Tuberculosis (TB) is an infectious disease caused by Mycobacterium Tuberculosis (MTb) and transmitted through aerosol droplets from people with active TB. ¹ It is preventable and generally curable. Despite this, TB affects over 10 million people annually and causes more than one million deaths each year. This positions TB as the foremost cause of mortality worldwide, attributable to a single infectious agent and ranks it among the top ten causes of death globally. The 2024 Global TB Report estimates approximately 10.7 million new tuberculosis cases, or 131 cases per 100,000 individuals. TB continues to be a major global public health issue, with progress towards the 2030 objectives stagnating in most regions. Indonesia ranks second in the incidence of new tuberculosis cases, following India. ²

Tuberculous pleural effusion (TPE) is a leading cause of pleural fluid accumulation in developing regions. It is the second most common type of extrapulmonary tuberculosis, following lymphadenitis. TPE occurs when TB infection involves the pleura, resulting in fluid collection within the pleural cavity, with an incidence of 3% to 25%. ³ It may result from primary infection or disease reactivation. Primary pleural effusion occurs when MTB antigens infiltrate the pleural space, typically due to the rupture of a caseous lung lesion, which triggers local inflammation. Inflammatory cytokines increase pleural capillary permeability, leading to exudative effusion initially dominated by polymorphonuclear cells (PMN), followed by macrophages and lymphocytes. Another pathogenic mechanism involves a delayed hypersensitivity reaction mediated by T-helper type 1 lymphocytes (TH1), which activates CD4+ T cells previously sensitised to MTB. ⁴

The diagnosis of TPE depends on the identification of MTb in clinical specimens, including sputum, pleural fluid, or tissue biopsy, which can be corroborated by the presence of granulomatous tissue in the pleural cavity. ⁵ Diagnostic tools include molecular rapid tests, Ziehl-Neelsen staining for acid-fast bacilli, microbiological culture, and measurement of increased adenosine deaminase (ADA) activity in pleural fluid. ^{6, 7} ADA values of 40–45 U/L generally indicate TB, with higher levels increasing the diagnostic likelihood. Exudative pleural fluid in TPE typically demonstrates elevated protein exceeding 5 g/dL, lymphocyte predominance, and low glucose concentration. ⁸

Although lymphocyte predominance is common, approximately 6.7% of TPE cases show pleural fluid dominated by neutrophils (PMN), the first responders in acute bacterial infections. ^{5, 9} Neutrophil-predominant pleural effusion is often overlooked as TB, leading to a delayed diagnosis and treatment. Untreated TB can increase mortality by up to 50%. ² Delays in diagnosis and treatment are correlated with worse outcomes and increased transmission risk. This study aimed to compare the clinical characteristics of PMN- and MN-predominant pleural effusions in patients with TB.

This study included 60 patients diagnosed with bacteriologically confirmed tuberculosis with pleural effusion. Among them, seven patients were positive for AFB in the pleura, one patient was positive for the molecular rapid test (TCM) in the pleura, 44 patients were positive for TCM in sputum, two patients were positive for TCM and culture in sputum, one patient was positive for AFB, TCM, and culture in sputum, and five patients were positive for AFB and TCM in sputum. The participants’ ages ranged from 20 to 76 years, with a mean age of 47.5 ± 14.80 years. The pleural fluid characteristics of the study participants showed a predominance of MN in 36 subjects (60%) and PMN in 24 subjects (40%). The distribution of the basic characteristics of the study subjects is presented in Table 1.

There was a significant difference between sex and the predominant cell type in pleural fluid (p = 0.038). Male patients were more common than female patients in both PMN- and MN-predominant pleural effusion groups. Additionally, smoking was more prevalent in patients with PMN-predominant effusions than in those with MN effusions (p = 0.019). Comorbidities such as diabetes mellitus, chronic kidney disease, heart disease, underweight, and HIV did not show a significant difference regarding the predominant cell type in the pleural fluid of TB patients ( Table 2).

The clinical manifestations in this study, such as fever, cough, dyspnoea, and chest pain, did not differ significantly between the PMN-predominant and MN-predominant pleural effusion groups. However, there was a significant difference in the main cell type found in TPE related to clinical symptoms, particularly weight loss (p < 0.001) and symptom duration (p < 0.034). Weight loss was more common in the group with predominantly mononuclear (MN) cells. Additionally, the MN cell-predominant group included more patients with symptoms lasting more than two weeks ( Table 3).

There was a significant difference between clinical severity and predominant cell type in the pleural fluid of patients with TB (p = 0.033). The percentage of patients with severe clinical conditions was higher in the PMN-predominant group (56%) than in the MN-predominant group (44%). Mild-to-moderate clinical cases were more frequently observed in the MN-predominant group. The odds ratio (OR) of 3.182 indicates that patients with PMN predominance had more than three times the likelihood of experiencing severe clinical severity compared to those with MN predominance ( Table 4).

There was a significant difference between pleural fluid leukocyte and LDH levels and the predominant cell type in patients with TPE (p < 0.001). The PMN cell–predominant group showed higher leukocyte counts and LDH levels than the MN cell–predominant group ( Table 5).

This study involved 60 patients; male patients were more prevalent than female patients in both the PMN and MN predominant TPE groups. Hormonal differences and varying immunological responses are thought to contribute to the increased susceptibility to Mycobacterium tuberculosis infection in males. Oestrogen has been shown to enhance interferon-gamma (IFN-γ) secretion and potentiate macrophage activation, whereas testosterone suppresses immune responses. ^{11, 12} In human studies, oestrogen exerts an immunoenhancing effect, while testosterone and progesterone are considered immunosuppressive. ¹³ Additionally, the higher prevalence of smoking habits among men likely contributes to the increased proportion of TB cases in this group.

A significant difference was also observed between smoking status and the predominant cell type in pleural fluid (p = 0.019). The PMN-predominant group included a greater proportion of smokers than the MN-predominant group (52.9% vs. 47.1%). Neutrophil accumulation in the lungs is common among active smokers, who are more susceptible to various pulmonary inflammatory diseases and infections. ¹⁴ Jee et al. (2009) reported that smoking increased the risk of TB. Smoking adversely affects lung structure and function, impairs pulmonary and systemic defences, disrupts mucociliary clearance in the tracheobronchial mucosa, and reduces alveolar macrophage phagocytic activity. ¹⁵

The clinical manifestations in this study, including fever, cough, dyspnoea, and chest pain, did not differ significantly between the PMN and MN predominant pleural effusion groups. Similarly, Choi et al. (2016) found no difference in clinical manifestations between PMN- and MN-predominant TPE. ¹⁶ However, Zhao et al. (2020) reported that patients with neutrophil-predominant pleural TB experienced higher fevers (≥ 39°C) more frequently than those with MN predominance (51.5% vs. 32.4%, p = 0.03). ⁵ The higher fever in PMN-predominant pleural effusion is attributed to an intense inflammatory response with increased production of pyrogenic cytokines, such as interleukin (IL)-1β, tumour necrosis factor-alpha (TNF-α), and IL-6, which mediate fever induction. ¹⁷

A significant difference was found in disease duration (p < 0.034). Patients with illness lasting more than two weeks were more common in the MN-predominant group (31 patients, 67.4%). Bielsa et al. (2013) reported that TPE with PMN predominance was linked to a shorter symptom duration, such as fever (7 vs. 10 days) and chest pain (10 vs. 15 days), compared with MN predominance. PMN-predominant pleural effusion in patients with TB likely represents an early stage of the disease. ¹⁸ Evidence from animal studies and limited human data suggests that pleural fluid neutrophilia occurs during acute infection and soon changes to lymphocytosis. In rabbits, the neutrophil-dominant phase of TB pleural effusion lasts approximately 24 hours, whereas in humans, it may last up to two weeks. ^{3, 19} In contrast, Lee et al. (2016) found no significant difference between disease duration and cell predominance. ²⁰

Weight loss was more frequent in patients with MN-predominant pleural effusions. MN-predominant effusion is usually associated with chronic inflammation, where proinflammatory cytokines such as TNF promote muscle and fat catabolism, resulting in weight loss. ¹⁷ The relationship between TB and malnutrition is bidirectional: tuberculosis induces malnutrition, whereas malnutrition elevates the risk of developing active tuberculosis by six to ten times. TB infection commonly causes appetite loss and nutrient malabsorption. ²¹

A significant difference was found between the clinical severity and cellular predominance in pleural fluid (p = 0.033). This finding suggests that PMN predominance in pleural fluid reflects a more severe clinical presentation. Polymorphonuclear cells are the first responders to most invasive pathogens, including M. tuberculosis, and dominate the acute phase of inflammation. Neutrophils act as a double-edged sword in TB infections. In the early phase, they contribute to bacterial control through phagocytosis, enzyme release, and production of reactive oxygen species (ROS). However, excessive neutrophil accumulation in the later stages leads to pulmonary tissue damage and worsens disease progression through destructive and proinflammatory activities. Elevated neutrophil counts at infection sites and increased cytokine or enzyme release may underlie the hyperinflammatory state often observed in TB. Enhanced neutrophilic responses are associated with TB severity and lung destruction. ^{22, 23}

The PMN-predominant pleural effusion group also demonstrated higher pleural fluid leukocyte counts and LDH levels than the MN-predominant group. Bielsa et al. (2013) reported significantly higher leukocyte and LDH levels in PMN-predominant effusions. ¹⁸ Pleural LDH levels serve as a reliable indicator of pleural inflammation severity. The higher the LDH level, the greater the degree of inflammation. ²⁴ PMN predominance is thus linked to markedly increased inflammatory markers, such as pleural fluid leukocyte count, reflecting a heightened inflammatory response in the pleural cavity of patients with PMN-predominant TB effusion. ¹⁶

PMN-predominant TPE reflects an early, more severe inflammatory phase with severe clinical manifestations and elevated leukocyte and LDH levels in the pleural fluid. In contrast, MN predominance suggests a more chronic disease phase with longer symptoms and mild-to-moderate clinical severity.

The clinical implications of this study are as follows: in patients with suspected TPE and PMN cell predominance in pleural fluid, clinicians should consider this an early phase of TB pleurisy. Bacteriological examination is therefore essential to prevent delays in TB diagnosis and treatment.

This study had several limitations that should be considered. The study population was sourced from a single hospital, and this study used a small number of samples, which may limit the generalisability of our results. The severity of tuberculosis was assessed solely based on clinical parameters without evaluating lung destruction or lesion extent on radiological images. Further studies are required to evaluate the shift in predominant cells from PMNs to MNs over the course of pleural TB.

The Research Ethics Committee of the Faculty of Medicine, Hasanuddin University, granted approval for this study, as evidenced by the ethical approval letter number 459/UN4.6.4.5.31/PP36/2024, dated 21 June 2024.