Diagnosing pleural tuberculosis is simple, yet not so simple!

Mycobacterium tuberculosis (TB) continues to intrigue mankind, including physicians, even after 140 years of the established identity of oxygen-loving, acid-fast bacilli (AFB) by Sir Robert Koch in 1882.[1] Pleural TB is the second most common form of extrapulmonary TB after nodal TB and causes significant morbidity and mortality.[2] Pleura gets affected in only 3%–5% of all TB patients in the United States of America (USA), but as many as 30% of all cases in endemic areas, such as countries like ours.[3] Incidentally, human immunodeficiency virus (HIV)-positive patients are more likely to have TB and hence pleural involvement.[4] Interestingly, it mainly affects young adults in the developing world and middle-aged individuals in developed countries. A Turkish study from 1999-2003 on extrapulmonary TB established a mean age of 35 ± 14 years contrary to a mean age of 49.9 years in 14,000 patients studied in the USA.[3,5] Pleural TB usually manifests between 6 and 12 weeks after primary pulmonary TB or after several years as reactivation TB, usually due to the rupture of a subpleural tubercle into the pleural space. Both mycobacteria and hypersensitivity to mycobacterial antigens cause excess fluid formation, reduced absorption, and fluid accumulation in the pleural space, contrary to the previous notion that it is a hypersensitivity phenomenon alone.[2] The immune mechanism in the pleural space creates a clinical picture and thus the basis of various diagnostic tests, including thoracentesis and analysis of biomarkers such as adenosine deaminase (ADA) and interferon-gamma (IFN-gamma), and mycobacterial culture and pleural biopsy for a definitive diagnosis. TB bacilli in the pleural cavity stimulate a neutrophilic reaction for the first 24 h, followed by macrophage conversion, peaking at 72 h. Following this, lymphocytes predominate as a defence against the bacilli, and the Th1 immune response creates granulomas and entraps mycobacteria, releasing ADA. The predominant Th1 response is validated by high levels of IFN-gamma in the pleural fluid and poor fluid AFB culture rates over time (live bacilli are killed or trapped by granuloma formation). The fact that pleural TB is treatable in almost all cases makes it relevant to act to confirm the diagnosis. The disease is self-limiting in most instances, yet it could result in the recurrence of pulmonary or extrapulmonary TB years later and in a more severe form. The clinical hallmarks of this disease are cough, chest pain, fever, breathlessness, and chest radiography, which confirms the presence of pleural effusion instantaneously. Ultrasound of the chest is a standard of care not only for verifying the fluid but also for demonstrating septations, and loculations, aiding in thoracentesis and closed pleural biopsies. Computed tomography (CT) can be of significant value in establishing simultaneous parenchymal or disseminated disease involving the lungs, lymph nodes and pleural space. Parenchymal involvement is seen in 80% of cases of pleural TB, which defines the need and importance of induced sputum for microbiology by AFB smear and various nucleic acid amplification (NAA) assays such as Xpert/Hains and mycobacterial culture.[6,7] The gold standard for diagnosing pleural TB is demonstrating AFB in the smear, gene-based tests, and mycobacterial culture or granuloma with AFB in low-burden countries and caseating granuloma alone in the endemic areas. Pleural TB is paucibacillary, and AFB smear positivity is seen in only 10% of cases and 20% of HIV-positive cases.[8] Mycobacterial cultures remain the gold standard in diagnosing TB, yet they have limitations, taking almost 8 weeks for the final results to be available. The culture positivity rate of tubercular effusion has increased from 12% to 30% on solid media to 70% on liquid media, with a shorter turnaround time of 2 weeks.[9] A sputum mycobacterial culture and pleura fluid culture together have a better yield of around 80% and must be included in practice.[10] Thoracentesis is the cornerstone of diagnosis in endemic areas (>125 cases/100,000 population). It is an exudative fluid with a lymphocytic predominance and a high ADA level (>40 units). The fluid nucleated cell count lies between 1000 and 6000 cells, and more than 50% are lymphocytes. The biochemical markers ADA and IFN-gamma indicate the Th1 immune response at the helm of immunity and are both specific and sensitive, making them ideal for screening and diagnosis. In high-incidence countries, exudative lymphocytic effusion with a high ADA level is diagnostic and sufficient to merit treatment. ADA, having a high negative predictive value, rules out TB if low and mandates more invasive testing, such as image-guided closed pleural biopsy or thoracoscopic pleural biopsies and other tests, such as positron emission tomography-CT, to establish an alternative diagnosis. ADA may be more specific if the ADA-2 isoenzyme is measured. A few scenarios warrant caution where ADA could be fallaciously low, as in the elderly, and or smokers or may be spuriously high, as in empyema and rheumatoid arthritis-related pleural effusion.[10] Other biomarkers, such as IFN-gamma, are not commonly available, although they are equally or more sensitive and specific than ADA. Information regarding false-positive or false-negative scenarios is unavailable, making it less useful in low-TB burden settings. NAA techniques, which are commonly used, have low sensitivity (62%) and high specificity (98%) in pleural fluid. The Xpert assay in high HIV/TB settings has been tested and found to have a sensitivity of 28.7% and specificity of 96.6%. This test is neither validated nor recommended for suspected tubercular pleural fluid as part of the evaluation algorithm in cases of high clinical suspicion. Apleural biopsy obtained using any technique has the highest possible yield in diagnosing TB and establishes an alternative diagnosis with certainty. Biopsies can be image-guided (ultrasound or CT), and obtained using a rigid or flexi-rigid thoracoscope or surgical pleural biopsy. Image-guided closed pleural biopsy is a cost-effective method for obtaining pleural tissue, especially in high-prevalence and low-resource settings; however, BTS guidelines advise against blind biopsies in low-prevalence settings with low operator experience, and thoracoscopic biopsies are preferred. In a study involving 100 exudative undiagnosed effusions, second thoracentesis increased the yield to 78%, ultrasound-guided biopsy to 83%, and thoracoscopic biopsy to unmatched 100% using histology and bacteriology, establishing the usefulness of tissue diagnosis.[11] A study conducted in Italy, a low prevalence area, showed a meagre yield if only thoracentesis were performed for the diagnosis (only in 29% of cases), and 8% of cases were proven to be tubercular further when mycobacterial culture of pleural fluid results came out to be positive, 2–8 weeks later, which emphasises the significance of tissue diagnosis by image-guided or thoracoscopic pleural biopsy in low incidence countries and is a must not to let the rest of the cases undiagnosed.[12] The Xpert polymerase chain reaction (PCR) analysis or gene expert on pleural tissue scores over mycobacterial culture in some studies with small sample sizes. A 9-year retrospective study involving 333 patients with proven pleural TB showed 100% sensitivity of thoracoscopic biopsies (histopathology and microbiologic assessment) in making a diagnosis, with only three inconclusive biopsies. The American Thoracic Society also endorses thoracoscopic tissue sampling in pleural diseases with AFB smear and culture, genetic assays, PCR, and histopathological examination. It is not only 100% sensitive; it also drains the fluid completely by breaking adhesions, making it a gold standard for pleural TB diagnosis.[13] Over the past few years, there has been an increase in pleural TB cases owing to an increased population with compromised immune status from multiple aetiologies, such as HIV, organ transplants and the cancer epidemic. These cases pose a unique challenge to the diagnosis and understanding of pleural TB [Figure 1]. The diagnostic approach varies in high-burden and low-burden areas: an exudative, lymphocytic predominant, high ADA fluid ascertains the diagnosis mainly in the first scenario but has a poor yield in the latter, which makes thoracoscopy a vital tool for definitive diagnosis everywhere and more so in low-burden settings.Figure 1: A practical approach for the diagnosis of suspected tuberculous pleural effusion.[ 11 ] *Waiting for TB culture can lead to delays in care. A high prevalence of TB is considered to be ≥125 per 100,000 population, whereas a low prevalence is <125 per 100,000. ADA: Adenosine deaminase, AFB: Acid-fast bacillus, MTB-PCR: Mycobacterium tuberculosis polymerase chain reaction, TB: Tuberculosis