Investigating the appropriate adenosine deaminase cutoff value for the diagnosis of tuberculous pleural effusion in a country with decreasing TB burden

Abstract

As the burden of tuberculosis (TB) in South Korea decreases while that of malignancy increases with an aging society, the composition of etiology for pleural effusion is changing. The aim of this study was to investigate the diagnostic value of adenosine deaminase (ADA) for diagnosis of tuberculous pleural effusion (TPE) in this circumstance. Medical records of patients who underwent medical thoracoscopy from May 2015 to September 2020 in Incheon St. Mary Hospital, Korea were retrospectively reviewed. TPE was diagnosed if one of the following criteria was met: (1) granuloma in pleura, (2) positive TB polymerase chain reaction or culture in pleural fluid or tissue with non-specific pathologic findings in pleura, or (3) bacteriologically confirmed pulmonary TB with non-specific pathologic findings in pleura. A total of 292 patients, including 156 with malignant pleural effusion (MPE), 52 with TPE, and 84 with other benign effusion, were analyzed. Among 206 patients with lymphocyte dominant pleural effusion, the area under receiver characteristic curve of ADA for diagnosis of TPE was 0.971. The sensitivity and specificity of a current cutoff value of 40 IU/L were 1.00 and 0.61, respectively, whereas those of a raised cutoff value of 70 IU/L were 0.93 and 0.93, respectively. Among 54 patients with ADA levels of 40-70 IU/L, 30 (55.6%) patients were diagnosed as MPE, 21 (38.9%) as other benign effusion, and only 3 (5.6%) as TPE. Caution is needed in clinical diagnosis of TPE with current ADA cutoff value in countries with decreasing TB incidence, due to many false positive cases.

Figure 1

Patient enrolment flow chart.

Figure 2

Receiver operating characteristic (ROC) curves presenting the performance of ADA in the diagnosis of TPE. ADA, adenosine deaminase; TPE, tuberculous pleural effusion; AUC, area under the curve Among patients with lymphocyte dominant exudative pleural effusion (panel A), ADA was an excellent tool for diagnosing tuberculous pleural effusion (AUC = 0.971). However, when applying the current cutoff value (40 IU/L), false positive cases presented with suboptimal specificity (0.61) could be a problem. Raising the cutoff value to 70 IU/L improved the specificity without sacrificing the sensitivity significantly. Among patients with non-lymphocyte dominant effusion (panel B), although ADA showed a lower diagnostic performance, it was a still good tool for diagnosing tuberculous pleural effusion (AUC = 0.823). With the current cutoff value (40 IU/L) and even the best cutoff value (56 IU/L) found in the ROC curve, specificity was still suboptimal when compared to that in lymphocyte dominant effusion.

Figure 3

Distribution of ADA levels by the disease (tuberculous effusion, malignant effusion and other benign effusion). Lymphocyte dominant exudative pleural effusion was defined as a pleural effusion of which lymphocyte accounted for more than 50% of total leukocyte count. Patients with lymphocyte dominant exudative pleural effusion (panel A) were classified into three groups by ADA level with current cutoff value of 40 IU/L and raised cutoff value of 70 IU/L. There was no TPE case in the group presenting ADA level < 40 IU/L. In the gray zone (ADA level: 40–70 IU/L), the proportion of TPE was only 5.6%. Patients with non-lymphocyte dominant effusion (panel B) were also classified into three groups with cutoff values of ADA level 40 IU/L and 70 IU/L. There was no TPE case in the group presenting ADA level < 40 IU/L, as in patients with lymphocyte dominant pleural effusion. However, the proportions of TPE in the group presenting ADA level ≥ 40 IU/L and the group with ADA level ≥ 70 IU/L were relatively low when compared with patients with lymphocyte dominant effusion.

Figure 4

Plot of multiple correspondence analysis representing the relation between each feature of thoracoscopic findings and 5 subgroups by disease and ADA level. MPE, malignant pleural effusion; TPE, tuberculous pleural effusion; ADA, adenosine deaminase. Horizontal axis reflects the degree of pleural inflammation, right direction is related with more severe adhesion, pleural thickening, hyperemia and diffuse infiltration. In this plot, MPE patients with high ADA level and those with low ADA level showed disparate features in gross findings. Features of MPE patients with high ADA were similar with those of TPE patients. This finding implies that substantial proportion of MPE could be presented as severe pleural inflammation, which is related with elevated ADA level.