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Dr. Kataria is Professor of Medicine and Director of the Sarcoidosis Clinic, and Mr. Khurshid is a member of the Section of Pulmonary & Critical Care Medicine, Brody School of Medicine at East Carolina University, Greenville, NC.
Correspondence to: Yash P. Kataria, MD, FCCP, 3E-149 Brody Science Building, Brody School of Medicine at East Carolina University, Greenville, NC 27858; e-mail: katariay{at}mail.ecu.edu
In some parts of the United States, pleural tuberculosis accounts for < 5% of all cases of tuberculosis.1 In some countries, the incidence of pleural tuberculosis is much higher. It is generally linked to the local prevalence of tuberculosis. Pleurisy with effusion as a complication of primary pulmonary tuberculosis has been reported to occur in 2 to 38% of children with pulmonary disease, but it is more likely to occur in adolescents and adults.2 3 4 5 6 7 8 However, tuberculous pleural effusion in older patients with classic reactivation of tuberculosis also can occur.1 Tuberculous pleural effusion is thought to result from a delayed hypersensitivity reaction in response to the presence of mycobacterial antigens in the pleural space.9 These mycobacterial antigens may gain access to the pleural space from the rupture of a small subpleural focus.10 A significant number of patients (50 to 59%) with primary tuberculosis who develop pleural effusion may have roentgenographically apparent parenchymal tuberculosis.1 8 Delayed hypersensitivity reaction causes the stimulation and differentiation of lymphocytes that perform a variety of functions, including the release of certain lymphokines that activate macrophages for enhanced mycobactericidal effect.11
The diagnosis of tuberculous pleural effusion can be difficult because of the low sensitivity of the various diagnostic tools. Lymphocytic exudate seen in tuberculous pleural effusion also can occur in other diseases such as malignancy and collagen vascular diseases (ie, rheumatoid arthritis and systemic lupus erythematosus).12 13 14 Cultures for acid-fast bacilli are positive in 20 to 30% of pleural fluid samples and in 50 to 80% of pleural biopsy specimens.15 16 The sensitivity of polymerase chain reaction for active disease is 78%.17 The cutaneous response to purified protein derivative may also be negative in one third of the patients.18 Thus, despite a comprehensive evaluation, almost 20% of tuberculous pleural fluids will defy a definitive diagnosis.
The reliability of the early diagnosis of pleural tuberculosis has been
greatly improved by the use of biochemical markers such as adenosine
deaminase (ADA), interferon-
, and lysozyme.12
18
19
20
21
The determination of the ADA level in the suspected pleural fluid
appears to be the most promising marker because of the ease, rapidity,
and cost-effectiveness of the ADA assay. ADA is found in most cells,
but its chief role concerns the proliferation and differentiation of
lymphocytes, especially T-lymphocytes. For that reason ADA has been
looked on as a marker of cell-mediated immunity, which encompasses the
delayed hypersensitivity reaction.
The determination of ADA activity was first proposed as a serologic diagnostic marker for lung cancer in 1970.22 Later, Piras et al23 in 1978 reported the usefulness of ADA in diagnosing tuberculous pleurisy. ADA is an enzyme involved in the purine catabolism. It catalyzes the deamination of adenosine to inosine and of deoxyadenosine to deoxyinosine. There are several isoforms of ADA, but the prominent ones are ADA1 and ADA2, which are coded by different gene loci.24 ADA1 isoenzyme is found in all cells, with the highest concentration found in lymphocytes and monocytes, whereas ADA2 isoenzyme appears to be found only in monocytes.25 ADA2 is the predominant isoform in the tuberculous pleural effusion, accounting for 88% (median) of total ADA activity, whereas ADA1 is elevated in empyema, accounting for 70% (median) of total ADA activity.20 This would suggest that ADA2 is the more efficient marker of tuberculous pleural effusion. However, in clinical practice, the difference in the use of total ADA and isoform ADA2 is not significant. In fact, there is an advantage in the measurement of total ADA because of its low cost and rapid turnover. ADA1 activity is determined by subtracting ADA2 from total ADA. The measurement of ADA2 is almost 10 times more expensive and is not available in the United States except for research purposes. The colorimetric method for the measurement of total ADA described by Guisti and Galanti26 has an advantage over other methods because of its low cost, simplicity of technique, and rapid turnover. With this technique, the sensitivity and specificity of elevated level of ADA in the tuberculous pleural fluid ranges from 91 to 100% and 81 to 94%, respectively.12 19 27 28 The positive and negative predictive values range from 84 to 93% and 89 to 100%, respectively.12 19 27 28 The reported diagnostic cutoff value for ADA varies from 40 to 60 U/L,12 18 19 20 21 27 28 29 and choosing a lower value will increase sensitivity at the expense of specificity. The diagnostic value of ADA is independent of HIV serologic status.30
In this issue of the CHEST, Lee and colleagues (see page 356) have published some important observations that point toward the value of measuring ADA in patients with suspected tuberculous pleural effusion. They have examined the specificity and sensitivity of ADA in a variety of nontuberculous lymphocytic pleural effusions. They analyzed 106 pleural effusion samples, all with lymphocytic counts of > 50%. They found that the ADA levels were significantly higher in malignant, post-coronary artery bypass graft, and other exudative effusions than in transudative effusions. However, with the exception of increased ADA levels in pleural effusions from two patients with lymphomas and one with complicated parapneumonic effusion, the ADA level in other groups of patients did not exceed the diagnostic cutoff level for tuberculous pleural effusion. With a false-positive test result rate of < 3%, this study emphasizes the value of determining the ADA level as an aid in making the diagnosis of pleural effusion in a patient suspected of tuberculosis.
The sensitivity and specificity of ADA depends on the prevalence of tuberculosis in the population.27 With the decline in the prevalence of tuberculous pleural effusion, the positive predictive value of pleural fluid ADA also declines, but the negative predictive value remains high. So, the measurement of the pleural fluid ADA level is an excellent test to rule out a tuberculous etiology of pleural effusion, irrespective of the rate of prevalence of the disease. In areas in which the prevalence of disease is low, there is a higher likelihood of false-positive test results, and this can lead to the unnecessary administration of antituberculous therapy or a delay in making an alternative diagnosis such as malignancy. Another potential problem in the use of ADA is in patients with drug-resistant tuberculosis who may get treated inadequately because of the lack of immediate availability of culture and drug-sensitivity results. So, an increased ADA level should not be equated with a mycobacterial presence in the pleural fluid and pleural biopsy specimens or with the characteristic histopathology of caseating granuloma. Rather, ADA level should be looked on as a screening test to guide further management. The consequence of a false-positive test result that may cause delay in the diagnosis of malignant pleural effusion, an incurable condition, is not as significant as missing a potentially curable tuberculous effusion.
Despite being a simple, rapid, and inexpensive test, the use of the ADA assay in the diagnosis of tuberculous pleural effusion is rather uncommon in the United States. A marked decline in the prevalence of tuberculous pleural effusion may have contributed to the sparse availability of the ADA assay on a commercial basis. The unfamiliarity of physicians with this test also has an impact on the situation.
Countries with a high prevalence of tuberculous pleural effusions have a high degree of specificity and sensitivity for the ADA test, which makes it an integral part of a diagnostic workup of lymphocyte-rich exudative body fluids. Despite the low prevalence of tuberculous pleural effusion in the United States, the negative predictive value of the ADA test remains high, which provides an excellent means to rule out tuberculous etiology. It should be added to the armamentarium of the diagnostic workup of body fluids in patients who are suspected of having tuberculosis.
References
This article has been cited by other articles:
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  J. C. Palomino Nonconventional and new methods in the diagnosis of tuberculosis: feasibility and applicability in the field Eur. Respir. J., August 1, 2005; 26(2): 339 - 350. [Abstract] [Full Text] [PDF]
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 R. Laniado-Laborin Adenosine Deaminase in the Diagnosis of Tuberculous Pleural Effusion: Is It Really an Ideal Test? A Word of Caution Chest, February 1, 2005; 127(2): 417 - 418. [Full Text] [PDF]
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J. M. Porcel and M. Vives Etiology and Pleural Fluid Characteristics of Large and Massive Effusions Chest, September 1, 2003; 124(3): 978 - 983. [Abstract] [Full Text] [PDF]
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J. M. Porcel and M. Vives Adenosine Deaminase Levels in Nontuberculous Lymphocytic Pleural Effusions Chest, April 1, 2002; 121(4): 1379 - 1380. [Full Text] [PDF]
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