Diagnostic value of pleural fluid and serum CRP/lymphocyte ratio as a marker for discrimination of infectious-non-infectious pleural effusion

Authors

Abstract

Aim This study aims to investigate the diagnostic role of the C-reactive protein to lymphocyte ratio (CLR) in identifying the etiology of pleural effusions, specifically in distinguishing between infectious and non-infectious causes through transudate-exudate analysis.
Materials and methods A total of 106 patients who were evaluated for pleural effusion in our department were retrospectively analyzed. In addition to biochemical, microbiological, and cytological examinations of pleural fluid, CRP and lymphocyte levels were measured simultaneously in both serum and pleural fluid.
Results A total of 106 patients were included in the study, 78(73.6%) of whom were male. Pleural fluid was identified as exudative in 66(62.3%) cases and transudative in 40(37.7%) cases. In the infectious group, the pleural fluid and serum CLR were significantly higher compared to the non-infectious group (p<0.001;p<0.001). When the threshold value for pleural fluid CLR was set at 27, it exhibited a sensitivity of 89.2% and a specificity of 88.7% in differentiating between infectious and non-infectious pleural effusions (AUC 0.941,p<0.001).In the exudative group, the pleural fluid and serum CLR values were significantly higher compared to the transudative group (p<0.001;p<0.001).
Discussion This study shows that CLR can support clinicians in identifying the cause of pleural effusions and distinguishing between infectious/non-infectious and transudative/exudative types. Further studies are needed to confirm its diagnostic value.

Keywords

Introduction

The pleural space contains a small amount of fluid that facilitates the easy movement of the pleural membranes. Changes in the hydrostatic and osmotic pressures of the vascular structures, increased endothelial permeability, and insufficient lymphatic drainage can lead to the accumulation of excess fluid between the pleural membranes, resulting in the development of pleural effusion [1]. The etiology of pleural effusion is crucial for selecting the appropriate treatment approach. Delays in diagnosing infectious effusions and initiating appropriate treatment can lead to complications. Therefore, it is essential to rapidly identify infectious pleural effusions and begin treatment without delay.
C-reactive protein (CRP), associated with pentraxins, is secreted by the liver in response to various inflammatory cytokines. CRP levels rise rapidly in response to trauma, inflammation, and infection, and decrease at the same rate after treatment [2]. A substantial amount of research has been conducted on CRP, with its role in pleural effusion, malignancy, trauma, psoriasis, pulmonary embolism, acute myocardial infarction, ischemic stroke, and many other diseases being widely discussed in the literature [3, 4, 5]. In one study, the CRP levels in both blood and pleural fluid were found to be higher in the parapneumonic effusion group compared to other groups in patients with pleural effusion (p<0.001)[6]. In another study, pleural fluid CRP levels were found to be higher in empyema, parapneumonic effusion, and tuberculous pleurisy compared to malignant effusions and transudates [7]. CRP is associated not only with infectious conditions but also with numerous malignant diseases. High CRP levels before treatment have been shown to be associated with poor prognosis in patients with non-small cell lung cancer (NSCLC), multiple myeloma, renal cell carcinoma, prostate cancer, gastrointestinal cancer, and hepatocellular carcinoma. There are studies in the literature regarding pleural fluid CRP levels in distinguishing malignancy-related pleural effusions from those caused by non-malignant factors [8, 9]. Lymphocytes, a component of the complete blood count, are white blood cells that help the body fight viruses, bacteria, and cancer [10]. The C-reactive protein/lymphocyte ratio (CLR) has been shown to play a key role in the prognosis of severe aneurysmal subarachnoid hemorrhage, pancreatic cancer, and colorectal cancer [11, 12]. In a retrospective study, CLR was evaluated in distinguishing between COVID-19 patients with pneumonia and those without pneumonia, and the results revealed that CLR values were significantly higher in the group with pneumonia compared to the group without pneumonia [13]. There are no studies investigating CLR in patients with pleural effusion. In this study, we aimed to explore the role of complete blood count parameters and CRP in determining infectious and non- infectious etiologies through transudate-exudate analysis of pleural fluid.

Materials and Methods

A total of 106 patients who were investigated and treated for pleural effusion between March 2020 and July 2021 were included in the study. Inclusion criteria were age over 18 years and consent for thoracentesis. Other conditions that could elevate CRP levels (such as urinary tract infection, skin infection, severe renal failure [GFR<15], and insufficient clinical data) were considered exclusion criteria. Demographic data of all patients included in the study (age, gender, exposure, occupation, etc.), smoking status, comorbidities, pregnancy, and medication history were recorded. Complete blood count (CBC), pH, glucose, total protein, albumin, lactate dehydrogenase (LDH), adenosine deaminase (ADA) (if tuberculosis was suspected), creatinine, brain natriuretic peptide (Pro-BNP), CRP, lymphocyte count, pleural fluid culture, tuberculosis culture, and pleural fluid cytological examination results were all documented in the patient follow-up form. The CRP and lymphocyte values measured at the time of diagnosis were used to calculate the CLR. The Light criteria were used to differentiate between exudate and transudate. In our study, CRP measurements were performed using the nephelometric method.
Diagnostic Criteria
1. Empyema: Patients with low pH, low glucose, high LDH in pleural fluid samples, along with microbial growth in pleural fluid culture and/or the presence of pus on thoracentesis, and/or radiological findings consistent with empyema, were included in this group.
2. Parapneumonic effusion: Patients were included in this group if they presented with clinical symptoms and signs (fever, chills, shaking, purulent sputum), had pneumonic infiltration on chest radiography on the fluid side, and showed low pH, low glucose, and high LDH levels in pleural fluid. Additionally, patients with no microbial growth in pleural fluid culture and those who responded positively to antimicrobial treatment were also included.
3. Malignant pleural effusion: Patients with malignant cells identified in pleural fluid cytology or pleural biopsy were included in this group.
4. Paramalignant effusion: Patients with an existing malignancy but no malignant cells found in pleural fluid cytology and/or pleural biopsy, and no alternative diagnosis, were included in this group.
5. Tuberculous (TB) pleurisy: Diagnosis was made in patients with the detection of Mycobacterium tuberculosis in pleural fluid and/or necrotizing granulomatous inflammation in pleural biopsy, and/or an ADA level >70 IU/L in the pleural fluid sample, with regression of pleural effusion after the initiation of tuberculosis treatment.
Statistical Analysis
Statistical analysis was performed using IBM SPSS 26.0 software. Descriptive statistical analysis included means ± standard deviation and median (minimum-maximum) for continuous variables, depending on the normality of distribution, and frequencies and percentages (%) for categorical variables. The distribution of continuous variables was assessed using the Kolmogorov-Smirnov test, and nonparametric tests were applied based on the test results. The Mann-Whitney U test was used for comparing nonparametric data between two groups. Receiver Operating Characteristic (ROC) analysis was used to determine the diagnostic value of pleural and serum CLR levels for exudative and infectious pleural effusion and whether they could be used for this purpose. Pearson correlation analysis was used for correlation analysis. A statistical significance level of p<0.05 was considered.
Ethical Approval
This study was approved by the Ethics Committee of Gazi University Faculty of Medicine (Date: 2022-12-19, No: 922).

Results

A total of 130 patients diagnosed with pleural effusion were screened in the study. Twenty-four patients were excluded, and 106 patients were ultimately included in the analysis. Among the patients, 78 (73.6%) were male, and 28 (26.4%) were female. The mean age of the patients was 63.27 ± 12.86 years. In 66 (62.3%) of the cases, exudate was detected, while in 40 (37.7%), transudate was observed. Among these, 46 (43.4%) had an infectious etiology, and 60 (56.6%) had a non-infectious etiology. According to the final diagnoses, 10 patients were diagnosed with tuberculous (TB) pleurisy, 15 with empyema, 21 with parapneumonic effusion, 10 with malignant effusion, and 10 with paramalignant effusion (Figure 1).
The patients were divided into two groups: those with pleural infection (infectious; empyema, parapneumonic effusion, tuberculous pleurisy) and those without pleural infection (non-infectious; malignant effusion, paramalignant effusion, transudate). The CRP and CLR values in pleural fluid and serum were then examined (Table 1).
The pleural fluid CRP and CLR levels were found to be 99 (77- 155) and 102.6 (28-234) in empyema, 99 (30.9-238) and 98.21 (27.72-345) in parapneumonic effusion, 44.85 (8.85-110) and 31.64 (2.67-88.15) in tuberculous pleurisy, and 11 (2.1-25) and 16.27 (2.02-50) in malignant effusion, respectively. Both values were significantly higher in empyema, parapneumonic effusion, and tuberculous pleurisy compared to malignant effusion (p<0.001, p<0.001, p<0.001, respectively). In the transudate group, pleural fluid CRP was 8.08 (2.0-35.0) and CLR was 10.5 (0.9-34.7). Similarly, pleural fluid CRP and CLR were significantly higher in the groups with empyema, parapneumonic effusion, and tuberculous pleurisy compared to the transudate group (p<0.001, p<0.001, p<0.001, respectively). No significant difference in pleural fluid CRP and CLR levels was observed between the patients with empyema and parapneumonic effusion (p=0.33, p=0.35, respectively).
In the infectious group, the pleural fluid CLR was 69.8 (2.6-345), and the serum CLR was 140.3 (10.3-640). In the non-infectious group, the pleural fluid CLR was 12.5 (0.9-50), and the serum CLR was 20.8 (1.3-76.6). Pleural fluid CLR and serum CLR levels were significantly higher in the infectious group (p<0.001; p<0.001, respectively). ROC analysis was performed to determine the threshold values of pleural fluid and serum CLR for the discrimination of infectious/non-infectious causes. For pleural fluid CLR, a threshold value of 27 yielded a sensitivity of 89.2% and a specificity of 88.7% for the differentiation of infectious and non-infectious pleural effusion (AUC 0.941, p<0.001) (Figure 2, Table 2). For serum CLR, a threshold value of 54.5 resulted in a sensitivity of 91.9% and a specificity of 91.5% (AUC 0.968, p<0.001) (Figure 2).
In distinguishing empyema from other causes, when the pleural fluid CLR threshold was set at 64.1, a sensitivity of 80% and specificity of 85.7% were observed (Table 2). For differentiating empyema and parapneumonic effusion from other causes, when the pleural fluid CLR threshold was set at 39.5, a sensitivity of 92.6% and specificity of 93.8% were achieved (AUC 0.976, p<0.001) (Table 2).
In the transudate group, pleural fluid CLR was measured at 10.5 (0.9-34.7), and serum CLR was 17.8 (4.0-57.6), both of which were statistically significantly higher in the exudate group (p<0.001, p<0.001, respectively). ROC analysis was performed to determine the threshold for pleural fluid CLR in differentiating exudates from transudates. When the threshold was set at 14, the sensitivity was 69.7%, the specificity was 62.5%, and the AUC was 0.768 (Figure 3, Table 2). A correlation analysis was performed between serum and pleural fluid CLR levels in all patients included in the study, regardless of the cause of pleural effusion. A strong positive correlation was found between pleural fluid and serum CLR levels, which was statistically significant (r=0.925, p<<0.001). Additionally, independent of the diagnosis, a positive correlation was also observed between pleural fluid and serum CRP levels (r=0.929, p<0.001).

Discussion

In this study, we found that pleural fluid CRP and CLR levels were significantly higher in cases of empyema and parapneumonic effusion compared to other effusion etiologies. Furthermore, in cases of infectious pleural effusion, the levels were significantly higher when compared to non-infectious effusions. The differential diagnosis of pleural effusion is quite broad. Clarifying the etiology is crucial for determining the appropriate treatment approach. The Light criteria are currently used routinely to differentiate transudative effusions from exudative effusions. In the diagnostic approach to exudative pleural effusion, which develops secondary to various diseases, pleural fluid biochemical, cytological, and pathological examinations are performed. For patients with undiagnosed conditions or those requiring further investigation, invasive procedures such as bronchoscopy or thoracoscopy are performed. However, delays in diagnosis and treatment can occur due to patients either refusing invasive procedures or being unable to tolerate them due to their overall condition. Therefore, there is a need for new biomarkers that provide rapid diagnosis with high specificity and sensitivity.
A retrospective study has demonstrated that pleural fluid CRP levels can be used to differentiate parapneumonic effusions from other exudative effusions. In this study, CRP levels ≥ 1.38 mg/dL were found to be significant for an infectious etiology [14]. Similarly, another study found that pleural fluid CRP levels were higher in parapneumonic effusions compared to tuberculous and malignant effusions [8]. In our study, we found that pleural fluid CRP levels were higher in empyema and parapneumonic effusions compared to other etiologies. Additionally, serum CLR levels were found to be higher in parapneumonic effusions when compared to the other groups. In the study conducted by Watanabe et al, pleural fluid CRP levels were found to be lower compared to serum CRP levels [10]. In our study, we found that pleural fluid CRP and CLR levels were lower compared to serum values. Our results support the hypothesis that the elevated CRP levels in pleural fluid are primarily due to the transfer of CRP from the serum into the pleural space, rather than local production of CRP within the pleural cavity The higher pleural fluid CRP levels observed in empyema and parapneumonic effusion, compared to other etiological causes, may be associated with more severe systemic inflammation in pulmonary infections.
Several studies have been conducted evaluating the role of CRP in distinguishing exudative effusions from transudative effusions [15, 16, 17]. One study identified that CRP could be a useful diagnostic marker for differentiating exudative and transudative pleural effusions. Additionally, it was demonstrated that in patients receiving diuretic therapy, CRP levels were more valuable than protein levels in cases where the effusion was mistakenly classified as exudative according to the Light criteria [16]. Mansour Ahmed et al. found that CRP levels measured in pleural fluid were significantly higher in the exudative group (p=0.0001) [17]. In our study, CRP in pleural fluid was 30.2 (2.1–238.0) and CLR was 27.8 (2–345) in the exudative group, both of which were higher compared to the transudative group.
CLR has been shown to be an effective and simple prognostic marker as an independent risk factor for mortality in HBV- associated decompensated liver cirrhosis [18]. Similarly, another study demonstrated that elevated CLR upon admission in COVID-19 patients was indicative of poor prognosis [19]. In a study evaluating CLR in 1380 patients with NSCLC, it was shown that the prognosis in the high CLR group was significantly worse compared to the low CLR group. The study concluded that preoperative CLR is a useful marker in predicting the prognosis of surgically treated NSCLC patients [20]. Our study is the first clinical investigation in the literature to explore the role of CLR in pleural effusion. In both empyema and parapneumonic effusion, CLR levels were found to be higher compared to other groups. When a threshold value of 27 for pleural fluid CLR was used, the sensitivity for distinguishing between infectious and non-infectious effusions was 89.2%, and the specificity was 88.7%, both of which were remarkably high.

Limitations

The main limiting factor in our study was the inability to include an adequate number of patients in each disease group, causing pleural effusion. Additionally, the study was conducted at a single center and was retrospective in nature. Therefore, it is suggested that our findings be supported by studies with larger sample sizes to enhance their generalizability.

Conclusion

In conclusion, our study found a strong positive correlation between pleural fluid and serum CLR, independent of the cause of pleural effusion. We also determined that pleural fluid CLR is significant in differentiating between infectious and non- infectious effusions, as well as in distinguishing between exudative and transudative effusions. There are currently no studies in the literature evaluating CLR in patients with pleural effusion, and it is anticipated that with future research, the role of CLR in the diagnosis of pleural effusion will become clearer.

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