INTRODUCTION

Pleural effusion is a widespread clinical condition, and its differential diagnosis may be troublesome requiring numerous investigations, including invasive maneuvers ¹.

The gold standard for diagnosis of para-pneumonic effusion is the detection of a micro-organism in the pleural fluid (PF). Regrettably, about 40% of aspirated fluids are negative in ordinary cultures², but this outcome is increased when blood culture bottles are used simultaneously.³

Diagnosis of tuberculous pleural effusion (TPE) relays on positive smear and/or culture of Mycobacterium tuberculosis in (PF) or biopsies.⁴ However, reaching the diagnosis could be opposed by many facts; 1) less than 10% of (TPEs) are AFB positive by direct smear, 2) liquid media cultures of (TPE) have a yield of about 45% only and 3) reported sensitivity for Xpert Ultra PCR on (TPE) is low (38-75%).⁵

Diagnosis of malignant pleural effusion (MPE) depends on positive PF cytology or pleural biopsy. Unluckily, the cytology outcome is almost 60%, and it is rarely to obtain positive results beyond the second trial of PF sampling.⁶

Many studies have checked biochemical markers to aid in the diagnosis of exudative pleural effusion, and some of them had scored some clinical viability.¹ Recently, neutrophil to lymphocyte ratio (NLR) has been tested as a new inflammatory marker.⁷ and few studies used its value in pleural fluid for the differentiation between various etiologies.⁸

This work aimed at assessing the role of (NLR) in either blood or pleural fluid as a simple biomarker in detecting the underlying etiology of exudative pleural effusion.

PATIENTS AND METHODS

This cross sectional study took place at Bab Al-Sha’reia University Hospital in the period between February 2021 and February 2022. It included 100 patients diagnosed to have exudative pleural effusion according to Light’s criteria.⁹

Exclusion Criteria

Patients were totally excluded from the study if they had any of the following conditions; transudative pleural effusion according to Light’s criteria, minimal amount of pleural effusion that could not be safely sampled under ultrasound guide, undiagnosed exudative pleural effusion after performing all investigations including pleural tissue biopsy, missing data and refusal to participate in the study.

Clinical Data and Diagnostic Work-up

At the time of being included in the study, all patients were not diagnosed yet. Patients were submitted to detailed history taking, thorough clinical examination, routine laboratories including: complete blood count (CBC), liver and kidney function tests, random blood sugar (RBS) and coagulation profile (PT, APTT and INR). Plain chest x-ray (PA and lateral views) and chest computed tomography (CT) were performed to all participants. After that, diagnostic work-up for unexplained exudative pleural effusion was performed to all cases through ultrasound guided diagnostic thoracentesis to collect a fluid sample for: chemical analysis to confirm the exudative nature according to Light’s criteria (pleural total protein to serum total protein ratio > 0.5, pleural LDH to serum LDH ratio >0.6 and pleural LDH level >2/3 upper limit of the laboratory reference range of serum LDH), differential leucocytic count, examination for acid-fast bacilli, culture for Gram positive and negative micro-organisms and cytology for malignant cells in pleural fluid (if needed). Tissue biopsies were taken via medical thoracoscopy or closed pleural biopsy when all previous investigations failed to show up a definite diagnosis.

Medical Thoracoscopy Technique

The procedure was done in the Interventional Pulmonology Unit by the hands of skillful pulmonologists. Each patient was located in the lateral position, with the side of the effusion directed upward, and his/her ipsilateral arm elevated above head to widen the intercostal spaces. Under the guide of ultrasound, the optimal site for intervention was chosen. After proper skin preparation and draping with povidone iodine 10%, about 10-15 cc of local anesthesia (lidocaine 2%) were injected at the site of entry, followed by conscious sedation by intravenous medazolam. Single incision (1-1.5 cm length) was done, and blunt dissection was performed to reach the parietal pleura. The pleura was pierced by a metal tocar, and the pleural fluid was aspirated using a suction catheter. A rigid thoracoscope of 7 mm diameter (Karl Storz Endoscope; Karl Storz; Tuttlingen, Germany) was introduced inside the pleural cavity to visualize it, and multiple biopsies were obtained from suspicious lesions. An intercostal tube was left to allow further drainage of residual and re-accumulated pleural fluid ¹⁰. Heart rate, respiratory rate, oxygen saturation (SO₂) and arterial blood pressure were all closely monitored throughout the procedure. Oxygenation via nasal cannula (1-6 L/m) was applied to maintain SO₂ above 90%.

Closed Pleural Biopsy Technique

The maneuver was performed in a well-equipped room by well-trained chest physicians. The patient was asked to adopt sitting position, with his/her arms leant on a table at shoulder level, the site of entry (usually located at the dorso-lateral thoracic wall) was determined by the aid of ultrasonography. Under complete aseptic conditions, 5-10 cc of local anesthesia (lidocaine 2%) were applied, a 3-5 mm incision was made on the skin and subcutaneous tissues, and the Abram’s needle was withdrawn in a rotating manner with steady pressure through the incision to traverse the subcutaneous tissues and intercostal muscles above the superior border of the inferior rib, so as to escape damaging the intercostal neurovascular bundle. On passing to the pleural cavity, the notch of the needle trocar was engaged to the pleura, and the required tissue sample was cut off and taken. This process was recurred several times to get sufficient tissue biopsies (usually 4-8 biopsies).¹¹

Categorization of Patients According to Diagnosis 

Following establishing diagnoses, patients were divided according to the underlying cause into three groups; 1) malignant pleural effusion group, 2) tuberculous pleural effusion group and 3) para-pneumonic pleural effusion group. Finally, neutrophil to lymphocyte ratios were determined in both blood (using parameters of CBC done on presentation) and pleural fluid for all patients, and the means were compared among different groups.

Ethical Considerations 

The study was approved by the Ethical Committee of Al-Azhar University. All participants signed an informed written consent to share in the study.

Statistical Analysis

Data were analyzed using Statistical Program for Social Sciences (SPSS) version 24 (IBM corp., Armonk, NY, USA). Numerical data were expressed as mean ± standard deviation (SD), whereas qualitative data were expressed as frequency and percentage. Kruskal Wallis (KW) test was applied to compare the abnormally distributed data among the study groups. Tukey’s post-Hoc was used to define means that are significantly different from each other, after (KW) test had showed a statistically significant relationship. P-values

RESULTS

MPE: malignant pleural effusion, TPE: tuberculous pleural effusion, PPE: para-pneumonic effusion, SD: standard deviation.

Table (1): Demographic data distribution among studied groups

The patients of (MPE) group were the eldest with a mean age of (61.95±9.88) years, followed by (PPE) group (44.2±14.59) years, while (TPE) group patients were the youngest (37.14±12.89) years. Male sex was predominant in all study groups accounting for (58.3%, 59.3% and 56%) in (MPE), (TPE) and (PPE) groups respectively. The majority of (MPE) group (77.1%) had an occupational and/or resident (Shobra El-Kheima or Helwan) history of exposure to asbestos fibers (Table 1).

Table (2): Malignant pathological pattern distribution in MPE group

Malignant mesothelioma was the responsible cause in (83.33%) of the (MPE) group, followed by metastatic adenocarcinoma (10.4%), Metastatic squamous cell carcinoma (4.18%) and finally metastatic lymphoma (2.09%) (Table 2).

MPE: malignant pleural effusion, TPE: tuberculous pleural effusion, PPE: para-pneumonic effusion, TM: toxic manifestations, PS: pressure symptoms.

                Table (3): Clinical data distribution among studied groups

Dyspnea and chest pain were more prominent among patients of (MPE) group. Cough and toxic manifestations were more frequent in (PPE) group patients. Hemoptysis existed more in (TPE) group compared with other groups, while pressure symptoms were confined to (MPE) group. The right side was more frequently affected than the left side in all study groups, whereas bilaterality was more evident in (TPE) group (Table 3).

MPE: malignant pleural effusion, TPE: tuberculous pleural effusion, PPE: para-pneumonic effusion, KW: Kruskal Wallis test, P1: p-value calculated by Tukey’s post-Hoc test between malignant and tuberculous groups, P2: p-value calculated by Tukey’s post-Hoc test between malignant and para-pneumonic groups, P3: p-value calculated by Tukey’s post-Hoc test between tuberculous and para-pneumonic groups, SD: standard deviation, *: statistically significant, **: statistically highly significant, TLC: total leucocytic count, Neut.: neutrophils, Lymph.: lymphocytes, mm3: cubic milliliter, NLR: neutrophil to lymphocyte ratio, TP: total protein, LDH: lactate dehydrogenase, -: Tukey’s post-Hoc test could not be applied due to non-significant p-value calculated by Kruskal Wallis test.

Table (4): Pleural fluid parameters distribution among studied groups

The mean pleural fluid total leucocytic count (TLC) was significantly higher among the patients of (PPE) group compared with other groups (p <0.001). The mean neutrophils count and percentage in pleural fluid were greatly higher in (PPE) group compared with the other groups (p <0.001). In turn, the same count and percentage were significantly lower in (TPE) group compared with (MPE) group (p <0.001). The mean lymphocytes percentage in pleural fluid was significantly higher in (TPE) group compared with others (p <0.001). Likewise, this percentage was also higher in (MPE) group compared with (PPE) group (p <0.001). The mean lymphocytes count in pleural fluid did not differ significantly among the study groups (p= 0.052). The mean pleural fluid neutrophil to lymphocyte ratio (NLR) was significantly different among the three studied groups (p <0.001), being lowest in (TPE) group (0.2±0.1), intermediate in (MPE) group (0.62±0.41) and highest in (PPE) group (7.49±12.04) (Table 4).

MPE: malignant pleural effusion, TPE: tuberculous pleural effusion, PPE: para-pneumonic effusion, KW: Kruskal Wallis test, P1: p-value calculated by Tukey’s post-Hoc test between malignant and tuberculous groups, P2: p-value calculated by Tukey’s post-Hoc test between malignant and para-pneumonic groups, P3: p-value calculated by Tukey’s post-Hoc test between tuberculous and para-pneumonic groups, SD: standard deviation, *: statistically significant, **: statistically highly significant, TLC: total leucocytic count, Neut.: neutrophils, Lymph.: lymphocytes, mm3: cubic milliliter, NLR: neutrophil to lymphocyte ratio, TP: total protein, LDH: lactate dehydrogenase, -: Tukey’s post-Hoc test could not be applied due to non-significant p-value calculated by Kruskal Wallis test.

Table (5): Peripheral blood parameters distribution among studied groups

The mean peripheral blood TLC was significantly higher among the patients of (PPE) group compared with (MPE) and (TPE) groups (p= 0.0013 and <0.001) respectively. The mean neutrophils count and percentage in peripheral blood were greatly higher in (PPE) group compared with the other groups (p <0.001). Furthermore, the same count was higher in (MPE) group versus (TPE) group (p <0.001), but the percentage was not significantly differ (p= 0.054). The mean hematological lymphocytes percentage was significantly higher in (TPE) group compared with (MPE) and (PPE) groups (p= 0.0019 and <0.001) respectively. Moreover, the previos percentage was also higher in (MPE) group compared with (PPE) group (p= 0.0058). However, the mean lymphocytes count in peripheral blood did not differ significantly among the study groups (p= 0.17). The mean hematological (NLR) was significantly lower in (TPE) group compared with other groups (p <0.001). As well, this ratio was significantly lower in (MPE) group versus (PPE) group (p= 0.006). The mean (NLR) in peripheral blood was (3.2±0.87) in (TPE) group, (4.55±2.55) in (MPE) group and (6.94±3.47) in (PPE) group. (Table 5).