**2. Epidemiology**

In many regions of the world tuberculous effusion maintains its role as the leading inflam‐ matory pleural disease. With the worldwide unabated HIV epidemic and related immune deficiency syndrome this state of affairs is likely to continue or being even aggravated within least in certain high risk populations. On a global scale the current significance of human immunodeficiency virus (HIV)-co-infection may be illustrated by WHO data, indicating at a TB-prevalence of 1/3 of the world´s population – similar to the past decade – a HIV-association

© 2013 Frank; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of approximately 13 % by the year 2009 [1, 2]. Conversely it is assumed, that 33 % to 50 % of HIV infected individuals are co-infected with M. tuberculosis [2]. The MTB/HIV-association however shows a huge intercontinental and regional variance, with the highest rate of HIVpleural tuberculosis-coincidence being reported in Zimbabwe where 95 % of Patients with tuberculosis pleurisy were HIV positive [3]. In Burundi and Tansania a HIV-coinfection was found in 60 % of all cases of tuberculous pleurisy [4]. One of the lowest rates is reported from Spain with 10 % [5]. Am example of the impact of a high HIV-endemic environment on the incidence of tuberculous pleurisy is also given in a series from Ruanda, where TB accounted for as much as 86 % of all diagnosed pleural effusions [4]. Pleurisy incidence obviously and essentially parallels variability of global TB prevalence with an overwhelming share of 95 % occurring in developing countries. In TB-patients as a whole, pleural involvement varies between ~ 3-5 % in Western Europe and the USA vs. ~ 30 % in developing, HIV-high-preva‐ lence-countries [6, 7, 8]. The differences clearly underline the modifying role of immunological determinants, stage and severity of the disease, general health status and nutritional factors. The effect of HIV on the occurrence of pleural involvement in a given TB-patient is illustrated by a study reporting a 38 % pleurisy incidence in AIDS-associated TB as compared with 20 % in matched HIV-negative TB patients [5]. On the basis of the presented data according to even conservative WHO estimates the TB-pleurisy incidence throughout the current decade is expected to remain grossly unchanged compared to the past decade, i. e. 18.2 – 62/100.000 in the developing countries vs. 0.42-0.77/100.000 in Western countries [6, 7, 10]. When the epidemiology of pleurisy (or pleural effusion in general) is analysed in terms of the magnitude of TB-contribution, a probably still valid estimate in Western countries is as low as 0.1 – 0.2 % and remains distinctly < 1 % even when referring to pleurisy in a strict sense (i. e. exudates) [11]. By comparison the previously reported percentages of 30-86 % in developing countries are – and remain – indeed dramatically different.

**•** the sometimes abundant isolation of specifically purified protein derivative (PPD)- protein

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 269

**•** more recently the inducible pleurisy in previously PPD-sensitized animals when exposed

Also the vigorous expression of inflammatory mediators interleukins (IL) like interferon (IFN) γ, IL-1 and IL-8 observed in this model (or conversely their suppression by antilymphocyte

On the other hand there is also strong evidence, that infectious invasion of the pleural space actually occurs at a substantial, albeit variable degree. At thoracoscopy, even with negative fluids studies, extensive inflammatory granuloma formation and fibrin deposits with unex‐ pected abundant mycobacteria recovery are a common finding (see also section on invasive endoscopic-bioptic studies) [18]. The increasingly emerging evidence of a preferred association of TB-pleurisy with reactivated TB in Western populations clearly points to infectious as well as immunological mechanisms being interrelated and operative in a complex manner. Direct infectious invasion however clearly prevails in chronic tuberculous involvement of the pleura

According to present views and based on experimental evidence the sequence of immunologi‐ calprocesses involvedinTB-pleuritis appears tofollowa three stagepatternof cellularreactions and granuloma formation as a topic variant of general interaction mechanisms between MTB and the human immune system. A schematic representation is given in figure 1 [19, 20].

Any trigger-mechanism that allows access of mycobacterial protein to the pleura will set off a rapid mesothelial cell initiated and IL-8 mediated polymorphonuclear neutrophil (PMN) influx within a few hours [21]. In addition macrophages and blood-borne monocytes deter‐ mine this IL-1, IL-6 and tumor necrosis factor (TNF)-α-orchestrated *early stage* reaction.

Within roughly 3 days, in the following *intermediate stage* lymphocyte subpopulations, mainly of CD4+ helper cells but also a substantial CD8+ cytotoxic (natural killer cells) fraction dominate the scene resulting in a CD4+/CD8+-ratio of ~ 4.3 [22]. A minor contribution includes so-called T-cell receptor double negative (DN) αβ-T-cells and γδ-T-cells which appear to have regulatory functions. More recently in tuberculous pleural fluid another unique CD4+CD25+ T-cell-class could be demonstrated being specifically involved in the down-regulation of autoreactive IFN-γ-producing T-cells, thus preventing inflammatory overshoot [23]. IFN-γ a strong promoter of macrophage activation and granuloma formation (together with TNF-α) is the predominant interleukin in this stage. IFN-γ-producing cells have been phenotypically indentified as CDW29+ subpopulation and make up a substantial portion of the granuloma

The *late phase* is characterised by an equilibrated and sustained CD4+/CD8+ cell-based response with continued IFN-γ release and prolonged granuloma formation. Several modulating interleukins are involved in this process such as T-helper-cells (CD4+)-support‐ ing IL-12 and counter-regulatory antiinflammarory cytokines like IL-10 and transforming

sensitized T-lymphocytes from pleural fluid [15] and

to intra-pleural mycobacterial protein.

serum) support this view [16, 17].

as in specific empyema.

core structure [24].

growth factor (TGF-β).
