|Ahead of print
|The role of pleural fluid lactate dehydrogenase-to-adenosine deaminase ratio in differentiating the etiology of pleural effusions
Chun-Yee Ho1, Yu-Hui Tsai2, Chih-Chun Chang3, Huei-Ling Huang2, N-Chi Tan2, Wei-Chi Chen4, Ka-I Leong5
1 Department of Surgery, Far Eastern Memorial Hospital, New Taipei, Taiwan
2 Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei, Taiwan
3 Department of Clinical Pathology, Far Eastern Memorial Hospital, New Taipei; Department of Nursing, Cardinal Tien Junior College of Healthcare and Management, Yilan, Taiwan
4 Department of Nursing, Cardinal Tien Junior College of Healthcare and Management, Yilan; Public Health Bureau, New Taipei, Taiwan
5 Division of Thoracic Surgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei, Taiwan
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|Date of Submission||26-Nov-2021|
|Date of Decision||25-Feb-2022|
|Date of Acceptance||30-Mar-2022|
|Date of Web Publication||14-May-2022|
Exudative pleural effusion includes tuberculous pleural effusion (TPE), parapneumonic pleural effusion (PPE), and malignant pleural effusion (MPE). An elevated pleural fluid adenosine deaminase (ADA) typically implies TPE, but the rule may not apply to every individual case. Recent studies proposed that the pleural fluid lactate dehydrogenase (LDH)-to-ADA ratio showed a higher diagnostic power than pleural fluid ADA alone in differentiating the etiology of pleural effusion. Hence, we aimed to investigate the performance of pleural fluid LDH-to-ADA ratio as a biomarker in assistance with the diagnosis of TPE, PPE, and MPE. All patients who underwent thoracentesis for the first time with a pleural fluid ADA >40 U/L were included in this retrospective study. The clinical data including pleural fluid ADA and LDH-to-ADA ratio were analyzed. A total of 311 patients were enrolled during the study interval. The pleural fluid LDH-to-ADA ratio <14.2 (sensitivity: 74.2%; specificity: 90.4%) favored TPE, while the pleural fluid LDH-to-ADA ratio >14.5 (sensitivity: 79.9%; specificity: 78.5%) favored PPE. Besides, the pleural fluid LDH-to-ADA ratio >46.7 (sensitivity: 56.3%; specificity: 78.3%) favored MPE owing to primary lung cancers. In conclusion, the pleural fluid LDH-to-ADA ratio was an effective indicator in differentiating the etiology of pleural effusions in the cases of high ADA level in the pleural fluid.
Keywords: Adenosine deaminase, lactate dehydrogenase-to-adenosine deaminase ratio, pleural effusion
|How to cite this URL:|
Ho CY, Tsai YH, Chang CC, Huang HL, Tan NC, Chen WC, Leong KI. The role of pleural fluid lactate dehydrogenase-to-adenosine deaminase ratio in differentiating the etiology of pleural effusions. Chin J Physiol [Epub ahead of print] [cited 2022 May 24]. Available from: https://www.cjphysiology.org/preprintarticle.asp?id=345281
Chun-Yee Ho, Yu-Hui Tsai have contributed equally to this work
| Introduction|| |
Pleural effusions could be attributed to various diseases, including pulmonary tuberculosis, pneumonia, and heart failure., To approach the etiology of pleural effusions, Light's criteria were commonly used to identify whether pleural fluid was exudative or transudative. An exudative pleural effusion implies the tuberculous pleural effusion (TPE) resulting from Mycobacterium tuberculosis infection of the pleura, the parapneumonic pleural effusion (PPE) due to pneumonia, or the malignant pleural effusion (MPE) owing to pleural carcinomatosis. Besides, a number of biomarkers were available for differential diagnosis of pleural effusions, including adenosine deaminase (ADA), lactate dehydrogenase (LDH), glucose, and differential count of white blood cells in the pleural fluid. Among these, ADA was an important enzyme in purine degradation and was abundantly presented in macrophages and T lymphocytes. In general, TPE, PPE, and MPE would be considered if a high concentration of ADA (usually more than 35–40 U/L) was detected in the pleural fluid. However, the diagnostic performance and cutoff level of ADA varied in different regions or studies.,,, Moreover, identifying the underlying cause of pleural effusions could be difficult if a pleural fluid ADA level was measured around the cutoff level. In such circumstances, it was reported that the pleural fluid LDH-to-ADA ratio could offer further information for diagnostic evaluation of pleural effusions.,, Nevertheless, studies were limited for differentiating the etiology of pleural effusions by using pleural fluid LDH-to-ADA ratio. Hence, the objective of this study is to evaluate the performance of pleural fluid LDH-to-ADA ratio as a biomarker in assistance with the diagnosis of TPE, PPE, and MPE in the setting of high pleural fluid ADA level.
| Materials and Methods|| |
Patient and data collection
From July 2015 to June 2020, patients who received thoracentesis for the first time because of pleural effusions in Far Eastern Memorial Hospital (FEMH) were enrolled in this study. Clinical data were retrospectively collected through electronic chart review, including demographic information (patient age and gender), laboratory results of the pleural fluid (total and differential counts of white cells, ADA, and LDH), and relevant information for the diagnosis of tuberculous and nontuberculous infections, primary lung cancers, and malignant tumor metastasis to the lungs. Patients who had a pleural fluid ADA level of 40 U/L and more were included, and those who had incomplete data of white cell count and differential cell count were excluded from the study. Among these, patients diagnosed as tuberculosis with TPE were based on the positive results for M. tuberculosis in the specimens of sputum, pleural fluids and/or tissues, as well as a clinical response to anti-tuberculosis therapy. For those who had MPE, a pre-existing diagnosis of primary lung cancer or metastasis to the lung should be established before patients develop pleural effusions on the basis of pathological evidence proved using tissue specimen, or the presence of malignant cells in pleural fluid cytology. Patients who have bacterial pneumonia, bronchiectasis, or lung abscesses and then develop pleural effusions with positive results of sputum or pleural fluid cultures would be considered to have PPE. Those who have pleural effusions but did not meet the criteria mentioned above would be categorized into the miscellaneous group. We then grouped patients into the TPE, PPE, MPE, and miscellaneous groups for further analysis. The study was approved by the Institutional Review Board of FEMH (110114-E).
Continuous and categorical variables were shown as the medians with interquartile ranges and the counts with percentages in each group, respectively. Kruskal–Wallis, Pearson's Chi-square, and Fisher's exact tests were applied for analysis as appropriate. The receiver operating curve (ROC) analysis was conducted to detect the area under the curve (AUC), as well as the sensitivity and specificity to calculate the optimal cutoff values. Odds ratio (OR) with 95% confidence interval (CI) was expressed in the assessment of relative risk. Binary logistic regression analysis was then performed with adjusting factors of patient age, sex, white cell count, and percentage of lymphocytes in the pleural fluid. A P value of less than 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS 19.0 software (SPSS Inc., Chicago, IL, USA).
| Results|| |
During the study interval, 3067 patients received thoracentesis for pleural effusions in FEMH. Among these, 353 patients received thoracentesis for the first time with the ADA level of 40 IU/L and more in the pleural fluid analysis. Forty-two patients were excluded because of unavailable or incomplete data of differential count of white cells, and a total of 311 patients were enrolled in the study. Epidemiological characteristics are shown in [Table 1], in which 125 cases with TPE, 16 cases with MPE owing to primary lung cancers, 20 cases with MPE due to metastasis to the lung, 139 cases with PPE, and 11 cases with miscellaneous causes were identified.
|Table 1: The demographic data and laboratory parameters in the pleural fluid in patients with different diagnoses|
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As shown in [Figure 1], ROC analysis revealed that there was a better performance using pleural fluid LDH-to-ADA ratio than ADA value to identify patients with TPE (AUC: 0.844 vs. 0.554) at a cutoff value of 14.2 (sensitivity: 74.2%, specificity: 90.4%). Similar results were also found to identify patients with PPE and MPE owing to primary lung cancers using pleural fluid LDH-to-ADA ratio at cutoff values of 14.5 (sensitivity: 79.9%, specificity: 78.5%) and 46.7 (sensitivity: 56.3%, specificity: 78.3%), respectively. The percentage of lymphocytes in differential count of white cells in the pleural fluid also revealed a good performance in identifying patients with TPE (AUC: 0.812, cutoff level: 44.5%, sensitivity: 87.2%, specificity: 71.0%). There was no remarkable finding in identification of cases with MPE in metastasis to the lung. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and AUC of pleural LDH-to-ADA ratio with multiple comparisons are also supplemented in [Table 2].
|Figure 1: The ROC analysis for evaluating the diagnostic performance of pleural LDH-to-ADA ratio and ADA level in TPE, PPE, and MPE owing to primary lung cancers. (a) Pleural LDH-to-ADA ratio for diagnosing TPE; (b) pleural ADA level for diagnosing TPE; (c) pleural LDH-to-ADA ratio for diagnosing PPE; (d) pleural LDH-to-ADA ratio for diagnosing MPE owing to primary lung cancers. ROC: Receiver operating characteristic; AUC: Area under the curve; LDH: Lactate dehydrogenase; ADA: Adenosine deaminase; TPE: Tuberculous pleural effusion; PPE: Parapneumonic pleural effusion; MPE: Malignant pleural effusion.|
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|Table 2: The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the curve of pleural fluid lactate dehydrogenase-to-adenosine deaminase ratio with multiple comparisons|
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We then used the respective cutoff values of pleural fluid LDH-to-ADA ratios to calculate crude ORs for recognizing various pleural effusions. Moreover, adjusted ORs were obtained by performing regression analysis with adjustment of confounding factors such as patient age, gender, total white cell count, percentage of lymphocytes in the pleural fluid, and the respective cutoff values of pleural fluid LDH-to-ADA ratios. As shown in [Table 3], the respective cutoff values of pleural fluid LDH-to-ADA ratios were positively correlated with TPE (crude OR: 27.07, 95% CI: 13.72–53.42, P < 0.001; adjusted OR: 9.14, 95% CI: 4.10–20.35, P < 0.001), PPE (crude OR: 14.46, 95% CI: 8.33–25.11, P < 0.001; adjusted OR: 5.14, 95% CI: 2.51–10.51, P < 0.001), and MPE owing to primary lung cancer (crude OR: 5.24, 95% CI: 1.92–14.31, P = 0.001; adjusted OR: 4.81, 95% CI: 1.22–18.97, P = 0.025).
|Table 3: Cutoff values of pleural fluid lactate dehydrogenase-to-adenosine deaminase ratio for differentiating the etiology of pleural effusion|
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| Discussion|| |
In this study, we mainly found that pleural fluid LDH-to-ADA ratio had a better performance to help diagnosing TPE when compared to pleural fluid ADA level only. Besides, respective pleural fluid LDH-to-ADA ratios help in the differential diagnosis of TPE, PPE, and MPE in primary lung cancers in the cases of high pleural fluid ADA level.
ADA, an important enzyme in purine degradation, was abundant in macrophages and T-cell lymphocytes. The pleural fluid ADA level may imply certain diseases in different situations. Besides, the diagnostic value of pleural fluid could vary in different regions as the prevalence of a certain disease could be different. For TPE, it was reported that there was a sensitivity of 89.2% and a specificity of 70.4%, with the cutoff value of pleural fluid ADA of 49 U/L in 54 Serbian patients. In a Spanish study, it was revealed that the cutoff value of pleural fluid ADA of 35 U/L yielded 93% sensitivity and 90% specificity in 2104 patients. While in a Japanese study which included 435 patients, the pleural fluid ADA >36 U/L yielded 85.5% sensitivity and 86.5% specificity. Apparently, the efficacy of diagnostic tools was affected by the disease prevalence. Although the diagnostic power was compromised in such circumstances, the pleural fluid ADA still remained a useful “rule-out” test in regions with low prevalence of tuberculous pleurisy.
In contrast to TPE, MPE was associated with a relatively low pleural fluid ADA level, typically <35–40 U/L.,, However, it was reported that pleural fluid ADA level could be increased in certain primary cancers, including lung malignancies, lymphoma, mesothelioma, and hematologic cancers. Interestingly, the serum LDH can be used as a surrogate to pleural fluid LDH and the diagnostic power of serum LDH to pleural fluid ADA ratio was satisfactory as that of pleural fluid LDH-to-ADA ratio for MPE prediction. A retrospective study showed that the median pleural fluid LDH-to-ADA ratio in TPE was significantly lower than that in other pleural exudates (8.2 vs. 30.5, P < 0.001), and suggested that pleural fluid LDH-to-ADA ratio threshold of <15 demonstrated 89.1% sensitivity and 84.8% specificity to differentiate TPE from PPE. While a cutoff pleural fluid LDH-to-ADA ratio of 16.2 was reported to have a sensitivity of 93.6% and a specificity of 93.1%. A recent study also revealed that a pleural fluid LDH-to-ADA ratio of 10 and less yielded 78% sensitivity and 90% specificity in distinguishing TPE from non-TPEs. Similar to the previous studies, our findings indicated that pleural fluid LDH-to-ADA ratio aided in differentiation between TPE, PPE, and MPE in primary lung cancers. Of note, the pleural fluid LDH-to-ADA ratio threshold seemed to be much higher in our results for distinguishment of MPE in primary lung cancers from other pleural exudates when compared with the previous studies. It could probably be explained that various expressions of LDH and ADA were associated with different types of cancer, thus affecting the cutoff ratio of pleural fluid LDH-to-ADA. To summarize, the pleural fluid LDH/ADA ratio was demonstrated to be superior to ADA alone as an easily accessible parameter for differentiating the etiology of pleural effusions.
Interpretation of our results should be careful as several limitations existed. First, this was a retrospective study with limited cases at a single center. Hence, there were some potentials for etiological attribution errors concerning investigators assigning cause from medical records. In addition, only patients with pleural fluid ADA level of 40 U/L and more were included and analyzed in our study. In a clinical scenario, however, the pleural fluid LDH-to-ADA ratio would be assessed to differentiate TPE from MPE or other conditions causing pleural effusions in a high pleural fluid ADA setting. Eventually, it was prone to be confirmation bias because clinical investigations for diagnosing tuberculous infection may be influenced by the result of pleural fluid ADA level to a certain extent.
| Conclusion|| |
The pleural fluid LDH-to-ADA ratio was an effective indicator in differentiating the etiology of pleural effusions in the cases of high ADA level in the pleural fluid. A pleural fluid LDH-to-ADA ratio of <14.2 favored TPE, a ratio of more than 14.5 favored PPE, while a ratio of more than 46.7 favored MPE owing to primary lung cancers.
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Conflicts of interest
There are no conflicts of interest.
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Division of Thoracic Surgery, Department of Surgery, Far Eastern Memorial Hospital, No. 21, Sec. 2, Nanya S. Road, Banqiao, New Taipei City
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]
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