Egyptian Journal of Chest Diseases and Tuberculosis (2015) 64, 97–102

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The Egyptian Society of Chest Diseases and Tuberculosis

Egyptian Journal of Chest Diseases and Tuberculosis

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ORIGINAL ARTICLE

Role of thoracentesis in the management

of tuberculous pleural effusion
a,*
Mohammed A. Agha , Mahmoud M. El-Habashy a, Mohamed A. Helwa b,
Rehab M. Habib c

a
Chest Department, Faculty of Medicine, Menoufiya University, Egypt
b
Clinical Pathology Department, Faculty of Medicine, Menoufiya University, Egypt
c
Radiology Department, Faculty of Medicine, Menoufiya University, Egypt

Received 23 September 2014; accepted 9 October 2014

Available online 13 November 2014

KEYWORDS
Adenosine deaminase;
Thoracentesis;
Tuberculous pleural effusion
Abstract Background: Tuberculous pleural effusion (TPE) is the second most common form of
extrapulmonary tuberculosis (EPTB). Up to 50% after treatment complicated with pleural thicken-
ing. Pleural biopsy has been considered the gold standard in diagnosis of TPE but it is invasive, so
that pleural fluid markers of TPE have been extensively evaluated as an alternative to pleural
biopsy. Thoracentesis for measuring these fluid markers is important.
Aim: Assessing the value of diagnostic thoracentesis (by measuring pleural adenosine deaminase
levels) and role of therapeutic thoracentesis in preventing pleural thickening.
Subjects and methods: 10 cases with transudative pleural effusion and 45 cases with already diag-
nosed exudative effusion (30 cases of TPE, and 15 cases of Malignant PE) were included. 50 ml
pleural fluid samples were aspirated and sent for measuring ADA levels. The 30 cases of TPE were
classified into 2 equal groups the 1st group started 6 months anti tuberculous therapy plus repeated
thoracentesis while the 2nd started anti tuberculous therapy only. Chest CT scan was done after 2
and 6 months for assessment of pleural effusion and pleural thickening.
Results: Patients with tuberculous pleural effusion had higher pleural effusion ADA levels
(mean ± SD 68.51 ± 24.06) than those with malignant pleural effusion (mean ± SD
25.47 ± 12.09) or transudative pleural effusion (mean ± SD 16.58 ± 2.93) and these levels had
highly a significant difference (P-value <0.001). Also, there was a significant difference (P-value
<0.05) between levels of ADA in malignant and transudative pleural effusion. Using a cut-off point
of the pleural fluid ADA (30.49 IU/L) with AUC of 96.7 (sensitivity 96.7%, specificity 84%, NPV
88%, PPV 95% and accuracy 91%) discrimination between tuberculous and other causes of pleural
effusion occurred. Regarding the pleural thickening, after 2 months of ttt, in group I, 3 cases devel-
oped pleural thickening, while in group II, 9 cases developed thickening. After 6 months, there was
one case of pleural thickening in group I, while in group II, 5 cases developed pleural thickening.
And there was a significant difference (P value <0.05) between both groups, after 2 and 6 months
of treatment.

* Corresponding author at: Chest Department, Menoufiya University, Shebin Elkom, Egypt. Mobile: +20 1004774422.
E-mail address: drmohammedagha@yahoo.com (M.A. Agha).
Peer review under responsibility of The Egyptian Society of Chest Diseases and Tuberculosis.
http://dx.doi.org/10.1016/j.ejcdt.2014.10.001
0422-7638 ª 2014 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier B.V. All rights reserved.
98
Conclusions: Thoracentesis is very important in the diagnosis of TPE either through diagnostic
thoracentesis by measuring fluid markers such as ADA or therapeutic thoracentesis which is not
only important for relieving dyspnea but also in preventing occurrence of pleural thickening that
complicated cases of TPE.
ª 2014 The Egyptian Society of Chest Diseases and Tuberculosis. Production and hosting by Elsevier
Introduction
Tuberculosis (TB) is a major public health problem in develop-
ing countries [1]. It is important to consider the possibility of
tuberculous pleuritis in all patients with an undiagnosed
pleural effusion. TB pleural effusion is the second most
common form of EPTB, only less frequent than lymph node
TB [2]. In contrast to pulmonary TB, most TB pleural effu-
sions manifest as an acute illness, with approximately one third
of patients being symptomatic for less than 1 week and two
thirds for less than 1 month. The most common presenting
symptoms are pleuritic chest pain (75%) and nonproductive
cough (70%). TB pleural effusion is being increasingly recog-
nized, even in developed nations, as the incidence of EPTB
has more than doubled following the HIV pandemic [3].
Between 3% and 25% of patients with tuberculosis will have
tuberculous pleuritis [3]. Pleural fluid cultures are positive for
Mycobacterium tuberculosis in less than 40% and smears are
virtually always negative. A pleural biopsy has been considered
the gold standard in diagnosis of TPE but it is invasive [4]. The
diagnosis cannot be established in 10–20% of the patients with
these methods even in the best conditions [4]. Pleural fluid
markers of TPE have been extensively evaluated as an attrac-
tive alternative to pleural biopsy.
Polymerase chain reaction (PCR) is an expensive diagnostic
test. Hence many markers that may be helpful in the differen-
tial diagnosis were studied in the pleural fluid. Two of these,
ADA and interferon gamma are the most widely used and cur-
rently the most accepted tests [5]. Especially ADA has been
more commonly preferred for the diagnostic algorithms in
the countries with a moderate to high incidence of tuberculosis
because it is a more inexpensive method that can be accessed
more quickly [6]. ADA is an enzyme catalyzing the conversion
of adenosine and deoxyadenosine to inosine and deoxyinosine
in the purine degradation pathway. Its quantity increases in
the immature and non-differentiated T-lymphocytes following
mitogenic and antigenic stimulation [7]. It has been estimated
that up to 50% of tuberculous pleural effusions develop pleu-
ral thickening and such development can result in restrictive
lung movement [8].
Aim of the work
The aim of this work was to study the role of diagnostic
thoracentesis assessed by measuring pleural ADA levels in
diagnosing tuberculous pleural effusion and the value of using
therapeutic thoracentesis beside anti-tuberculous therapy in
preventing pleural thickening associated with tuberculous
pleural effusion.
M.A. Agha et al.
B.V. All rights reserved.
Subjects and methods
During the period from March 2013 to June 2014, 55 patients
with already diagnosed pleural effusion admitted to the Chest
Department in Menoufiya University Hospital, Egypt, were
included in the study. After the diagnosis of pleural effusion
had been confirmed, thoracentesis was done. Using Light’s ori-
ginal criteria (ratio of pleural fluid/serum protein > 0.5, ratio
of pleural/serum LDH >0.6 or pleural fluid LDH more than
two-thirds of the upper limit of normal serum value), 10
patients with transudative pleural effusions were diagnosed.
Of the 45 patients with exudative pleural effusion, 30 cases
were tuberculous (diagnosed with Abram’s needle biopsies),
and 15 cases were malignant pleural effusion (diagnosed either
with cytology or histopathology).
Exclusion criteria
- Tuberculous pleural effusion diagnosed with VATS.
- TB pleuritis in patients with hepatic or renal impairments.
- Presence of pleural thickening before starting anti-tubercu-
lous treatment.
Ethical research approval from our hospital’s ethics com-
mittee and informed consent from the patients were obtained.
Step 1: thoracentesis was done for the already diagnosed 45
exudative pleural effusion and 10 transudative cases and sent
for measuring adenosine deaminase (ADA).
Specimen collection [9]
For each subject, at least 50 mL of pleural fluid was collected
in a syringe during thoracentesis. ADA activity was measured
by an auto analyzer using commercially available kits. The lab-
oratory clinical pathologist was blinded to the diagnosis of
each patient.
Step 2: Thirty tuberculous cases diagnosed with Abram’s
needle were classified into 2 groups; group I included 15 cases
that started anti-tuberculous therapy associated with repeated
therapeutic thoracentesis and group II included 15 cases that
started anti TB therapy alone for 6 months. Follow up chest
computed tomography (CT) scans were done following 2 and
6 months of treatment.
Radiologically: Using plain chest X rays (CXR), pleural
effusions were classified into; mild (border of effusion rising till
lower border of the anterior end of the 5th rib; moderate
(border of effusion rising till lower border of the anterior
end of the 3rd rib; and massive (border of effusion rising above
the 3rd rib) [10]. Chest computed scans were done 3 times; 1st
Role of thoracentesis in the management of tuberculous pleural effusion
before starting treatment, 2nd after 2 months of treatment and
the 3rd following 6 months of treatment.
Anti-tuberculous therapy [11]: Initial phase of a 6-month
regimen should consist of a 2-month period of isoniazid
(INH), rifampicin, pyrazinamide and ethambutol. The second
phase of the treatment was INH and rifampin given for
4 months.
Thoracentesis was done for group I by inserting the needle
in the most dependent area posteriorly (1000–1500 cc daily) till
spontaneous cessation of the fluid occurred or the patients
developed respiratory symptoms such as cough or dyspnea.
Statistical methodology [12]
The data collected were tabulated and analyzed by SPSS
(statistical package for the social science software) statistical
package version 11 on IBM compatible computer. Quantita-
tive data were expressed as mean and standard deviation
(X ± SD). Kruskal Wallis test was used for the comparison
of more than two groups of non-normally distributed
variables. Qualitative data were expressed as number and per-
centage (No. & %) and analyzed by applying chi-square test
(v2). The ROC (receiver operating characteristic) curve was
used to detect the cutoff value with highest sensitivity and
specificity.
P-value >0.05 was considered statistically non-significant.
P-value 60.05 was considered statistically significant.
P-value 60.01 was considered statistically highly
significant.
Results
Fifty-five patients with already diagnosed pleural effusion were
included in this study. 15 cases were malignant pleural
effusions (10 malignant mesothelioma and 5 metastasis from
carcinoma), 10 cases of transudative pleural effusions, and
the remaining 30 cases were tuberculous pleural effusions
(diagnosed with Abram’s needle). Table 1 shows that regard-
ing age, patients with tuberculous pleural effusion were youn-
ger (mean ± SD were 36.97 ± 9.07) than Patients with
malignant pleural effusion (mean ± SD were 54.27 ± 7.55)
and patients with transudative pleural effusions (mean ± SD
were 61.30 ± 8.33) and this difference was highly significant
Table 1 Comparison between different groups in the study.
Tuberculous pleural Malignant pleural Transudative pleural
effusion (TPE) effusion (MPE) effusion (TrPE)
Mean ± SD Mean ± SD Mean ± SD
Age 36.97 ± 9.07 54.27 ± 7.55 61.30 ± 8.33
Gender
Male 15 (50%) 8 (53.3%) 5 (50%)
Female 15 (50%) 7 (46.7%) 5 (50%)
Lymphocytes (%) 77.8 ± 21 76 ± 16.1
LDH (IU/L) 699 ± 154 715 ± 98
Protein (g/dl) 5.24 ± 2.21 5.11 ± 1.12
SD: standard deviation. P1: significance between TPE and MPE. P2: significance between TPE and TrPE. P1: significance between MPE and
TrPE. *HS: highly significant difference. NS: non-significant difference. LDH: lactate dehydrogenase.
99
(P value <0.001), while there was non-significant difference
between malignant and transudative effusions (P value
>0.05). Also Table 1 shows that there was non-significant dif-
ference among all groups regarding gender. Patients with
tuberculous pleural effusion had higher pleural effusion
ADA levels (mean ± SD 68.51 ± 24.06) than those with
malignant pleural effusion (mean ± SD 25.47 ± 12.09) or
transudative pleural effusion (mean ± SD 16.58 ± 2.93) and
these levels had a highly significant difference (P-value
<0.001) (Table 2). While the same table shows that there
was a significant difference (P value <0.05) between levels of
ADA in malignant and transudative pleural effusion. Table 3
and Fig. 1 show that using a cut-off point of pleural fluid
ADA (30.49 IU/L) with AUC of 96.7 (sensitivity 96.7%, spec-
ificity 84%, NPV 88%, PPV 95% and accuracy 91%) discrim-
ination between tuberculous and other causes of pleural
effusion occurred. The 2 groups of tuberculous pleural
effusions were comparable as there were non-significant
differences regarding age, gender, and ADA (P-value >0.05)
(Table 4). Of the 30 cases of TB effusion, group I had 6 cases
with massive effusion and 9 cases with moderate effusion,
while group II had 7 cases with massive and 8 cases with mod-
erate effusions. After 2 months of anti-tuberculous therapy,
group I had 2 cases with mild effusions with resolved effusions
in all other cases, while group II had 10 cases of mild effusion
and 3 cases still had moderate effusion. After 6 months, there
was no effusion in group I while in group II, 4 cases still had
mild pleural effusion (Table 5). Regarding pleural thickening,
after 2 months of treatment, in group I, 3 cases developed pleu-
ral thickening, while in group II, 9 cases developed thickening.
After 6 months, there was one case of pleural thickening in
group I, while in group II, 5 cases developed pleural thicken-
ing. And there was a significant difference (P-value 60.05)
between both groups, after 2 and 6 months of treatment
(Table 6).
Discussion
Exudative lymphocytic pleural effusions are commonly
encountered in clinical practice but often constitute difficult
diagnostic problems. The two most common causes are malig-
nancy and tuberculous effusions. The diagnosis of tuberculous
pleural effusion is important because tuberculosis is normally a
Kruskal Wallis test P value
33.86 <0.001*HS P1 < 0.001*HS
P2 < 0.001*HS
P3 > 0.05*S
Chi square test
0.049 >0.05 NS
0.191 P1 > 0.05 NS
12.7 P1 > 0.05 NS
2.43 P1 > 0.05 NS
100 M.A. Agha et al.

Table 2 Validity of pleural ADA levels in the diagnosis of tuberculous pleural effusions.
Tuberculous Malignant Transudative Kruskal Wallis test P value
pleural effusion pleural effusion pleural effusion
Mean ± SD Mean ± SD Mean ± SD
Pleural level of ADA (IU/L) 68.51 ± 24.06 25.47 ± 12.09 16.58 ± 2.93 36.60 <0.001*HS P1 < 0.001*HS
P2 < 0.001*HS
P3 < 0.05*S
ADA: adenosine deaminase. SD: standard deviation. P1: significance between TPE and MPE. P2: significance between TPE and TrPE. P1:
significance between MPE and TrPE. *HS: highly significant difference. *S: significant difference.

introduced. Many markers that may be helpful in the differen-

Table 3 ROC curve for ADA in the diagnosis of TB effusion.
tial diagnosis were studied in the pleural fluid. Two of these,
ADA and interferon gamma are the most widely used and cur-
Roc curve Pleural ADA rently the most accepted tests. Especially ADA has been more
Cut off point 30.49 commonly preferred for the diagnostic algorithms in countries
Sensitivity 96.7 with a moderate to high incidence of tuberculosis because it is
Specificity 84 a more inexpensive method that can be accessed more quickly
PPV 88 [7]. ADA is an enzyme catalyzing the conversion of the aden-
NPV 95
osine and deoxyadenosine to inosine and deoxyinosine in the
Accuracy 91
AUC 0.96
purine degradation pathway. Its quantity increases in the
immature and non-differentiated T-lymphocytes following
ROC: receiver operating characteristic. AUC: area under the curve. mitogenic and antigenic stimulation [8]. The aim of this study
PPV: positive predictive value. NPV: negative predictive value.
was to assess the value of diagnostic and therapeutic thoracen-
ADA: adenosine deaminase.
tesis in the management of tuberculous pleural effusions. The
present work showed that tuberculous pleural effusion unlike
malignant pleural effusion tends to occur in younger age with
mean age of 36, 9, the previous finding is in agreement with
work of Aho [13] who stated that TB pleural effusion was con-
sidered a disease of the young, with a mean age of 28 years,
compared to 54 years for parenchymal tuberculosis. However,
Epstein [14] demonstrated a rise in the median age (56 years) at
the presentation of TB pleural effusions with 19% of patients
having reactivation disease. Patients with tuberculous pleuritis
tend to be younger than patients with parenchymal TB. In one
recent series from Qatar, the mean age of 100 patients with
tuberculous pleuritis was 31.5 years [15]. However, in industri-
alized countries the mean age of patients with tuberculous
pleuritis tends to be older because it is a reactivation TB
[16]. In a study from the USA, the mean age of 14,000 patients
reported to the Communicable Disease Center between 1993
Figure 1 ROC curve for ADA. and 2003 was 49.9 years [7]. Also Helmy et al. [17] who stated
mean age of the MPE group was significantly higher than the
TPE group (P < 0.0001). Valdes et al. [18] also found that the
treatable cause of exudative lymphocytic pleural effusion [4]. mean age of the tuberculous group was 33.9 ± 13.2 years that
The primary difficulty in getting a diagnostic confirmation of of the malignant group was 45.5 ± 16.8 years. In the present
tuberculous pleural effusion is the identification of mycobacte- study, patients with tuberculous pleural effusion had higher
ria in the pleural fluid. Many biological parameters have been pleural effusion ADA levels (mean ± SD 68.51 ± 24.06) than

Table 4 Characteristics of both groups of TB effusion.

No. Group I Group II Mann Whitney U test P value
(15) (15)
Age 35.73 ± 8.56 38.20 ± 9.70 0.738 >0.05NS
Gender Chi square
Female 8 (53.3%) 7 (46.7%) 0.13 >0.05NS
Male 7 (46.7) 8 (53.3%)
ADA 67.71 ± 22.30 69.31 ± 26.47 0.180 >0.05NS
ADA: adenosine deaminase. NS: non-significant difference. No.: number.
Role of thoracentesis in the management of tuberculous pleural effusion
Table 5 Extent of TB effusion before and after treatment.
Group I
Mild Moderate
Before therapy 0 9
After 2 mn 2 0
After 6 mn 0 0
mn: month. No.: number.
Table 6 Pleural thickening in the 2 groups of TPE following
treatment.
Group I Group II Chi square test P value
(15) (15)
After 2 mn 3 9 5.01 60.05*s
After 6 mn 1 6 4.66 60.05*s
mn: month. *s: significant difference.
those with malignant pleural effusion (mean ± SD
25.47 ± 12.09) or transudative pleural effusion (mean ± SD
16.58 ± 2.93) and these level were highly significant differ-
ences (P-value <0.001). And with a cut off value of
30.49 IU/L, the sensitivity, specificity, PPV, NPV and accuracy
of ADA in diagnosing tuberculous pleural effusions were
96.7%, 84%, 88%, 91%, and 95% respectively. The signifi-
cance of ADA in diagnosing tuberculous pleural effusion
found in our work was in agreement with many studies.[19–26]
Reechaipichitkul et al. [19] stated that patients with tubercu-
lous pleural effusion tend to have high levels of ADA in their
pleural fluid and found that the mean value of ADA in the
tuberculosis group was 93.2 (SD 56.5) U/L, which was signif-
icantly higher than the malignancy and miscellaneous groups
(P < 0.05). Liang et al. [20] concluded that, ADA determina-
tion is a relatively sensitive and a specific test for the diagnosis
of tuberculous pleurisy and the measurement of ADA in pleu-
ral effusion is thus likely to be a useful diagnostic tool for
tuberculous pleurisy with sensitivity 92% and 90% specificity.
In the study of Anil Chander and Shrestha [21] they concluded
that, pleural fluid ADA levels were significantly higher in
tuberculous pleural effusions as compared with transudate
cases, and ADA estimation is a very useful biomarker in estab-
lishing an accurate and early diagnosis in the tuberculous pleu-
risy patients. Also Krenke and Korczynski [22] studied 94
patients (28 cases of TPE and 66 cases of the non-TPE group).
They found that ADA activity was significantly higher in TPE
than in non-TPE (614.1 ± 324.5 vs. 15.1 ± 36.0 pg/ml,
P < 0.0001). The diagnostic sensitivity and specificity were
100% and 93.9% at the cut off value of 40.3 U/L). Patel and
Choudhury [23] analyzed 53 patients with TPE and 96.67%
had pleural fluid ADA > 40 IU/L. Kalantri et al. [24] assessed
204 cases; 50 were confirmed pleural TB, 104 were probable
pleural TB and 50 formed the non-TB group. For confirmed
and probable pleural TB cases, ADA showed a sensitivity
and specificity of 92% and 73%, respectively. Agarwal [25]
investigated 30 cases of TPE and showed sensitivity, specificity,
PPV and NPV of 92%, 80%, 95.8% and 66.66%, respectively.
Helmy et al. [17] found that with cutoff value of ADA for
diagnosing TPE was 30 U/L, the sensitivity of ADA was
101
Group II
Massive Mild Moderate Massive
6 0 8 7
0 10 3 0
0 4 0 0
80%, specificity was 85% and the diagnostic accuracy was
83.3%. Positive predictive value was 84.2%, and negative
predictive value was 81%. Also Castro et al. [26] evaluating
consecutive 410 non tuberculous lymphocytic pleural fluid
samples, were identified the levels of ADA above 40 U/L only
in seven cases (1.71%). They can accurately use ADA levels
<40 U/L to rule out the tuberculosis. In the study of Chen
[27] One hundred forty-seven exudative samples were nontu-
berculous (non-TB) and 63 were tuberculous (TB). There
was statistically significant difference (P < 0.0001) between
the means of pleural fluid ADA levels among the TB and
non-TB populations. With a cutoff value for diagnosing TB
effusions >55.8 U/L, with a sensitivity of 87.3% (95% CI:
76.5–94.3%) and specificity of 91.8% (95% CI: 86.2–95.7%).
The positive predictive value was 82.1% and the negative
predictive value was 94.4%. A pleural fluid ADA value <
16.81 IU/L suggests that a tuberculous effusion is highly
unlikely. However, Kaur et al. [28] showed a poor diagnostic
value of ADA in pleural, peritoneal and cerebrospinal fluid
in tuberculosis. But one limitation of their study was that all
the cases in the TPE group were not confirmed by the pleural
biopsy diagnostic method, which is considered to be the gold
standard method for its confirmatory detection. In the present
study, Of the 30 cases of TB effusion, group I had 6 cases with
massive effusion and 9 cases with moderate effusion, while
group II had 7 cases with massive and 8 cases with moderate
effusions. After 2 months of antituberculous treatment, group
I had 2 cases with mild effusions with resolved effusions in all
other cases, while group II had 10 cases of mild effusion and 3
cases still had moderate effusion. After 6 months, there was no
effusion in group I while in group II, 4 cases still had mild
pleural effusion. Regarding pleural thickening, after 2 months
of treatment, in group I, 3 cases developed pleural thickening,
while in group II, 9 cases developed thickening. After
6 months, there was one case of pleural thickening in group
I, while in group II, 5 cases developed pleural thickening.
And there was a significant difference (P-value 60.05) between
both groups, after 2 and 6 months of treatment. Our results are
in agreement with those of Bhayuna et al. [29] who found that
after 6 months of anti tuberculous treatment alone (group B) 5
cases remain with mild pleural effusion while no effusion was
found in the other group (group A) who treated with anti
tuberculous drugs beside therapeutic thoracocentesis and also
they found that the incidence of pleural thickening was higher
in group B and this limitation was confirmed radiologically
and with repeated pulmonary functions. However many
[30–32] studies concluded that the therapeutic thoracentesis
had no beneficial effects over anti tuberculous alone on
preventing pleural thickening and recommended therapeutic
thoracentesis only for relieving dyspnea associated with tuber-
culous pleural effusions.
102
Conclusion
Testing for pleural fluid ADA levels is an easy and inexpensive
method for establishing the diagnosis of TPE. Pleural fluid
ADA is a good fluid marker in differentiating between tuber-
culous and malignant pleural effusions and also between
transudative and exudative pleural effusions. Repeated thera-
peutic thoracocentesis should be added to the anti tuberculous
therapy in the management of tuberculous pleural effusion to
avoid the occurrence of pleural thickening. Further studies
should be done using therapeutic thoracentesis in a larger
number of patients and also the added value of corticosteroid
to the therapeutic thoracentesis in cases of tuberculous pleural
effusion should be assessed.
Conflict of interest
None.
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