Paradigm shift in the diagnosis of tuberculous pleural effusion: impact of epidemiology

In 2023, an estimated 10.8 million people worldwide developed tuberculosis (TB) [incidence rate of 134 cases per 100,000 population; 95% confidence interval (CI): 125–145], of whom 1.25 million died (1). However, the incidence rate is not uniform across all regions of the world; while in some areas it exceeds 200 cases per 100,000 population (such as Southeast Asia or Africa), in others it hovers around 30 cases per 100,000 population (for instance, in Europe or the Americas) (1). In Galicia, a region in north-western Spain with an estimated population of 2.7 million, the incidence rate of TB declined from 71.8 cases per 100,000 population in 1996 (1,939 patients) to 11.2 cases per 100,000 population (302 patients) in 2023. Pleural tuberculosis (PTB) accounted for 12.6% of these cases (38 patients), with an incidence rate of 1.4 cases per 100,000 population (2).

The diagnosis of PTB presents significant challenges, both due to the heterogeneity of its clinical presentation and the limitations of the various diagnostic strategies. This commentary aims to highlight that the epidemiological changes observed in our region in recent years, and likely in other parts of Europe and the Americas, may affect the diagnostic value of certain tests, which, although useful in the past, may no longer hold the same value today.

PTB is a delayed-type hypersensitivity reaction mediated by T lymphocytes against mycobacterial antigens, triggered by the rupture of a subpleural caseous focus and the release of its contents into the pleural space. When this occurs, various cytokines attempt to stimulate the antimycobacterial activity of macrophages, resulting in increased capillary permeability and the development of a pleural effusion. These reactions account for several of the characteristic features of pleural fluid (PF) in this disease: PF cultures are usually negative; the lymphocyte percentage is inversely associated with the likelihood of a positive PF culture (3); and there is an elevation of Th1 cytokines [particularly interferon-gamma (IFN-γ)], as well as the enzyme adenosine deaminase (ADA), the latter due to stimulation of monocytes and macrophages by viable organisms growing within them (3). In addition, these processes lead to the formation of caseating granulomas in the pleural tissue.

The diagnosis of PTB presents significant challenges. The sensitivity of PF and tissue cultures is low due to the paucibacillary nature of the disease (4), and the demonstration of granulomas in pleural biopsy specimens rarely exceeds 80% (5). Moreover, the specificity of the latter is not absolute, as granulomas may also be observed in sarcoid pleuritis, among other conditions. The diagnostic performance of polymerase chain reaction (PCR) for TB in PF is limited by the low bacillary load, with an approximate sensitivity of 60% (6); therefore, a negative result does not exclude the diagnosis. As with culture, the yield of PCR when applied to pleural tissue may be higher (7). Next-generation sequencing allows for the detection of Mycobacterium tuberculosis-specific gene sequences in PF samples, although its sensitivity does not exceed 80% (8). For these reasons, and with the aim of improving diagnostic sensitivity in these effusions, biomarkers such as ADA, IFN-γ, and interleukin-27 have been used in PF, with promising results (3,9,10), especially in settings with a high prevalence of TB (11). The measurement of these biomarkers offers the advantage that, in certain circumstances, their high diagnostic accuracy may eliminate the need for pleural biopsy, thus reducing the risk of complications (7). However, some limitations must be acknowledged: both the ethnicity of the population and the detection method may affect the results and alter the diagnostic cut-off, meaning external reference values should only be applied when the populations and methodologies are comparable (3,12). In addition, up to one third of parapneumonic effusions and approximately two-thirds of empyemas may exhibit elevated ADA levels (13), as may other types of effusions, such as those associated with IgG4-related disease (14). Conversely, PTB can present with low ADA values, which does not exclude the diagnosis (15).

However, the main limitation of these determinations arises when they are used in countries with a low prevalence of TB. This is because the positive predictive value (PPV) and negative predictive value (NPV) of any test depend on the prevalence of the disease, in this case, PTB, in the population being studied, as can be seen in the following formulas:

PPV=(prevalence×sensitivity)(prevalence×sensitivity)+[(1−prevalence)×(1−specificity)][1]

NPV=[(1−prevalence)×specificity][(1−prevalence)×specificity]+[prevalence×(1−sensitivity)][2]

A recent retrospective study of 1637 patients (57 with TB; prevalence 3.5%) recruited between 2008–2014 in a low TB incidence country (New Zealand) confirms these results (low PPV and high NPV) (16). Therefore, the excellent results obtained with these parameters in regions with a high prevalence of TB cannot be extrapolated to low-prevalence areas, as is currently the case in many European and North American countries, where the prevalence of PTB in a series of pleural effusions would rarely exceed 10%. A clear example can be seen in Figure 1. Let us assume that the sensitivity and specificity of ADA for the diagnosis of PTB are both 90%, undeniably high values. If disease prevalence is 5%, the PPV would not exceed 32%, and would only reach 50% if prevalence were 10%. Therefore, under these circumstances, a high ADA value has limited utility for diagnosing PTB. For the PPV to approach 80%, the prevalence would need to be close to 25%, which is unlikely in these countries, although it may be the case in certain subpopulations (11). Conversely, in low-prevalence areas, the NPV would be very high (above 98%), meaning that the main usefulness of these tests would lie in ruling out the disease.

Figure 1 Effect of the prevalence of tuberculous pleural effusion on the positive and negative predictive values of adenosine deaminase for its diagnosis (sensitivity 90%, specificity 90%). When disease prevalence is high, the PPV also increases, making the test useful for confirming the diagnosis. Conversely, when disease prevalence is low, the PPV decreases, and the usefulness of the test lies in its ability to rule out the disease (high NPV). NPV, negative predictive value; PPV, positive predictive value.

In summary, ADA, IFN-γ and various cytokines are inflammatory biomarkers that neither replace culture nor provide information on susceptibility to anti-TB drugs. Their applicability in low-incidence TB areas would be limited to ruling out the disease. In such cases, pleural biopsy should be performed, with samples sent for culture and PCR, as well as drug susceptibility testing. Relying solely on one of these positive tests for the diagnosis of PTB could lead to overdiagnosis of the disease and, consequently, to the administration of unnecessary and potentially harmful treatment.

Acknowledgments

None.

Footnote

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