European Journal of Internal Medicine 21 (2010) 419–423

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European Journal of Internal Medicine

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Original article

Diagnostic performance of adenosine deaminase activity in pleural fluid: A single-center

experience with over 2100 consecutive patients
José M. Porcel a,⁎, Aureli Esquerda b, Silvia Bielsa a
a
Pleural Diseases Unit, Department of Internal Medicine, Arnau de Vilanova University Hospital, Institut de Recerca Biomèdica de Lleida, Lleida, Spain
b
Pleural Diseases Unit, Department of Laboratory Medicine, Arnau de Vilanova University Hospital, Institut de Recerca Biomèdica de Lleida, Lleida, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To determine the diagnostic utility of adenosine deaminase (ADA) in a large series of pleural
Received 12 September 2009 effusions of different etiologies.
Received in revised form 6 December 2009 Methods: A retrospective study of 2104 consecutive patients presenting with pleural effusion was carried out
Accepted 11 March 2010 at a Spanish university hospital. ADA levels in pleural fluid were determined using a non-Giusti automatic
Available online 1 May 2010
kinetic assay, and a receiver operating characteristics curve analysis was applied to estimate their
discriminative properties.
Keywords:
Results: Pleural tuberculosis (TB) accounted for 221 (10.5%) effusions. Pleural fluid ADA N 35 U/L yielded 93%
Adenosine deaminase
Tuberculosis
sensitivity, 90% specificity, a positive likelihood ratio (LR) of 10.05 and a negative LR of 0.07 for the diagnosis of TB
Pleural effusion among lymphocytic exudates. The ADA activity was significantly higher in neutrophil- (111.6 U/L) than in
Empyema lymphocyte-rich (62.4 U/L; p = 0.002) TB effusions. Overall, more than 40% of parapneumonics and half of
Lymphoma lymphomatous effusions exceeded the cutoff set for TB. These were the only causes of ADA activity above 250 U/L.
When the prevalence of TB as a cause of exudative effusions is low (e.g., 1%), the estimated positive predictive
value of the ADA test may be as low as 7%, although the negative predictive value remains high (99.9%).
Conclusion: Where available, pleural ADA should be routinely used to rule TB in or out in areas with moderate to
high or low TB prevalence, respectively. A high ADA level is a characteristic not only of lymphocytic, but also of
neutrophilic TB effusions. An extremely high ADA activity should raise suspicion of empyema or lymphoma.
© 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction
Since its description 30 years ago [1], the measurement of pleural
fluid adenosine deaminase (ADA) activity is considered by some to be
an important reference standard for identifying pleural tuberculosis
(TB) in clinical practice [2,3], while by others it is merely an aid to
differential diagnosis of pleural effusion [4]. Central to this contro-
versy is whether pleural ADA can supplant pleural biopsy for the
evaluation of suspected TB.
Four meta-analyses on the diagnostic accuracy of pleural fluid ADA
have been published [5–8]. However, differences in ADA measurement
methods (Giusti's colorimetric method vs non-Giusti), as well as prob-
lems of publication bias (e.g., selection of English-language databases
and journals) and the modest methodological quality of some selected
studies raise questions concerning the reliability of the pooled measured
efficacy of the test. Despite these studies having concluded that the
test performance is reasonably good, incorporation of ADA to routinely
examine pleural fluid has not been as widespread as would be expected,
particularly in countries with low incidence of TB.
Some of the design flaws of the primary studies included in the meta-
analyses can be avoided by simply using a large series of consecutive
patients from a single center, as we did here. Our purpose was to
describe the operating characteristics of pleural fluid ADA in the
differential diagnosis of pleural effusions. Our hypothesis was that in an
area with a moderate incidence of TB, such as Catalonia (Spain) [9], ADA
has enough sensitivity and specificity to confirm or exclude TB, thus
allowing immediate therapeutic decisions to be made in patients with
lymphocytic exudates. In addition, we estimated the predictive values of
the pleural ADA test in different geographical areas, according to the
hypothetical prevalence of TB among patients presenting with an
exudative effusion. Finally, we investigated whether or not the
predominant white blood cell count in pleural fluid, either neutrophil
or lymphocyte, influences ADA activity in TB patients.
2. Methods

2.1. Subjects
⁎ Corresponding author. Department of Internal Medicine, Arnau de Vilanova
University Hospital, Avda Alcalde Rovira Roure 80, 25198 Lleida, Spain. We retrospectively reviewed all consecutive patients with pleural
E-mail address: jporcelp@yahoo.es (J.M. Porcel). effusion who underwent a diagnostic thoracentesis at the Arnau de

0953-6205/$ – see front matter © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2010.03.011
420 J.M. Porcel et al. / European Journal of Internal Medicine 21 (2010) 419–423

Vilanova University Hospital (Lleida, Spain) since January 1994 to July
2009, for whom pleural ADA was available. We recorded demographic,
serum (protein, lactate dehydrogenase — LDH) and pleural fluid data
(cell count and differential, protein, LDH, ADA) as well as the final
diagnoses. If a patient had been submitted to repeated thoracentesis,
only the results of the first were considered. The local ethics committee
approved the study protocol.
coefficient described the linear association between ADA and other
pleural fluid biochemical parameters. Two-tailed p values ≤0.05 were
considered statistically significant. All statistical analyses were con-
ducted with a statistical software package (SPSS, version 15.0; SPSS Inc;
Chicago, IL, USA).
3. Results

2.2. Diagnostic criteria 3.1. Patient characteristics and diagnoses

A pleural effusion was categorized as malignant if malignant cells A total of 2193 patients with pleural effusion were identified from
were demonstrated in pleural fluid or pleural biopsy. A diagnosis of our computerized database during the study period, of which pleural
probable malignant effusion was made in patients with a known fluid ADA was available in 2104 cases. Of these, there were 591 (28%)
primary malignancy and negative pleural fluid cytological findings, malignant effusions, 493 (23.4%) transudates, 380 (18%) parapneumo-
after ruling out benign causes of the effusion. TB pleuritis was diag- nic effusions, 221 (10.5%) TB, and 419 (20%) miscellaneous exudates
nosed if Ziehl–Neelsen stains or Lowenstein–Jensen cultures of (Table 1). Among the 221 patients with TB effusions, 13 (5.8%) were HIV
pleural fluid, sputum or pleural biopsy specimens were positive or positive. Of the 80 patients with definite TB pleuritis, a pleural biopsy
the latter showed granulomas in the parietal pleura. TB was con- exhibited caseating granulomas in 17, a pleural fluid culture was
sidered probable in patients with lymphocytic exudates and high ADA positive in 40, and a sputum specimen was positive in 37.
levels (N40 U/L) in the pleural fluid, which cleared in response to The median (quartiles) age was significantly lower in patients with
antituberculous therapy. Neither probable malignant nor probable TB TB (31, 24.5 to 44.5 years) than in those with transudates (77, 70 to
subgroups were considered for most calculations because of the 83 years), malignancies (70, 59 to 78 years), parapneumonics (57, 41
different reference diagnostic standard applied to these participants. to 73 years) and miscellaneous exudates (69, 53 to 77 years; all
Parapneumonic effusion was defined as any exudative effusion p b 0.001).
associated with bacterial pneumonia, lung abscess or bronchiectasis.
Uncomplicated parapneumonic effusions described those effusions 3.2. Pleural fluid ADA in the etiological groups
that were successfully resolved with antibiotics alone. Complicated
parapneumonic effusions referred to those non-purulent-appearing Median ADA concentrations for each pleural effusion group are
effusions that required at least drainage and, eventually, further described in Table 2 and represented in Fig. 1. Patients with TB had
interventions whereas empyema described pus within the pleural higher median ADA levels (63.8 U/L, 53.3 to 78.2 U/L) than patients
space. The causes of other pleural effusions were determined by well- with non-TB effusions (16.3 U/L, 9.9 to 25.1 U/L; p b 0.001). However,
established clinical criteria. Finally, the terms transudate and exudate when parapneumonic effusions were categorized as non-complicated,
were based on the cause of the effusion (e.g., transudates encompass complicated and empyemas, the latter exhibited the highest ADA
those effusions that were clearly due to heart failure, cirrhosis or concentrations along with the TB group (Table 3). Notably, none of the
nephrosis). patients with pleural effusions due to TB had an ADA test exceeding
250 U/L, a feature that was only present in 19 empyemas and 3
2.3. Pleural fluid measurements
Table 1
Pleural fluid total ADA levels were determined immediately after Etiology of pleural effusions.
thoracentesis by using an automated ultraviolet kinetic assay (Roche
Causes N (%)
Diagnostics, Barcelona, Spain) on different discrete analyzers (Hitachi
717 and 911 or Hitachi Modular DP, Roche Diagnostics, Mannheim, Malignancy 591 (28)
Lung 222
Germany), according to the manufacturer's instructions. Other bio-
Breast 104
chemical measurements were performed using standard methodol- Unknown primary 54
ogies. White blood cells were manually counted in a Thoma chamber, Lymphoma 45
whereas differential cell counts were performed on pleural fluid Ovarian 44
smears after Wright's staining by counting, whenever possible, 200 Gastrointestinal 33
Mesothelioma 14
cells.
Others 75
Heart failure 390 (18.5)
2.4. Statistical analysis Parapneumonics 380 (18)
Uncomplicated 131
Complicated 133
Continuous and categorical data are presented as medians (quartiles)
Empyema 116
and percentages, respectively. Between-group comparisons of quanti- Tuberculosis 221 (10.5)
tative variables were performed with the nonparametric Kruskal–Wallis Definite 80
test. When significant differences were indicated by the Kruskal–Wallis Probable 141
test, a Mann Whitney U test with the Bonferroni correction was used to Non-cardiac transudates 103 (5)
Hepatic hydrothorax 60
determine which pair-wise differences were significant. The operating
Others 43
characteristics of pleural fluid ADA for identifying TB among patients Miscellaneous exudates 419 (20)
with lymphocytic exudates were assessed in terms of sensitivity, Idiopathic 74
specificity and likelihood ratios (LR). For these calculations only patients Abdominal surgery 71
Pericardial diseases 69
with definite TB or malignant effusions were considered. The diagnostic
Trauma 57
cutoff for ADA was optimized using receiver operating characteristic Pulmonary embolism 35
curves and selecting those values that provided the greatest sum of Cardiac surgery 23
sensitivity and specificity. Predictive values of ADA test according to the Connective tissue diseases 13
hypothetical prevalence of TB among exudative effusions were Others 77
Total 2104 (100)
calculated using the Bayes' formula [10]. The Spearman's correlation
 J.M. Porcel et al. / European Journal of Internal Medicine 21 (2010) 419–423 421

Table 2 Table 3
Pleural fluid ADA levels in the study population. Pleural fluid ADA levels in parapneumonic and tuberculous effusions.

Etiology of pleural effusion No. of patients Pleural fluid ADA (U/L)a Pleural effusion categorization No. of patients Pleural fluid ADA (U/L)a

Malignancy 591 18.7 (11.3–25.4) Non-complicated parapneumonic 131 20.4 (12.4–29.1)

Transudates 493 10.9 (6.5–14.8) effusion
Parapneumonics 380 29.2 (17.9–55.4) Complicated parapneumonic effusion 133 30.5 (23–48)
Tuberculosis 221 63.8 (53.3–78.2)b Empyema 116 75.9 (22–186.2)b
Miscellaneous exudates 419 16.7 (10.4–23.9) Definite tuberculosis 80 63.8 (51.6–87.3)b
a Probable tuberculosis 141 63.7 (53.3–77.7)b
Values are expressed as median (25th and 75th percentiles).
b a
Significantly higher than the respective values in other groups (p b 0.001). Values are expressed as median (25th and 75th percentiles).
b
Significantly higher than the respective values in non-complicated and complicated
parapneumonics (p b 0.001).

lymphoid malignancies (2 non-Hodgkin lymphomas and 1 acute

lymphoid leukemia).
3.3. Operating characteristics of pleural fluid ADA for identifying
tuberculosis
We calculated the discriminative properties of pleural ADA in
patients with lymphocytic exudates, which is the typical clinical
scenario where TB should be suspected. After excluding patients with
probable TB or probable malignancy, 555 exudates with lymphocytic
predominance (59 TB and 496 non-TB) entered the analysis. An ADA
level above 35 U/L had a sensitivity of 93% (95% CI 86–99%), a
specificity of 90% (95% CI 88–93%), a positive LR of 10.05 (95% CI 7.57–
13.35), a negative LR of 0.07 (95% CI 0.03–0.18) and an area under the
receiver operating characteristic curve of 0.94 (95% CI 0.91–0.97) for
identifying a TB effusion.
3.4. Causes of false-positive ADA levels
Regardless of the predominant white blood cell count in the pleural
fluid, 16% (21/131) of non-complicated parapneumonics, 44% (59/133)
of complicated parapneumonics, 70% (81/116) of empyemas, and 10%
(36/363) of confirmed malignancies showed pleural ADA levels greater
than 35 U/L. Specifically, 57% (17/30) of lymphomas, 28.5% (4/14) of
mesotheliomas, 10% (4/39) of unknown primaries, and 6% (8/128) of
lung tumors reached the diagnostic cutoff for TB.
3.5. Pleural ADA levels in tuberculous effusions with predominantly
polymorphonuclear leukocytes
The median values for ADA activity were significantly more
elevated in 13 patients with neutrophilic TB effusions (111.6 U/L;
60.3 to 228.5 U/L) than in 64 patients with lymphocytic TB effusions
(62.4 U/L; 48.5 to 76 U/L, p = 0.002). These results did not change
when probable TB patients were also included in the calculations
(77.4 U/L vs 62.5 U/L, p = 0.017).

After excluding probable malignant effusions, there were 47 (9.5%)
non-TB lymphocytic exudates that exceeded the cutoff established for
pleural TB, which included 27 malignant, 15 parapneumonic and 5
miscellaneous effusions (3 post-traumatic, 1 rheumatoid pleuritis and 1
idiopathic). The primary tumors associated with false-positive ADA
results were as follows: lymphoma (12 patients), lung (5 patients),
mesothelioma (4 patients), unknown primary (3 patients) and other
hematologic malignancies (2 lymphatic leukemias, 1 multiple myeloma).
3.6. Predictive values of the pleural ADA test related to the prevalence of
tuberculosis
The positive predictive value of the ADA test decreased in parallel
with the hypothetical prevalence of pleural TB among exudative
effusions, whereas the negative predictive value actually remained
high (Fig. 2). In our series, where TB represented about 14% of all
exudative effusions, the respective positive and negative predictive

Fig. 1. Box-plots showing the minimum, 25th, 50th, and 75th percentiles, and the maximum pleural fluid ADA levels (log scale) in different diagnostic groups. Footnote: Outliers
(open circles) and extreme values (stars) are plotted separately.
422 J.M. Porcel et al. / European Journal of Internal Medicine 21 (2010) 419–423

Table 5
Meta-analyses on the diagnostic accuracy of pleural fluid ADA in tuberculous pleural
effusions.

Source, year No. of Total No. of Mean Mean

included patients/No. sensitivity specificity
studies of TB effusions (95% CI) (95% CI)

Goto et al. [5], 2003 40 5485/ND 0.92 (ND) 0.92 (ND)

Greco et al. [6], 2003 31 4738/1621 0.93 0.93
Morisson and Neves 25 1674/857 0.92 0.88
[7], 2008 (0.90–0.94) (0.86–0.90)
Liang et al. [8], 2008 63 8093/2796 0.92 0.90
(0.90–0.93) (0.89–0.91)

ND: not done.

incidence is intermediate (30 cases/100,000 inhabitants in 2006) [9].

The prevalence of TB in the population can dramatically affect the
Fig. 2. Predictive values of the ADA test according to the prevalence of tuberculosis in predictive value of the ADA test. Therefore, an increased ADA level in a
patients with exudative effusions. Footnote: NPV: negative predictive value and PPV: country with low or very low prevalence of TB probably represents a
positive predictive value.
false-positive result. However, due to its maintained high negative
predictive value, irrespective of the rate of prevalence of the disease, an
ADA level below 35 U/L confidently excludes TB. Worth noting is that
the use of pleural biopsy to diagnose TB has substantially decreased in
values of the ADA test were 55.5% and 99.2%. Whereas, in a country some countries in favour of the simple, rapid and comparatively
with a pleural TB prevalence of 1%, the positive predictive value of inexpensive ADA determination in pleural fluid. Nevertheless, in high
ADA test would be 7.2%, although the negative predictive value would burden areas of drug-resistant TB, culture results (including those from
remain at 99.9%. pleural biopsy specimens) are particularly necessary.
We found that ADA was not affected by the predominantly white cell
3.7. Correlation between ADA and other biochemical analytes count in TB effusions, whether neutrophils or lymphocytes, as further
supported by the lack of correlation between them. To our knowledge,
As shown in Table 4, ADA was poorly or, at most, moderately this point has not been previously documented. In fact, neutrophil-rich
correlated with other pleural fluid biochemistries, both in the whole had higher ADA activity than lymphocytic TB effusions. In our series, 10%
population and the TB group. of the TB patients had pleural fluid with more than 50% polymorpho-
nuclear leukocytes. In this particular scenario, a differential diagnosis
4. Discussion with the 44% of non-purulent complicated parapneumonic effusions
that have a false-positive ADA test is challenging. However, as a recent
This study supports the use of ADA as a diagnostic tool for TB study showed [16], weight loss, initial leukocyte blood count ≤11,000/
pleuritis. Based on the operating characteristic curves, an ADA level of μL, a poor clinical response to empirical antibiotics in the first 3 days and
35 U/L was the most suitable cutoff, yielding a sensitivity and a shift toward mononuclear cell predominance of pleural fluid within 1-
specificity of 93% and 90%, respectively, for identifying TB among week all point toward TB pleurisy. Whether high ADA activity in
lymphocytic exudates. Furthermore, the positive LR was 10.05 and the neutrophil-rich TB effusions is due to an increase of the isoenzymes
negative LR was 0.07, indicating that the ADA is very useful in clinical ADA1 or ADA2 is a matter of speculation. ADA1 may be produced by
practice to rule in or out TB pleurisy. Our findings are consistent with many different cell types, including neutrophils, and explains most
those reported in smaller cases series [3,11–15] and the meta- false-positive cases in non-TB effusions. In contrast, ADA2 is secreted
analyses [5–8] (Table 5). The quoted diagnostic cutoff value for ADA only by monocytes and macrophages and is the predominant isoenzyme
has varied from 30 to 100 U/L, which can be attributed to the different in TB effusions [17]. According to experimental evidence, neutrophils
methods of analysis (i.e., Giusti vs non-Giusti). are the predominant cells in the early stages of TB effusions, while
Despite being highly accurate, ADA measurement has acquired lymphocytes predominate later. Since neutrophils release chemokines
popularity as a non-invasive diagnostic test only in moderate to high that attract monocytes and macrophages [18], isoenzyme ADA2 might
incidence areas of TB, such as South Africa, South Asia, Brazil or Spain. still be a major contributor to the high total ADA activity in neutrophilic
The present study was carried out in a geographical area where TB TB effusions.
Although the presence of elevated ADA levels in non-TB effusions
is well established, our study is the first that has systematically
Table 4 documented the frequency of this event in the different categories of
Correlation ρ (rho) values between ADA levels and other biochemical parameters in the parapneumonic and malignant effusions. Thus, false-positive rates
pleural fluid. were particularly relevant in empyemas (70%) and lymphomas (57%).
Pleural fluid variables All patients, ρ p TB group, ρ p Interestingly, an ADA activity greater than 250 U/L suggests that TB is
coefficient coefficient highly unlikely and should raise the suspicion of empyema or
Erythrocyte count 0.145 b0.01 −0.054 0.431 lymphoma. False-positive empyemas are easily identifiable at the
Total leukocyte count 0.413 b0.01 0.072 0.287 bedside by the appearance of pleural fluid and, therefore, ADA deter-
Total neutrophil count 0.273 b0.01 0.04 0.562 mination is superfluous. In contrast, lymphomatous effusions, which
Percentage neutrophil 0.056 0.02 0.048 0.484
are lymphocytic in nature, may be more difficult to differentiate from
Total lymphocyte count 0.370 b0.01 0.059 0.389
Percentage lymphocyte −0.062 0.01 −0.044 0.527 TB if they present in patients with no previous history of lymphoma
Glucose −0.474 b0.01 −0.348 b 0.01 and the pleural fluid cytological examination is negative.
Protein 0.546 b0.01 0.214 b 0.01 The strength of this investigation is the inclusion of a large
LDH 0.62 b0.01 0.491 b 0.01 consecutive number of patients from a single center where ADA
pH −0.456 b0.01 −0.199 0.005
measurement is part of the routine diagnostic work-up for pleural
 J.M. Porcel et al. / European Journal of Internal Medicine 21 (2010) 419–423
effusions. This fact lessens one of the study limitations, namely, its
retrospective design. Indeed, we only omitted 4% of all patients ad-
mitted with pleural effusion at our institution because ADA infor-
mation was not available. Another limitation was the small number of
patients with confirmed TB who presented with a neutrophilic pleural
fluid. A future prospective study comparing ADA and its isoenzymes
between neutrophil- and lymphocyte-rich TB effusions would be of
interest.
In conclusion, the use of pleural ADA levels provides a rapid and
accurate means of detecting TB pleurisy, thereby expediting the initial
decision-making process. We advocate a strategy of using ADA as a
routine screening test in all patients presenting with an exudative
pleural effusion of uncertain origin, regardless of the prevalence of TB
in the population.
5. Learning points
• Elevated concentrations of pleural ADA (N35U/L) are a hallmark of
TB effusions, whether lymphocytes or neutrophils predominate in
the pleural fluid.
• The diagnostic work-up of exudative effusions should include a
pleural fluid ADA measurement because, even in low TB prevalence
areas, an ADA value b35 U/L argues strongly against this disease.
• An ADA activity in pleural fluid N250 U/L is highly suggestive of
empyema or lymphoma rather than TB.
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