DIAGNOSTIC CHALLENGES IN TUBERCULOUS PLEURAL EFFUSION

By: Ismi Wahyu Riyanti, Adhella Menur

Pleural effusion overview

The pleural cavity is a space between the parietal and visceral pleurae that aids in the optimal functioning of the lungs during breathing. Normally, a small physiological amount of pleural fluid (0.1-0.3 mL per kg) resides within this space. This delicate balance of fluid is maintained by oncotic and hydrostatic pressures and by lymphatic drainage. If there is any disturbance leading to an excessive and abnormal accumulation of fluid in the pleural cavity, it is called pleural effusion (PE). To date, PE has remained a significant cause contributing to hospitalization, increasing medical costs, morbidity, and mortality. The actual burden of PE is uncertain since only a few epidemiological studies have been published, which are mostly retrospective, single-center, and based in Europe and the United States. In the US, it is estimated that there are 1.5 million new cases of PE annually.

PE can occur from various disorders of the pleura itself, lung parenchyma, and other organs or from systemic disorders. According to the underlying pathophysiology, PE is classified into transudates (e.g., heart failure, liver cirrhosis, nephrotic syndrome, or hypoalbuminemia) and exudates (e.g., inflammation, infection, or malignancy). The ability to distinguish between the two types of PE is crucial for patient management. For more than 50 years, the Light’s criteria have been used by clinicians as the benchmark test combination for differentiating between transudates and exudates.

The Light’s criteria classify PE based on the absolute lactate dehydrogenase (LDH) value, the pleural fluid to serum LDH ratio, the concentration of pleural fluid protein, and the pleural fluid to serum protein ratio.

Tuberculosis (TB) is one of the top four etiologies that account for about 75% of PE cases, along with heart failure (HF), malignancy, and pneumonia. In 2019, the WHO reported that 15% of global TB cases were associated with extrapulmonary TB (EPTB), and tuberculous pleural effusion (TPE) became the most dominant form in adults. The incidence of TPE varies from 3% to 30%, particularly high in TB-endemic areas and among individuals with comorbidities such as HIV. Indonesia is the second-highest TB burden country globally; therefore, TPE should be a significant concern. Even though primary TPE may resolve spontaneously, patients frequently develop active TB later. Additionally, if left untreated in immunocompromised patients, TPE can become complicated and fatal. TPE is unique due to its paucibacillary nature (low bacterial count), causing a diagnostic dilemma in resource-constrained settings. In this edition, we will discuss TPE and the challenges in diagnosis.

Tuberculous pleural effusion

Tuberculous pleural effusion (TPE) may occur in primary tuberculosis (TB) or with reactivation of the disease. It may present as isolated extrapulmonary TB or coexist with pulmonary TB. TPE is classified as an exudative type of pleural effusion (PE), and its incidence is linked to the local disease burden, population characteristics, and socioeconomic status. For example, the TB burdens in Malaysia and Nigeria in 2016 were estimated at approximately 92 and 219 cases per 100,000 population, respectively. Consequently, TB was identified as the major etiology of PE, followed by malignancy. In contrast, a study in Spain in 2016 reported that TPE was only the fourth leading cause (9%) of PE after malignancy (27%), heart failure (21%), and pneumonia (19%). Furthermore, in the US, heart failure, pneumonia, and malignancy were predominantly attributed as the causes of PE rather than TB.

Figure 1. Tubercu-lous pleural effusion (TPE). Inspired by a review from Vorster MJ, et al., 2015, doi: 10.3978/j.issn.2072-1439.2015.02.18. Created with Bioren-der.com

Although the pathogenesis has been debated, the current consensus agrees that TPE represents a delayed hypersensitivity reaction precipitated by Mycobacterium tuberculosis (MTB) antigens in the pleural cavity. It is marked by the accumulation of inflammatory cells and the significant presence of chronic effusion. In the absence of overt parenchyma lung disease, MTB is believed to access the pleural cavity following the rupture of a subpleural caseous focus. The infection in the pleural space triggers an early response by a rapid influx of macrophages and neutrophils. Lymphocyte T-helper type 1 (Th1) cells are involved in subsequent stages, with the release of adenosine deaminase (ADA) and the formation of pleural granulomas. The cytokine milieu favors a Th1 cell response with high levels of gamma interferon (IFN-γ), interleukin-12 (IL-12), and other related cytokines. This robust Th1 cell response, along with the compartmentalization of the pleural fluid and effective containment of MTB, is thought to be responsible for the paucibacillary nature of these effusions. A minority of patients progress from the lymphocytic phase to a second, neutrophil-predominant phase, presenting loculated effusion or frank empyema, which results in a higher rate of MTB culture positivity.

Diagnostic challenges in tuberculous pleural effusion

The gold standard for TPE diagnosis is the detection of MTB in pleural fluid or pleural tissue or histological demonstration of caseating granulomata on pleural biopsy, ideally in the presence of acid-fast bacilli (AFB). However, the diagnosis of TPE is inevitably hindered due to the low detection rate (paucibacillary nature) and long culture turnaround times. Limited access and skill to perform pleural biopsies, whether by closed pleural biopsies, thoracoscopy, or open surgical biopsies, also complicates diagnosis challenges.

Table 1. Summary of several strategies and challenges in the diagnosis of tuberculous pleural effusion
Figure 2. A suggested algorithm for the diagnostic evaluation of a patient who presents with a clinical and radiological suspicion of TPE. Microbiological confirmation includes positive AFB smear microscopy, Xpert MTB/RIF, or positive culture on sputum or pleural fluid. A high TB prevalence is ≥125 per 100,000 population (Vorster MJ et al., 2015).

In a suspected TPE case, it is still essential to obtain a sputum culture (expectorated or induced), even in the absence of obvious parenchymal lung involvement, especially in high TB burden settings. In those settings, the diagnosis of TPE is frequently concluded in patients who present with predominantly lymphocytic exudates and a high level of adenosine deaminase (ADA) in the pleural fluid. However, clinicians still face difficulty in differentiating TPE from malignancy and parapneumonic pleural effusion (PPE) due to similar biochemistry and cellular features. TPE and malignancy often present as lymphocytic effusions, while some cases of TPE and PPE present as neutrophilic effusions. The diagnostic challenge between TPE and PPE is prominent in multi-endemic regions since both diseases are prevalent. Furthermore, some cases of PPE, particularly complicated PPE (CPPE), present with elevated ADA levels similar to those of TPE. Therefore, accurate, simple, and safe diagnostic tools are needed to address these challenges.

Numerous studies have investigated the potential use of other pleural fluid biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT), preseason, tumor necrosis factor-alpha (TNF-α),
lysozyme, hyaluronic acid, neopterin, leptin, fibronectin, and cell-free DNA, with inconclusive results. There are also novel biomarkers such as pleural fluid nicotinamide phosphoribosyltransferase (NAMPT) and MTB HspX protein using a novel aptamer-linked immobilized sorbent assay (ALISA). NAMPT does not appear to have a benefit over ADA in distinguishing TPE from malignant PE, but it still has diagnostic ability, with a cutoff value of 31.93 ng/mL (sensitivity of 70% and specificity of 100%). The MTB HspX ALISA showed promise as a potential biomarker for TPE diagnosis with a sensitivity of 93% and specificity of 98% compared to the composite reference standard in one study.

Pleural fluid biomarker studies are still limited in Indonesia, primarily conducted as theses by residents in internal medicine, pulmonology, clinical pathology, or microbiology with small sample sizes. To our knowledge, there have been only three international publications from Indonesia: the use of IGRA with the ELISPOT method performed on pleural fluid mononuclear cells (PFMC) in 2016, a comparison of pleural fluid TNF-α in TPE and non-TPE in 2018, and an evidence-based case report on the diagnostic value of pleural fluid Cancer Anti-gen 125 (CA-125) in 2023. Therefore, there is a significant research gap that needs to be addressed.

A practical diagnostic approach is suggested in Figure 2 (different or updated versions may be available in each country). In conclusion, TPE should be appropriately diagnosed because the patient is at risk of developing a serious form of pulmonary or extrapulmonary TB. Combining strategies (e.g., microbiological analysis + more than one pleural fluid biomarker) may improve the diagnosis of TPE. Given the high number of people infected with TB worldwide and the increasing number of TPE cases, the threat of drug-resistant TB is also worrying. Progress in finding more accurate biomarkers to aid diagnosis and more sensitive molecular-based testing is expected to improve diagnosis and provide crucial information on drug resistance profiles. It is such a waste to fail to diagnose this treatable infectious disease.

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