be extended to 7 months
HIV-positive patients The optimal time to start ART in HIV-related tuberculosis depends on the CD4 cell
count: if it is \0.100 9 109 cells/l, start ART after 2 or more weeks of tuberculosis
therapy; if it is between 0.100 and 0.350 9 109 cells/l, start ART during the
continuation phase of tuberculosis therapy; if CD4 cell count is [350 9 109 cells/l,
delay ART until treatment for tuberculosis is completed
2 HRZE/4 HR Rifampin can be used for the treatment of tuberculosis in patients whose ART includes
the NNRTI efavirenz and 2 NRTIs (e.g., Atripla)
2 HRbZE/4 HRb For patients receiving PIs, rifampin should be replaced by rifabutin.
A potential ART regimen in these cases could be Truvada plus one of the following:
Kaletra, Lexiva/Norvir, Reyataz/Norvir, or Prezista/Norvir
Evidence of decreased antiretroviral drug activity should be assessed periodically by
measuring the HIV RNA levels
ART antiretroviral therapy, E ethambutol, H isoniazid, HIV human immunodeficiency virus, NNRTI non-nucleoside reverse transcriptase
inhibitor, NRTI nucleoside reverse transcriptase inhibitor, PI protease inhibitor, R rifampin, Rb rifabutin, Z pyrazinamide
a
Duration (months) initial phase/continuation phase

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drainage and instillation of fibrinolytics, in addition to anti-
TB medication, in patients with symptomatic loculated TB
effusions may hasten the resolution of pleural effusion and
reduce the incidence of residual pleural thickening [10, 53].
It should be noted that residual pleural thickening ([1 cm)
at the end of treatment has been reported in approximately
25% of cases. However, this decreases with time and has
negligible functional consequences [54].
A Cochrane review found no clear evidence supporting
the use of corticosteroids as adjunctive therapy in people
with TPE. Furthermore, in patients coinfected with HIV,
there is concern that corticosteroids may increase the risk
of Kaposi’s sarcoma [55]. Nevertheless, in selected patients
who continue to have severe systemic symptoms (e.g.,
fever) after 2 weeks of anti-TB treatment and therapeutic
thoracentesis, a short course of corticosteroids may be
beneficial.
Tuberculous empyema represents an uncommon
chronic, active infection of the pleural space [56]. A fibrous
membrane encapsulates thick pus and calcification can
occur. Acid-fast bacilli smears and cultures are usually
positive. Penetration of antituberculous drugs is impaired,
and surgical drainage is often needed to control the situa-
tion. A functionally incapacitating fibrin-trapped lung or
overt fibrothorax that results from a tuberculous pleural
effusion is rare and requires surgical decortication.
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