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San Ysidro, CA
Dr. Laniado-Laborín is affiliated with the Facultad de Medicina Tijuana, Universidad Autonoma de Baja California, México.
Correspondence to: Rafael Laniado-Laborín, MD, MPH, FCCP, PMB 953, 482 W San Ysidro Blvd, No. 2, San Ysidro, CA 92173; e-mail: rafaellaniado{at}hotmail.com
A definite diagnosis of tuberculous pleural effusion (TPE) can be difficult to make because of the low sensitivity and/or specificity of noninvasive traditional diagnostic tools. In most series of patients with TPE, the results of pleural fluid staining for acid-fast bacilli are virtually always negative, and pleural fluid cultures are positive for mycobacteria in < 25% of cases. On the other hand, a pleural biopsy specimen will demonstrate granulomatous pleuritis in 80% of patients with TPE, and when a culture of a biopsy specimen is combined with histologic examination, the diagnosis can be established in approximately 90% of cases.1
Tuberculous pleurisy is thought to be the result of a delayed hypersensitivity reaction in response to the presence of mycobacterial antigens in the pleural space.2 This immunologic reaction causes the stimulation and differentiation of lymphocytes, which release lymphokines, which in turn activate macrophages for an enhanced bactericidal effect.2
The levels of adenosine deaminase (ADA), an enzyme found in most cells, are increased in tuberculous pleural effusions, and this determination has acquired popularity as a diagnostic test in high-incidence areas for TPE because it is not invasive, the assay is not expensive, and it is readily accessible. ADA is involved in the proliferation and differentiation of lymphocytes, especially T lymphocytes. They release ADA when stimulated in the presence of live intracellular microorganisms.3 For this reason, ADA has been looked on as a marker of cell-mediated immunity and, in particular, as a marker of the activation of T lymphocytes.
Several reports3 have suggested that an elevated pleural fluid ADA level predicts tuberculous pleuritis with a sensitivity of 90 to 100% and a specificity of 89 to 100%.There are several isoforms of ADA, but the prominent ones are ADA1 and ADA2. ADA1 is present in all cells, whereas ADA2 is found only in monocytes.4 ADA2 is the predominant isoform in TPEs, accounting for most of the total ADA activity, however, in clinical practice the difference in the use of total ADA or the isoform ADA2 is not considered to be significant. Furthermore, the isoenzyme assay is more expensive and not readily available.2
The reported cutoff value for ADA varies from 47 to 60 U/L3. Specificity is increased when the lymphocyte/neutrophil ratio in the pleural fluid (of > 0.75) is considered together with an ADA concentration of > 50 U/L.5
Some of the discrepancy in the results among the studies reported in the literature can be attributed to the use of different methods for ADA analysis, with the most frequently reported method being the colorimetric ADA assay described by Guisti and Galanti.6 Consequently, when interpreting results, physicians should be conscious of the differing cutoff levels that can occur with the different methods of ADA analysis.7 Also, we should be aware that ADA levels in pleural fluid maintained at ambient temperature, as reported by Miller et al,8 will decrease with time. As they elegantly demonstrated in their study, the addition of glycerol and ethylene glycol or glycerol and sodium sulfate to pleural fluid stabilizes ADA levels for up to 3 weeks at 37°C, obviating the need to freeze or refrigerate the specimens while awaiting analysis.
An ideal test for tuberculous pleurisy should be economic, minimally invasive, of high accuracy, and quick to perform. The ADA test has been hailed lately as the ideal test for the diagnosis of TPE. However, this test has some limitations that should be taken into consideration when facing the challenge of diagnosing a pleural effusion of unknown origin.
In practice, the ability to predict the presence or absence of disease from test results is dependent on the prevalence of the disease in the population tested, as well as on the sensitivity and specificity of the test. Even when utilizing a test with very high sensitivity and specificity (for example the ADA test), when the prevalence of disease in the population is low (ie, 
1%), such as that of TPE in developed countries, the predictive value of a positive test, or the proportion of true-positive results among all those who have positive test results, can be as low as 15% (this means that 85% of the subjects with a positive test result will not have a TPE).9 The incidence of TPE is generally associated with the regional prevalence of tuberculosis.2 In the United States, only a small proportion of exudative pleural effusions are caused by tuberculosis.10
In TPE, a lymphocyte-dominant pleurisy, ADA is released in the presence of live intracellular Mycobacterium tuberculosis. It is thought that false-positive diagnoses of TPE by ADA level determination can be significantly reduced if ADA measurement is limited to lymphocytic pleural fluids. Theoretically, however, other lymphocyte-rich pleural effusions associated with live intracellular microorganisms also could have elevated ADA pleural fluid levels,11 including those caused by coccidioidomycosis and histoplasmosis, which are endemic mycoses in vast areas of the United States.
High levels of ADA also have been reported in noninfectious conditions associated with pleural fluid lymphocytosis, including malignant conditions (eg, adenocarcinomas, leukemias, and lymphomas) and collagen vascular diseases (eg, rheumatoid pleuritis and systemic lupus erythematosus),57 which make the test less useful in countries with a low prevalence of tuberculosis.1213 Therefore, an increased ADA level should not be considered as an equivalent to the presence of mycobacteria in the pleural fluid or pleural biopsy specimens.2 A higher rate of false-positive test results can lead to the unnecessary administration of antituberculous therapy or a delay in making an alternative diagnosis.
In areas with a high prevalence of tuberculosis, the proportion of false-positive results will be obviously lower. However, a limitation of the test in this setting, as a sole method of diagnosis, is that culture results will not be available to guide antituberculosis chemotherapy. Culture results are particularly necessary if drug-resistant tuberculosis is prevalent,10 an increasingly frequent scenario in countries with high rates of tuberculosis. Patients with drug-resistant tuberculosis may receive treatment with inefficient drugs due to the lack of availability of culture and drug-sensitivity results.
With the decline in the prevalence of TPE, the positive predictive value of pleural fluid ADA also declines, but the negative predictive value actually increases. Therefore, the measurement of the pleural fluid ADA level could be used to rule out a tuberculous etiology of lymphocytic pleural effusions, regardless of the rate of prevalence of the disease.24
In conclusion, the ADA assay should not be considered as an alternative to biopsy and culture, but rather as a screening test to guide further diagnostic procedures and management of an exudative pleural effusion of unknown origin.23
References
This article has been cited by other articles:
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  A. Gopi, S. M. Madhavan, S. K. Sharma, and S. A. Sahn Diagnosis and Treatment of Tuberculous Pleural Effusion in 2006 Chest, March 1, 2007; 131(3): 880 - 889. [Abstract] [Full Text] [PDF]
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