**3. Pathophysiology and natural history**

#### **3.1. Immunological and microbiological factors**

MTB may affect the pleura at different stages of pulmonary or systemic disease and by a number of different mechanisms. Thus pleural involvement occurs in primary, postprimary and reactivated TB alike and is basically believed to arise directly from contiguous macroscopic or microscopic lung lesions or else lymphogenic or hematogenic spread, but probably also via immunogenic mechanisms. Pleuritis exudativa tuberculosa is by far the most common clinical variety and has been classically interpreted as an early delayed-hypersensitivity-type phe‐ nomenon rather than direct organ involvement [12, 13]. Many clinical observations and experimental findings are in favour of this hypothesis such as:


**•** the sometimes abundant isolation of specifically purified protein derivative (PPD)- protein sensitized T-lymphocytes from pleural fluid [15] and

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

MTB may affect the pleura at different stages of pulmonary or systemic disease and by a number of different mechanisms. Thus pleural involvement occurs in primary, postprimary and reactivated TB alike and is basically believed to arise directly from contiguous macroscopic or microscopic lung lesions or else lymphogenic or hematogenic spread, but probably also via immunogenic mechanisms. Pleuritis exudativa tuberculosa is by far the most common clinical variety and has been classically interpreted as an early delayed-hypersensitivity-type phe‐ nomenon rather than direct organ involvement [12, 13]. Many clinical observations and

**•** its frequent association with known primary infection and a typical 6-12 weeks latency,

**•** an often striking absence of significant pulmonary or systemic TB-lesions,

are – and remain – indeed dramatically different.

268 Tuberculosis - Current Issues in Diagnosis and Management

**3. Pathophysiology and natural history**

**3.1. Immunological and microbiological factors**

experimental findings are in favour of this hypothesis such as:

**•** an often culturally negative or paucibacillary effusion [14],

**•** more recently the inducible pleurisy in previously PPD-sensitized animals when exposed to intra-pleural mycobacterial protein.

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 serum) support this view [16, 17].

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 as in specific empyema.

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 core structure [24].

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 growth factor (TGF-β).

**3.2. Other factors**

reactivated TB.

The mechanisms of fluid accumulation and of abundant protein leakage to the pleura with often extensive fibrin deposits in tuberculous pleurisy have so far not been fully elucidated. In actual fact pleuritis exudativa tuberculosa generally presents with the highest protein levels commonly seen in exudative conditions. The intensity of inflammation and a proportionately increased vascular permeability would provide a satisfying explanation [25, 27] although at least in animal models, no such significantly altered vascular permeability could be demon‐ strated [12]. Current opinion holds that grossly impeded lymphatic protein clearance from the pleura due to altered parietal lymphatic channels is probably of tantamount importance.

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 271

Again the *entry mechanism* of mycobacteria to the pleura has remained unclear. It is usually assumed that the release of infectious material from a ruptured subpleural TB-lesion is the most common mechanism. While this is likely to occur in more or less extensive pulmonary TB, it would not explain the frequent association of tuberculous pleuritis with an – at least radiographically – unaffected lung. There are also no convincing data yet to quantify the contribution of a purported hematogenous or lymphogenous contribution. One might reasonably speculate that different patterns of pleural tuberculous involvement are operative which might correspond to the different clinical settings of primary, post-primary and

*Caseous tuberculous pleuritis or specific empyema* is nowadays a rare condition which is believed to be the result of longstanding or chronic infection of the pleura, when either caseous material gains access to the pleura or chronic pleuritis develops on the background of impaired local defence such as pre-existing fibrous damage of the pleura or as a sequel and complication of artificial pneumothorax, oleothorax or other TB-specific surgery dating back to the prechemotherapy era. Correspondingly there is usually an extremely long history often with a remarkable paucity or even absence of symptoms. Penetration to deeper chest wall structures (specific abscess) and ultimately transcutaneous discharge (empyema necessitans) or creation of a specific bronchopleural fistula, as not infrequently seen in the pre-chemotherapeutic era, may complicate this condition [27]. Putrid discharge from a thoracic mass or putrid expecto‐

Tuberculous pleurisy may occur as an acute, subacute or rather chronic disease. At times the course is also surprisingly oligosymtomatic. Therefore duration of symptoms or major illness priortohospital admissionanddiagnosisvaries considerably from< 1 week (31 %)to < 1months (62%)or evenlonger(7%)[28].Thesedata refertothepre-HIVera andwouldnot applyforHIVseropositive patients and elderly populations, which both tend to have a particularly long symptomatic or else oligosymtomaticperiod.Aninfectious,i. e.febrile illness isnevertheless by far the most common clinical presentation. As a general rule, an acute febrile illness is the more likely to occur the younger and the more immunocompetent a given patient is. In developing, high-prevalence and high primary-TB-affected countries the age peak of incidence is in the mid

ration with or without haemoptysis may ultimately advert to the condition.

**4. Clinical manifestations and natural course**

**Figure 1.** Mechanisms and immunogenesis of tuberculous pleurisy: the three stages of protective immune response. IFN: interferon; TNF: tumor necrosis factor; IL: interleukin; PMN: polymorphonuclear granulocyte; X: undefined cell; MΦ: macrophage, MTB: mycobacterium tuberculosis; PPD purified protein derivative

Results of HIV and AIDS research also emphasize the importance of T-cell response. Several working groups have shown, that the prevalence of tuberculous pleurisy in HIV-infected patients with TB is strikingly correlated with their CD4+ blood lymphocyte count. In one series pleuri‐ sy prevalence in individuals with a count of > 200 cells/ml was 27 % as compared to 10 % in those with a count of < 200 cells/ml [25]. The data support the view, that the clinical expression of exudative pleural effusion requires a largely intact cellular immune system and features pleurisy as a high activity response in a still immunocompetent individual. In epidemiologic terms one would conclude that pleural effusion should be more frequent in the still immunocompetent host than in patients with AIDS. In reality however in most HIV-high-prevalence countries like South Africa, Uganda and Zimbabwe the percentage of thoracic TB-patients with pleural effusion is reportedly higher in HIV+ patients [26]. As an explanation the situation is probably blurred by a variable and poorly defined immune status in HIV+ individuals.
