Original article
Diagnostic performance of adenosine deaminase activity in pleural fluid: A single-center experience with over 2100 consecutive patients

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Abstract

Objective

To determine the diagnostic utility of adenosine deaminase (ADA) in a large series of pleural effusions of different etiologies.

Methods

A retrospective study of 2104 consecutive patients presenting with pleural effusion was carried out at a Spanish university hospital. ADA levels in pleural fluid were determined using a non-Giusti automatic kinetic assay, and a receiver operating characteristics curve analysis was applied to estimate their discriminative properties.

Results

Pleural tuberculosis (TB) accounted for 221 (10.5%) effusions. Pleural fluid ADA > 35 U/L yielded 93% sensitivity, 90% specificity, a positive likelihood ratio (LR) of 10.05 and a negative LR of 0.07 for the diagnosis of TB among lymphocytic exudates. The ADA activity was significantly higher in neutrophil- (111.6 U/L) than in lymphocyte-rich (62.4 U/L; p = 0.002) TB effusions. Overall, more than 40% of parapneumonics and half of 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.

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 controversy 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], [6], [7], [8]. However, differences in ADA measurement methods (Giusti's colorimetric method vs non-Giusti), as well as problems 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.

Section snippets

Subjects

We retrospectively reviewed all consecutive patients with pleural effusion who underwent a diagnostic thoracentesis at the Arnau de 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

Patient characteristics and diagnoses

A total of 2193 patients with pleural effusion were identified from our computerized database during the study period, of which pleural fluid ADA was available in 2104 cases. Of these, there were 591 (28%) malignant effusions, 493 (23.4%) transudates, 380 (18%) parapneumonic effusions, 221 (10.5%) TB, and 419 (20%) miscellaneous exudates (Table 1). Among the 221 patients with TB effusions, 13 (5.8%) were HIV positive. Of the 80 patients with definite TB pleuritis, a pleural biopsy exhibited

Discussion

This study supports the use of ADA as a diagnostic tool for TB pleuritis. Based on the operating characteristic curves, an ADA level of 35 U/L was the most suitable cutoff, yielding a sensitivity and specificity of 93% and 90%, respectively, for identifying TB among lymphocytic exudates. Furthermore, the positive LR was 10.05 and the negative LR was 0.07, indicating that the ADA is very useful in clinical practice to rule in or out TB pleurisy. Our findings are consistent with those reported in

Learning points

  • Elevated concentrations of pleural ADA (> 35U/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 < 35 U/L argues strongly against this disease.

  • An ADA activity in pleural fluid > 250 U/L is highly suggestive of empyema or lymphoma rather than TB.

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