ORIGINAL ARTICLE |
https://doi.org/10.5005/jp-journals-11010-1057 |
The Role of Pleural Lactic Acid in the Diagnosis and Differentiation of Various Causes of Exudative Pleural Effusion
1,3Department of Chest Diseases, Sohag University, Sohag, Egypt
2Department of Clinical Pathology, Sohag University, Sohag, Egypt
Corresponding Author: Doaa Gadallah, Department of Chest Diseases, Sohag University, Sohag, Egypt, Phone: +201021777683, e-mail: drdoaagad@yahoo.com
Received on: 07 April 2023; Accepted on: 16 July 2023; Published on: 30 October 2023
ABSTRACT
Background: Pleural effusion (PE) represents a prevalent issue clinically for different diseases, such as tuberculosis (TB), pneumonia, malignancy, and heart failure (HF). So, we need specific investigations, such as measuring the level of lactic acid, for the rapid diagnosis of exudative PE causes.
Objective: To assess pleural fluid (PF) lactic acid level in exudative PEs and to detect its role as a diagnostic test with the determination of a cutoff level of PF lactic acid to distinguish between the different causes of exudative PEs, such as tuberculous, parapneumonic, and malignant.
Methods: Initial diagnostic thoracentesis was performed in all cases. The PF lactic acid level was assessed by a calibrated blood gas analyzer.
Results: We studied 80 patients. A total of 32 patients had parapneumonic pleural effusion (PPE) (15 simple and 17 complicated), 19 had tuberculous pleural effusion (TPE), and 29 had malignant pleural effusion (MPE). PF lactic acid median level was significantly more regarding the complicated PPE (CPPE) [mean 7.19 mmol/L with range (2.7:11.6)] in comparison to other groups. The area under the curve (AUC) scored 0.912 [p < 0.0001, 95% confidence interval (CI) (0.757:0.983)]. PF lactic acid cutoff level of >3.4 mmol/L was significant in predicting CPPE with high specificity and positive predictive value scored, with low sensitivity and negative predictive value (100, 100, 82.4, and 83.3%, respectively). Also, PF lactic acid could be used to discriminate between TPE and MPE. The AUC scored 0.735 [p < 0.001, 95% CI (0.588:0.852)], and the PF lactic acid optimal cutoff level was ≤2.8 mmol/L resulting in 79.3% sensitivity, 68.4% specificity, 68.4% negative predictive value, and as well as 79.3% positive predictive value regarding the prediction of MPE.
Conclusion: Pleural fluid (PF) lactic acid level measurement has a high accuracy for the diagnosis and discrimination between the different causes of exudative PE.
How to cite this article: Khalaf AR, Sedky A, Gadallah D. The Role of Pleural Lactic Acid in the Diagnosis and Differentiation of Various Causes of Exudative Pleural Effusion. Indian J Respir Care 2023;12(3):214–221.
Source of support: Nil
Conflict of interest: None
Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.
Keywords: Effusion, Malignant, Pleura, Tuberculosis
INTRODUCTION
Pleural effusion (PE) represents a prevalent issue clinically for different diseases,1 such as tuberculosis (TB), pneumonia, malignancy, and heart failure (HF).2 Searching the PE reasons includes analyzing the pleural fluid (PF) through thoracentesis. However, several PF analyses may not have adequate specificity or sensitivity and may need further invasive measures, including thoracoscopy and closed pleural biopsy.3
Although parapneumonic pleural effusion (PPE) and tuberculous pleural effusion (TPE) have different pathogenesis, PPEs are considered a complication of pneumonia due to enhanced anaerobic metabolism, causing the production of lactic acid that occurs in complicated parapneumonic pleural effusion (CPPE), and TPE results from the delay of hypersensitivity reaction prompted by rupturing subpleural caseous foci in the pleural cavity.4
But both diseases may share similar PF biochemistry, including adenosine deaminase (ADA) level, which is raised in several PPEs and TPE, particularly in CPPE. Thus, the differentiation between both diseases plays a crucial role in determining the specific treatment of each condition. Some cases of TPE may need pleural biopsy and culture, so this takes a long time and leads to delay diagnosis and treatment.5
The differentiation between TPE and malignant pleural effusion (MPE) was also difficult, especially with lacking radiological features suggestive of both diseases, and TPE may take place even with lacking radiological features suggestive of pulmonary TB and initial or extraprimary diseases.6
The presence of malignant cells in PF and tissue is associated with a higher tumor mass in the pleural space and poor outcomes.7
So, we need other investigations, such as measuring the level of lactic acid, which is characterized as being a rapid bedside test that can be executed directly by a physician and a reliable test for the rapid diagnosis of exudative PE causes.8
Lactic acid results from the anaerobic metabolism of pyruvate through the catalyzation of lactate dehydrogenase (LDH). Different pieces of research were done to evaluate lactic acid levels in biological fluids, such as ascites, pleural, synovial, and cerebrospinal fluid, and how they correlate with bacterial infections, TB, autoimmune conditions, empyema, and neoplastic conditions.9 The differences in PPE and TPE pathogenesis urged us to hypothesize that PF lactate could prevail more in PPE than in TPE.10
This paper aimed to assess PF lactic acid level in exudative PEs and to detect its role as a diagnostic test with the determination of a cutoff level of PF lactic acid to distinguish between the different causes of exudative PF, such as tuberculous, parapneumonic, and malignant.
METHODOLOGY
Study Design and Participants
This prospective study included cases with the diagnosis of exudative PE admitted to the Department of Chest Diseases and TB at the Faculty of Medicine, Sohag University. It was conducted from March 2022 to August 2022.
Sample Size
This study included 80 participants with the diagnosis of exudative PE who were differentiated into MPE, TPE, and PPE.
Data Collection
Cases diagnosed with exudative PE that differentiated into MPE, TPE, and PPE were included, but cases suffering from other causes of exudative PE, transudative PE, and other diseases that affect pleural lactic acid levels, such as hypoxemia, hypoperfusion, or shock, were excluded.
The included cases underwent several procedures, such as thorough history taking (i.e., age, respiratory symptoms, for example, cough, exertional dyspnea, and chest pain), clinical examination, and radiological evaluation (i.e., chest radiograph, and high-resolution computed tomography scanning of the chest).
The protocol of PE workup of patients was done as follows: 6 mL of pleural aspirate was taken from each participant under aseptic conditions with sterile disposable gloves, about 1.8 mL of the sample was put in 0.2 mL sodium citrate, and the remaining part was put in a plain tube.
Physical, chemical, and microscopic examinations (with total protein and LDH dosage) were done from the provided sample, culture and cytology were done, and the PF levels of glucose, LDH, pH, and lactic acid were measured.
pH was measured using the ABL800 FLEX arterial blood gas (ABG) apparatus (ABG Radiometer, the United States of America) by the potentiometric measuring principle, where the electrode measured a change in voltage due to a change in ion concentration across a membrane.
Lactic acid was measured by the same apparatus depending on amperometric measuring, where the lactate molecules were transported across the outer membrane to be converted by the enzyme to form hydrogen peroxide, which then oxidized the oxygen and electrons. The amount of the current product was directly related to the amount of lactate in the participants. Following the recommendations of the manufacturer, we daily calibrated the blood gas analyzer at certain intervals.
Lactate dehydrogenase (LDH) and glucose were measured by the Cobas c311 Chemistry Analyzer System (Roche Diagnostic GmbH, Indianapolis, Indiana, the United States of America).
Diagnosing MPE was identified as having atypical cells in PF or malignant cells in histopathological examinations of pleural tissue.
Diagnosing TPE was identified as raised pleural level of ADA in which the cutoff level of ADA was >40 IU11 and having cesium granulomas in the pleural biopsy when their sputum and PF smear were negative for acid-fast bacilli.
The diagnosis of PPE was identified by having an exudative PF with the clinical history, radiography, and computed tomography agreeing with pneumonia.
Complicated PPE (CPPE) was identified as PPE with PF pH < 7.2 and/or PF glucose <2.6 mmol/L, Patients with Gram stain or positive culture of PF that may require chest tube drainage.12
Parapneumonic pleural effusions (PPEs) lacking those standards were defined as simple PPE.
Statistical Analysis
Stata version 14.2 (Stata Statistical Software: Release 14.2 College Station, TX: StataCorp LP) was used to analyze data. The range, standard deviation, and mean were used to represent quantitative data. Data underwent analysis by the student t-test to draw comparisons between the means of two groups and analysis of variance (ANOVA) to compare the means of three or more groups. Because the data were not normally distributed, the Kruskal–Wallis test was used to compare three or more groups, but the Mann–Whitney U test was employed to make comparisons between two groups. Qualitative data were represented in the percentage/number form, and the groups were compared using tests of Chi-square or Fisher exact. Receiver operating characteristic (ROC) curve analysis helped determine the best cutoff. Positive predicted value, negative predictive value, specificity, and sensitivity were estimated. Spearman correlation analysis tests were also used. Graphs were made by the Stata or Excel program. The p-value was set as significant in the case of being below 0.05.
RESULT
The research paper was conducted on 80 patients. Of these, 51 patients (63.75%) were males, while 29 of them (36.25%) were females. They were divided based on the diagnostic cause of PE into four groups, parapneumonic effusion (32), which included simple (15) and complicated (17) cases. The histological or cytological confirmation of neoplasia was provided in 29 cases and diagnosed as malignant effusion, and 19 cases were diagnosed as TB effusion.
The relation between the demographic data and different groups was demonstrated—the median age of the participant was 53.5 (interquartile range 16:80) years old; there were highly significant differences among all groups (p = 0.0001). Patients with TPE diagnosis were younger, while malignant and complicated parapneumonic cases were older (p = 0.053). As regards sex differentiation, no significant difference was reported between all groups (p = 0.68) (Table 1).
| Variable | Total | Simple N = 15 | Complicated N = 17 | Tuberculosis N = 19 | Malignant N = 29 | p-value |
|---|---|---|---|---|---|---|
| Age/year | ||||||
| Mean ± standard deviation (SD) | 49.81 ± 18.5 | 53.73 ± 13.74 | 50.41 ± 17.78 | 30.42 ± 11.78 | 60.14 ± 16.24 | 0.0001 |
| Median (range) | 53.5 (16:80) | 54 (31:75) | 45 (16:57) | 26 (16:50) | 62 (17:18) | |
| P1 = 0.87, P2 = 0.0001, P3 = 0.06, P4 = 0.003, P5 = 0.053, P6 = 0.0001 | ||||||
| Gender | ||||||
| Females | 29 (36.25%) | 6 (40.00%) | 7 (41.18%) | 8 (42.11%) | 8 (27.59%) | 0.68 |
| Males | 51 (63.75%) | 9 (60.00%) | 10 (58.82%) | 11 (57.89%) | 21 (72.41%) | |
p-value comparison in the four groups; pairwise comparisons were carried out if the p-value was significant; P1, compared simple and complicated, P2, compared simple and TB; P3, compared simple and malignant; P4, compared complicated and TB; P5, compared complicated and malignant; P6, compared TB and malignant
Clinical criteria revealed a significant difference among all patient groups. Regarding smoking, most patients were nonsmokers in 53 cases (66.23%), clinical symptoms such as dyspnea in 76 cases (95%), cough in 65 cases (81.25%), and chest pain in 41 cases (51.25%) were significantly presented in all groups (p < 0.0001, p = 0.01, p < 0.0001, correspondingly) (Table 2).
| Variable | Total | Simple N = 15 | Complicated N = 17 | Tuberculosis N = 19 | Malignant N = 29 | p-value |
|---|---|---|---|---|---|---|
| Smoking | ||||||
| Nonsmokers | 53 (66.23%) | 6 (40.00%) | 13 (76.47%) | 19 (100%) | 15 (51.72%) | 0.002 |
| Current smokers | 15 (18.75%) | 4 (26.67%) | 4 (23.53%) | 0 | 7 (24.14%) | |
| Ex-smokers | 12 (15.00%) | 5 (33.33%) | 0 | 0 | 7 (24.14%) | |
| P1 = 0.02, P2 < 0.0001, P3 = 0.74, P4 = 0.03, P5 = 0.08, P6 = 0.002 | ||||||
| Dyspnea | ||||||
| No | 4 (5.00%) | 4 (26.67%) | 0 | 0 | 0 | <0.0001 |
| Yes | 76 (95.00%) | 11 (73.33%) | 17 (100%) | 19 (100%) | 29 (100%) | |
| P1 = 0.04, P2 = 0.03, P3 = 0.01 | ||||||
| Chest pain | ||||||
| No | 39 (48.75%) | 3 (20.00%) | 5 (29.41%) | 19 (100%) | 12 (41.38%) | <0.0001 |
| Yes | 41 (51.25%) | 12 (80.00%) | 12 (70.59%) | 0 | 17 (58.62%) | |
| P1 = 0.69, P2 < 0.0001, P3 = 0.16, P4 < 0.0001, P5 = 0.53, P6 < 0.0001 | ||||||
| Cough | ||||||
| No | 15 (18.75%) | 5 (33.33%) | 1 (5.88%) | 0 | 9 (31.03%) | 0.01 |
| Yes | 65 (81.25%) | 10 (66.67%) | 16 (94.12%) | 19 (100%) | 20 (68.97%) | |
| P1 = 0.08, P2 = 0.01, P3 = 1.00, P4 = 0.47, P5 = 0.07, P6 = 0.01 | ||||||
p-value comparison in the four groups; pairwise comparisons were carried out if the p-value was significant; P1, compared simple and complicated; P2, compared simple and TB; P3, compared simple and malignant; P4, compared complicated and TB; P5, compared complicated and malignant; P6, compared TB and malignant
Pleural Fluid (PF) Lactic Acid Level
Pleural fluid (PF) lactic acid median level was significantly more in the complicated than in the simple PPE groups, TPE, and malignant PE groups (7.19 vs 2.7 mmol/L, P1 < 0.001, 7.19 vs 3.47 mmol/L, P4 = 0.0001, 7.19 vs 2.13 mmol/L, P5 = 0.0001, respectively), while PF lactic acid median level was significantly higher in the TPE group than the MPE group and simple PPE (3.47 vs 2.13 mmol/L, P6 = 0.006, 3.47 vs 2.7 mmol/L, P2 = 0.02, respectively) (Table 3).
| Variable | Simple N = 15 | Complicated N = 17 | Tuberculosis N = 19 | Malignant N = 29 | p-value |
|---|---|---|---|---|---|
| pH | <0.0001 | ||||
| Mean ± SD | 7.47 ± 0.28 | 6.98 ± 0.25 | 7.52 ± 0.26 | 7.55 ± 0.26 | |
| Median (range) | 7.3 (7.3:8) | 7 (6.6:7.6) | 7.4 (7.22:8) | 7.5 (7.2:8) | |
| P1 < 0.0001, P2 = 1.00, P3 = 1.00, P4 < 0.0001, P5 < 0.0001, P6 = 1.00 | |||||
| Pleural protein | |||||
| Mean ± SD | 5.1 ± 1.19 | 4.72 ± 0.67 | 4.99 ± 0.75 | 4.0 ± 0.89 | 0.11 |
| Median (range) | 4.9 (4.2:7.9) | 4.4 (3.8:5.7) | 5.4 (3.1:5.5) | 3.8 (2.1:5.3) | |
| Type of leukocyte | |||||
| Lymphocytes | 0 | 3 (17.65%) | 19 (100%) | 29 (100%) | <0.0001 |
| Neutrophil | 15 (100%) | 14 (82.35%) | 0 | 0 | |
| P1 = 0.23, P2 < 0.0001, P3 < 0.0001, P4 < 0.0001, P5 < 0.0001 | |||||
| LDH | |||||
| Mean ± SD | 670.3 ± 435.3 | 676.0 ± 282.9 | 903.1 ± 570.96 | 603.34 ± 651.2 | 0.048 |
| Median (range) | 550 (211:1466) | 677 (319:1469) | 741 (252:1722) | 408 (116:3570) | |
| P1 = 0.35, P2 = 0.13, P3 = 0.24, P4 = 0.48, P5 = 0.03, P6 = 0.02 | |||||
| Glucose | |||||
| Mean ± SD | 67.47 ± 45.52 | 69.18 ± 67.55 | 78.21 ± 74.22 | 91.90 ± 37.34 | 0.06 |
| Median (range) | 40 (10:116) | 56 (8:202) | 72 (8:209) | 100 (16:182) | |
| P1 = 0.78, P2 = 0.62, P3 = 0.35, P4 = 0.53, P5 = 0.01, P6 = 0.02 | |||||
| Lactic acid | |||||
| Mean ± SD | 2.59 ± 0.74 | 6.98 ± 2.46 | 3.57 ± 1.28 | 2.49 ± 1.41 | 0.0001 |
| Median (range) | 2.7 (0.8:3.4) | 7.19 (2.7:11.6) | 3.47 (2:5.5) | 2.13 (0.8:5.5) | |
| P1 = 0.0001, P2 = 0.02, P3 = 0.32, P4 = 0.0001, P5 = 0.0001, P6 = 0.006 | |||||
p-value compared the four groups; pairwise comparisons were made if the p-value was significant; P1 compared simple and complicated; P2, compared simple and TB; P3 compared simple and malignant; P4 compared complicated and TB; P5 compared complicated and malignant; P6, compared TB and malignant
Pleural fluid (PF) lactic acid median level illustrated statistically higher significant differences between all groups of patients (p = 0.0001) (Fig. 1).
Fig. 1: Pleural level of lactic acid among different groups
Lactate dehydrogenase (LDH), pH, white cell count, glucose, and protein pleural levels in the participating groups—statistically significant differences were reported in LDH level between all groups (p = 0.048) that was significantly higher in TPE and CPPE than MPE (P6 = 0.02, P5 = 0.03, respectively).
pH was statistically lower in CPPE than simple PE, TPE, and MPE (p < 0.0001).
The PF white cell count illustrated statistically high significant differences among the groups (p < 0.0001) in which there was lymphocytic predominant in TPE and MPE (100%), while neutrophil predominated in simple and CPPE (100 and 82.35%, respectively).
No statistically significant difference was reported in pleural glucose level and protein level among all groups of PE (p = 00.6, p = 0.11) (Table 3).
The Spearman’s coefficient correlation (r) of PF lactic acid level to PF pH, glucose, and LDH levels in the participating groups shows—in the simple group (n = 15), PF lactic acid level revealed a significantly high positive correlation with the PF pH (r = 0.61, p = 0.02) and glucose (r = 0.67, p = 0.01) and a weak nonsignificant positive correlation with PF LDH (r = 0.33, p = 0.24).
In the complicated group (n = 17), PF lactic acid level correlated negatively with a significantly high value with the PF pH (r = –0.57, p = 0.02), a positive correlation with PF LDH, and negative correlation with PF glucose, which were weak and not significant (r = 0.39, p = 0.12 and r = –0.34, p = 0.18, correspondingly).
In the tuberculous group (n = 19), PF lactic acid level demonstrated that there was a significantly strong negative correlation with PF pH and PF glucose level (r = –0.65, p = 0.003 and r = –0.56, p = 0.01, correspondingly), while there was a nonsignificant positive correlation between PF lactic acid and LDH (r = 0.37, p = 0.12).
In the malignant group (n = 29), PF lactic acid level demonstrated that there was a significantly high positive correlation with PF LDH (r = 0.57, p = 0.001). Between PF lactic acid and pH, it was weak and not significant, and the correlation between PF lactic acid and PF glucose was weak negative and not significant (r = 0.29, p = 0.12 and r = –0.32, p = 0.09, correspondingly) (Table 4).
| Correlation between PF lactic acid and | All | Simple | Complicated | Tuberculous | Malignant | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| r | p | r | p | r | p | r | p | r | p | |
| pH | –0.36 | 0.001 | 0.61 | 0.02 | –0.57 | 0.02 | –0.65 | 0.003 | 0.29 | 0.12 |
| LDH | 0.44 | <0.001 | 0.33 | 0.24 | 0.39 | 0.12 | 0.37 | 0.12 | 0.57 | 0.001 |
| Glucose | –0.21 | 0.07 | 0.67 | 0.01 | –0.34 | 0.18 | –0.56 | 0.01 | –0.32 | 0.09 |
PF lactic acid cutoff level to differentiate simple from CPPE, the ROC curve analysis was utilized to identify the efficacy of PF lactic acid in differentiating the simple from the complicated one. PF lactic acid cutoff level of >3.4 mmol/L was significant in predicting CPPE with high specificity and positive predictive value scored, with low sensitivity and negative predictive value (100, 100, 82.4, and 83.3%, respectively) (Table 5). The AUC scored 0.912 [p < 0.0001, 95% CI (0.757:0.983)] (Fig. 2).
| Cutoff point | AUC (95% CI) | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | p-value | |
|---|---|---|---|---|---|---|---|
| Lactic acid | >3.4 | 0.912 (0.757:0.983) | 82.4 | 100 | 100 | 83.3 | <0.0001 |
| LDH | >550 | 0.596 (0.409:0.765) | 64.7 | 73.3 | 73.3 | 64.7 | 0.37 |
| PH | ≤7.23 | 0.953 (0.814:0.997) | 94.1 | 100 | 100 | 93.7 | <0.0001 |
| Glucose | ≤81 | 0.529 (0.346:0.707) | 82.4 | 46.7 | 63.6 | 70.0 | 0.79 |
Fig. 2: The ROC curve study to evaluate the performance of different parameters to differentiate between simple and complicated pleural effusion
As regards PF lactic acid cutoff level to differentiate TPE from MPE, PF lactic acid cutoff level of ≤2.8 mmol/L illustrated 79.3% sensitivity, 68.4% specificity, 68.4% negative predictive value, as well as 79.3% positive predictive value in the prediction of MPE (Table 6). The AUC scored 0.735 [p < 0.001, 95% CI (0.588:0.852)] (Fig. 3).
| Cutoff point | AUC (95% CI) | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | p-value | |
|---|---|---|---|---|---|---|---|
| Lactic acid | ≤2.8 | 0.735 (0.588:0.852) | 79.3 | 68.4 | 79.3 | 68.4 | 0.001 |
| LDH | ≤641 | 0.693 (0.544:0.818) | 75.9 | 68.4 | 78.6 | 65.0 | 0.02 |
| pH | >7.4 | 0.552 (0.401:0.695) | 62.1 | 68.4 | 75.0 | 54.2 | 0.554 |
| Glucose | >75 | 0.699 (0.549:0.823) | 75.9 | 78.9 | 84.6 | 68.2 | 0.03 |
Fig. 3: Receiver operating characteristic (ROC) curve study to evaluate the performance of different parameters to differentiate between tuberculosis and malignant pleural effusion
DISCUSSION
Evaluating PF cases started with determining whether the effusion is exudate or transudate. The exudative effusion can be diagnosed when the case fulfills Light’s criteria. As known, the chemical evaluation of the fluid (especially LDH, albumin, and total proteins) in comparison to the one obtained from blood tests is the accepted criterion for the differentiation between both types.13 However, Light’s criteria can misclassify nearly 25% of transudates, particularly in HF cases treated with diuretics. Such misclassification requires additional testing with fluid-serum albumin gradient and natriuretic peptides to confirm the diagnosis. Thus, this highlights that other components of the fluid analysis, including routine biochemical and cytological examination, are crucial and can further increase diagnostic accuracy.14
Once a case shows a transudative effusion, treatment has to address the underlying cause, including cirrhosis or HF.
In contrast, when the case demonstrates exudative effusion, the etiology has to be defined. Pneumonia, pulmonary embolism, cancer, and TB are responsible for the majority of the causes. Several PF tests can help in the differential diagnosis of exudative effusion.15,16
Pleural fluid (PF) pH is the best marker to differentiate between uncomplicated parapneumonic effusion (UPPE) and CPPE.17 However, these methods could be inadequate for diagnosing and treating PPEs, especially in the early phase of the disease.18,19
For these previous reasons, the authors utilized the level of lactic acid in PF in diagnosing exudative PF because they are easily categorized than the pH and obtainable. The levels of PF lactic acid could be particularly beneficial in the case of starting antibiotic therapy before collecting the specimen. High levels of lactic acid were noticeable many days after chemotherapy commenced. Moreover, measuring lactic acid in cerebrospinal, pleural, and ascitic fluid is utilized in differentiating bacterial infectious etiologies from other issues.20
In our study, PF samples from 80 cases were analyzed to assess the helpfulness of pleural lactic acid level as a diagnostic test for different causes of exudative PEs.
Our findings illustrated that the median level of PF lactic acid in the CPPE was higher than the simple PPE, TPE, and malignant PE groups. This result matches the findings of Santotoribio et al.,21 who reported a higher PF lactate concentration in PPE patients than patients who had PE by another etiology.
Our results showed that PF lactic acid concentration had high accuracy (AUC = 0.912) for the diagnosis of CPPE with PF lactic acid cutoff level of >3.4 mmol/L showed 82.4% sensitivity and 100% specificity that matched the study of Gästrin and Lovestad,22 in which the optimal cutoff value was 10 mmol/L with 94% sensitivity and 100% specificity in diagnosing PPE.
The study of Kho et al. reported23 a significantly elevated PF lactic acid level in CPPE than in TPE. This finding agreed with our results. It may be explained by the difference in pathogeneses and metabolic pathways in CPPE and TPE, in which high metabolic cell activity during pleural infection in CPPE is associated with bacterial metabolism producing lactic acid while in TPE determined by delayed-type hypersensitivity reaction with granulomatous pleuritis.24
So, from these results, we thought that the utility of PF lactic acid level in the diagnosis of PPE that we could have a decision toward early insertion of a chest tube for CPPE or toward more investigation for TPE or malignant effusion (such as closed pleural biopsy and/or other diagnostic tests).
In our study, PF lactic acid level in the complicated PPE also correlated negatively with a high significance level with the PF pH (r = –0.57, p < 0.02). Many studies confirmed that the results in our study, as regards PF pH, are the best marker to differentiate between simple and CPPE.17 Nevertheless, many factors, such as having lidocaine or air in the blood gas syringe and analysis delay, may cause significant variations in the pH readings.25 Other parameters, such as PF glucose level and protein level, may be inadequate for diagnosing and managing PPEs, especially in the early stage of the disease.18,19 This agreed with our results as there were no statistically significant differences in pleural glucose level and protein level among our PPE groups.
This research illustrated that the median level of PF lactic acid was higher in TB patients (3.47 vs 2.13 mmol/L) than for the malignant group.
This can be explained by the fact that the increase of PF lactate in TB effusions involves the activation of a high quantity of immune system cells that leads to lactate overproduction.26,27 This agrees with Gästrin and Lovestad, which carried out a study on 198 cases of exudative effusion and reported that malignancy accounted for the lowest level of lactic acid, while the highest accounted for empyema.22
The common values in differentiating PEs, including glucose level, pH, and PF protein, usually decline in TB.6 This finding correlates with our study results that PF lactic acid level correlated negatively with a high significance level with the PF glucose level (r= –0.56, p = 0.01) in the tuberculous group. Low PF glucose levels and PF acidosis occur secondary to anaerobic glucose metabolism with local production of lactate and carbon dioxide (CO2).28
According to the results of our study, a PF lactic acid cutoff level of ≤2.8 mmol/L gave a sensitivity of 79.3% and specificity of 68.4% for predicting MPE. This can be explained by the increasing pH of the effusion, causing low glucose transfer into the pleural space and the reduction of the efflux of hydrogen ions, CO2, as well as lactic acid through an abnormal pleural membrane.29,30
We think that these results could be useful in differentiating between TPE from malignant one that overcomes the following difficulties as the bacteriological confirmation of tuberculous pleuritis as in the majority of immunocompetent patients, below 40% of cultures were positive.32 Delaying getting the finding (even when using rapid methods) caused implementing other diagnostic methods, for example, ADA level, which is often raised in tuberculous pleuritis but may be highly demonstrated in other infections, rheumatoid arthritis, and some malignancy.31
Other diagnostic tests can be done, including interferon and polymerase chain reaction (PCR). The disadvantages of this method are due to being expensive, a person may get contaminated, and it requires qualified staff. Additionally, within the United States, the Food and Drug Administration (FDA) has not validated interferon-γ and lysozyme concentrations in PEs.5,31,32
While diagnosing malignant effusion relies on the amount and cellularity of the analyzed sample, it often needs assistance from invasive measures.33 Other predictive rules were published to differentiate tuberculous pleurisy from malignant effusion,34,35 and we thought in our study PF lactic acid level detection could be helpful.
Determining the lactic acid can play a role in other body fluids. Contemporary meta-analysis proves that cerebrospinal fluid lactic acid illustrates a somewhat relatively strong specificity and sensitivity in diagnosing post-neurosurgical bacterial meningitis.36
Our research paper is limited to the following limitations—the analysis covered a single-center population with a small unequal sample size. More new studies are necessary for the assessment of the diagnostic value of PF lactic acid.
CONCLUSION
Pleural fluid (PF) lactic acid level measurement can be used as a diagnostic tool for discrimination between the different causes of exudative PE as parapneumonic, tuberculous, and malignant, and our research has arrived at different cutoff levels of PF lactic acid levels for different types of exudative PE, which can guide a decision for management of each type of exudative PE.
DECLARATIONS
Ethics Approval and Consent to Participate
This study was approved by the Medical Research and Ethics Committee of the Faculty of Medicine, Sohag University, under the IRB registration number: Soh-Med-22-03-38.
And it was carried following the principles of the 1964 Declaration of Helsinki and its 2013 revision.
ORCID
Doaa Gadallah https://orcid.org/0000-0003-4217-0385
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