*5.1.1. Signs at physical examination*

Physical examination clearly will provide only non-specific signs of pleural effusion in general including dullness to percussion and the occasional demonstration of a pleural rub at auscul‐ tation ("snow-ball-crunching sign") in particular in the presence of chest pain. Signs of a trapped or loculated rather than free flowing fluid collection may suggest a tuberculous aetiology, but this observation holds also true for "plain" parapneumonic pleurisy. Usual signs of systemic infection, as mentioned above, that should be looked for, may alert to the possibility of a HIV-related background.

#### *5.1.2. Imaging studies*

thirties, whereas in industrialized countries with a major contribution of reactivated TB it has shifted to about 50 yrs [29]. But still the age-related incidence peak of tuberculous pleuritis is distinctly lower than of parenchymal pulmonary TB which used to peak around 55 yrs [30]. Implicitly by the same statement in Western populations TB-pleurisy was historically more symptomatic than is currently the case. In a representative series from the 1960-1970s ~ 60 % of patientsdevelopedanacute illnessmimickingbacterial(pleuro)-pneumoniawithcough(70%), chest pain (75 %) and low- to high-grade fever (86 %) as the most frequent symptoms [31, 32]. Other symptoms include those commonly occurring in various TB disease states such as weight loss,malaiseandnight sweat.Severeorevenlivethreateningdisease,definedaspersistenthighgrade fever > 38,3°C over > 2 weeks or respiratory distress has been in reported in a more recent series in only 7 % [31], whereas an oligosymptomatic or a febrile course is described in 14-33 % [32]. Tuberculous pleurisy usually involves one hemithorax only (90-95 %) and is of limited size (roughly up to one-half of the hemithorax volume). In a major series (n=254) effusions occupy‐ ing more than 2/3 of a hemithorax were noted in only 18 % [33]. Rarely effusion will occupy the entirehemithoraxandwillalmostneverrevealcompressiveordisplacingfeatures [31].Basically there are no specific clinical clues to tuberculous etiology in pleurisy unless some TB-contact is revealed or suspected. An HIV-related background may be suspected in a compatible clinical and history setting or when there is a long preclinical period, unusual additional symptoms like diarrhea and more hepato(spleno)-megaly or lymphadenopathy as might be attributed to the tuberculous condition. Untreated, lone pleuritis exudativa tuberculosa in the short term seems to be a self-limited inflammatory process in most instances, terminating in complete or incom‐ plete resolutionwithinweeksormonth.Frequentlyobservedotherwiseunexplaineddiaphrag‐ maticadhesionsmaybealatesequelofclinicalsilentoroligosymtomaticTBpleurisy.Importantly however progression or reactivation to active pleuropulmonary or extrapulmonary TB occurs inanimportantfraction.Inone follow-upstudythe recurrence ratewithin1yearwas 5%,where TBdidnotrelapseearlierthan8monthaftertheonsetofpleurisy.Withina4-5yrperiodhowever the rate was dramatically higher and in initially culture positive and culture negative subjects with 65 % and 60 % respectively roughly alike [27]. One major outcome determinant clearly is the presence and the extent of pulmonary involvement. At a similar therapeutic intensity in a very recent major clinical study from Taiwan, 51 (24,9 %) out of 205 hospitalised patients having beenidentifiedtohaveisolated(lone)pleuritishadasignificantlybetteroutcome,shorterhospital

272 Tuberculosis - Current Issues in Diagnosis and Management

stay and less comorbidity than the patients with pleuropulmonary disease [34].

Physical examination clearly will provide only non-specific signs of pleural effusion in general including dullness to percussion and the occasional demonstration of a pleural rub at auscul‐ tation ("snow-ball-crunching sign") in particular in the presence of chest pain. Signs of a trapped or loculated rather than free flowing fluid collection may suggest a tuberculous

**5. Diagnosis**

**5.1. Clinical findings**

*5.1.1. Signs at physical examination*

Imaging techniques are engaged in the evaluation of tuberculous pleurisy following general diagnosticpathwayrecommendationsforeffusion.*Conventionalchestradiography(CRX)*requires fluid amounts of at least 150 ml to become clearly detectable as blunting of the costodiaphrag‐ matic angle in standard projections. Profuse effusion with opacification of an entire hemithor‐ ax wouldratherfavourdifferentialdiagnoses likemalignancy inthe elderly andafebrilepatient [35]. Free flowing effusion may be easily identified, but one should look specifically for signs of loculation, pleural thickening or adhesions and in profuse effusion for compressive signs interfering with the respiratory performance. Apart from pleural changes pulmonary infil‐ trates, nodules, lymphnodes and other suggestive signs of TB like encapsulated or cavitary lesions must be carefully looked for using routine *CT-imaging*. CT-based prevalence of lung perenchymal tuberculous lesions in mixed populations appears to be significantly higher than previously assessed based on conventional radiography. In one recent series from Korea comprising 106 patients with an age distribution from 16-89 yrs (mean 53) with 86% a remarka‐ ble high rate of parenchymal changes was found, presumed to represent active tuberculosis in 59 % [36]. Most of these lesions revealed features of reactivated rather than primary tuberculo‐ sis. *Sonography (Ultrasound, US)* using innovative technical achievements like high frequency (5-7.5 MHz) – US and convex or sector scanners allow extended exploration of the chest wall structures, the diaphragm and the anterior mediastinum up to a penetration depth of ~ 25 cm. Specific advantages of US are a more precise fluid volumetry than by CRX, precise localisation of septae, membranes and chambers as well as pleural thickening along with its particular versatility for bedside diagnosis. On demand guidance for interventions such as thoracentesis is a particular asset of US.. Examples are shown in figure 2, 3. *Magnetic-resonance imaging (MRI)* isahighlyrefined,notgenerallyavailabletechnique,whichwillrarelyberequiredbutdoeshave differential diagnostic merits in the analysis of critical borderline relationships i. e. distinguish‐ ingbetweeninflammatory-infiltrativeandmalignant-destructivepleuralprocessesviadifferent T-weighted sequences [37]. Very recently a role of PET-CT has also been described. PETimagingmayindeedprovidedifferentlyextensive focal andimpressinglaminar changeswhich however remain indistinguishable from malignant lesions [38].

#### **5.2. Immunologic tests**

#### *5.2.1. Tuberculin skin reaction*

The tuberculin skin reaction is traditionally considered an indispensable tool in the diagnosis of tuberculosis in general and likewise in tuberculous pleurisy although it is less reliable than in pulmonary TB. The rate of false negative reactions to PPD has been given as high 30 % of cases but even figures up to < 41 % have been reported [31, 32, 33], the variability possibly reflecting non-standardised test doses. Still however there remains an amazing false negative rate. There is no absolutely satisfying hypothesis to explain this paradoxon, let alone unequiv‐

ocal experimental evidence. It appears a valid speculation to consider a local pooling of sensitised T-lymphocytes at the site of infection responsible. Animal experiments and clinical investigations have shown sequestration of PPD-sensitized lymphocytes to the pleural compartment actually to occur in the early phase of infection leading to their systemic depletion [39]. As a presumptive additional mechanism the presence of adhering suppressor cells to blood lymphocytes has been demonstrated in PPD-anergic patients [39]. While the explanatory evidence may remain scanty, it should be emphasised that in clinical practice the phenomenon appears to be transitory and restricted to the early phase of tuberculous infection. It might thus be associated with the pre-allergic phase of tuberculous infection, since conver‐ sion of skin reactivity has been subsequently observed within a 6-8 weeks delay [27]. As a reverse conclusion in the framework of discussed hypotheses the observation of a delayed PPD-conversion might be interpreted as a clue to primary infection to have occurred. Persisting anergy would then point to other immune-modulating factors like advanced age, certain drug

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 275

In Europe commercially available Interferon-γ-release assays (IGRA) are the QuantiFERON-TB-Gold-Test and the T-Spot-TB-Test. Both use the MTB-RD1-region antigen sequences CFP10 and ESAT 6 and measure the specific lymphocyte-induced quantitative IFN-γ-response or the sensitized IFN-γ-producing lymphocyte response, respectively. There has been elaborated a body of clinical data in practical use highlighting both the assets and pitfalls of the investiga‐ tion. In summary and in general there is distinct superiority to the PPD-skin-test with an overall sensitivity of ~ 85 % and a high specificity well > 90 % [40]. The concordance of the PPD-test and IFN-γ-release assays is in the order of 60-85 % [41]. However in the identification of active clinical tuberculosis blood-based IFN-γ-release assays also have revealed a considerable rate of false negative findings. In several studies including pulmonary a well as pleural tubercu‐ losis, sensitivity was limited to 60-64 % [42, 43, 44]. There have also been a number of incon‐ sistent and equivocal reports where the results obviously vary with different TB-prevalence settings (i. e. pretest probability). In a number of studies the variability of sensitivity ranges between 96 % in low prevalence settings down to 58 % in studies featuring high prevalence areas, also specificity setbacks are reported [45]. Blood-based IGRA´s therefore seem to share the limitations of PPD-testing. Since they cannot distinguish latent from active TB, in conclu‐ sion, the diagnostic value for identification of tuberculous pleurisy in high prevalence settings

When there is enough effusion to allow safe puncture and TB is suspected*, thoracentesis* is a mandatory diagnostic step. The effusion will be invariably and markedly exudative with a (unless in tuberculous empyema) clear, straw- to amber-coloured appearance and a mean protein content above 5.0 g/dl, in one series (n=83) it was 5.2 g/dl (range 3.5 – 7.0) [32]. Glucose and pH-values have traditionally believed to be characteristically low in TB. It appears however, that on the basis of more recent data, as also confirmed in the author´s own experi‐

is very low and has even only limited value in industrialized countries.

interference or immune-compromising comorbidity.

*5.2.2. Interferon-γ-release assays*

**5.3. Pleural fluid analysis**

*5.3.1. Biochemical parameters*

**Figure 2.** Ultrasound detection of inflammatory visceral membranes and consecutively trapped lung in pleuritis exu‐ dativa tuberculosa

**Figure 3.** Ultrasound detection of multiple chambers in pleuritis exudativa tuberculosa

ocal experimental evidence. It appears a valid speculation to consider a local pooling of sensitised T-lymphocytes at the site of infection responsible. Animal experiments and clinical investigations have shown sequestration of PPD-sensitized lymphocytes to the pleural compartment actually to occur in the early phase of infection leading to their systemic depletion [39]. As a presumptive additional mechanism the presence of adhering suppressor cells to blood lymphocytes has been demonstrated in PPD-anergic patients [39]. While the explanatory evidence may remain scanty, it should be emphasised that in clinical practice the phenomenon appears to be transitory and restricted to the early phase of tuberculous infection. It might thus be associated with the pre-allergic phase of tuberculous infection, since conver‐ sion of skin reactivity has been subsequently observed within a 6-8 weeks delay [27]. As a reverse conclusion in the framework of discussed hypotheses the observation of a delayed PPD-conversion might be interpreted as a clue to primary infection to have occurred. Persisting anergy would then point to other immune-modulating factors like advanced age, certain drug interference or immune-compromising comorbidity.

#### *5.2.2. Interferon-γ-release assays*

In Europe commercially available Interferon-γ-release assays (IGRA) are the QuantiFERON-TB-Gold-Test and the T-Spot-TB-Test. Both use the MTB-RD1-region antigen sequences CFP10 and ESAT 6 and measure the specific lymphocyte-induced quantitative IFN-γ-response or the sensitized IFN-γ-producing lymphocyte response, respectively. There has been elaborated a body of clinical data in practical use highlighting both the assets and pitfalls of the investiga‐ tion. In summary and in general there is distinct superiority to the PPD-skin-test with an overall sensitivity of ~ 85 % and a high specificity well > 90 % [40]. The concordance of the PPD-test and IFN-γ-release assays is in the order of 60-85 % [41]. However in the identification of active clinical tuberculosis blood-based IFN-γ-release assays also have revealed a considerable rate of false negative findings. In several studies including pulmonary a well as pleural tubercu‐ losis, sensitivity was limited to 60-64 % [42, 43, 44]. There have also been a number of incon‐ sistent and equivocal reports where the results obviously vary with different TB-prevalence settings (i. e. pretest probability). In a number of studies the variability of sensitivity ranges between 96 % in low prevalence settings down to 58 % in studies featuring high prevalence areas, also specificity setbacks are reported [45]. Blood-based IGRA´s therefore seem to share the limitations of PPD-testing. Since they cannot distinguish latent from active TB, in conclu‐ sion, the diagnostic value for identification of tuberculous pleurisy in high prevalence settings is very low and has even only limited value in industrialized countries.

#### **5.3. Pleural fluid analysis**

#### *5.3.1. Biochemical parameters*

**Figure 3.** Ultrasound detection of multiple chambers in pleuritis exudativa tuberculosa

**Figure 2.** Ultrasound detection of inflammatory visceral membranes and consecutively trapped lung in pleuritis exu‐

dativa tuberculosa

274 Tuberculosis - Current Issues in Diagnosis and Management

When there is enough effusion to allow safe puncture and TB is suspected*, thoracentesis* is a mandatory diagnostic step. The effusion will be invariably and markedly exudative with a (unless in tuberculous empyema) clear, straw- to amber-coloured appearance and a mean protein content above 5.0 g/dl, in one series (n=83) it was 5.2 g/dl (range 3.5 – 7.0) [32]. Glucose and pH-values have traditionally believed to be characteristically low in TB. It appears however, that on the basis of more recent data, as also confirmed in the author´s own experi‐ ence these values are not substantially different from exudates due to other aetiologies. SAHN [46] found pH-values < 7.29 and glucose values < 30 mg/dl in only 20% of patients and this has been confirmed by others [47]. Interestingly however, if low values actually occur, they appear to correlate with the pleural bacillary load and are to some extent predictive of cultural results. In one thoracoscopic study positive pleural fluid culture yield was 59 % when the glucose level was < 50 mg/dl but only 25 % when the glucose values were > 50 mg/dl (p<0.005) [18]. Lactic dehydrogenase (LDH) is a non-specific marker of pleural inflammation, which may be excessively elevated in tuberculous pleurisy, although with a mean value of 423 IU/ml (range 43 – 1.575) as reported in a representative series again does not discriminate TB from para‐ pneumonic and not even from malignant effusion [32]. Adenosine deaminase (ADA) has been a promising and much hailed semispecific biochemical parameter. ADA is an inflammatory enzyme expressed predominantly by sensitized and activated T-lymphocytes. Isoenzymes (ADA2) in addition reflect to some extent monocyte/macrophage activation. Thus increased ADA-activity in general indicates various T cell/macrophage interactive inflammatory processes like granulomatous disease but also empyema and collagen vascular disease. It appears however particularly sensitive to TB. In a key study (n=129) in patients < 35 yrs a receiver operating characteristics (ROC) –derived cut-off level of 47 U/ml allowed distinction of tuberculous effusion from empyema, rheumatic and neoplastic disease with a 100 % sensitivity and 87.5 specificity. When empyema was eliminated, specificity and the positive predictive value even attained 100 % [48]. There are important limitations to the interpretation of these results and their clinical relevance:

pleuritis tuberculosa exudativa is by far the most frequent cause of pleural lymphocytosis [46]. Rarely, in particular in the early phase of inflammation fluid cytology may reveal neutrophil leucocyte (PMN) predominance. Expansion of the eosinophil compartment would be an extremely unusual finding. In the presence of significant numbers of eosinophils (> 5 %)

The microbiological yield from diagnostic (low volume) thoracentesis as far the smear is concerned is very low unless the whole effusion or large amounts are being centrifuged or the patient has a tuberculous empyema [14, 29]. In HIV positive individuals, particularly in those

one study to 37 % vs. 0 % in non HIV-patients [53]. In a comprehensive study on microbiologic smear findings in pleural fluid specimens in non-selected HIV negative out-patients, the positive acid fast smear yield (n=232) again was actually zero [54]. Cultures should be obtained both from the sputum and pleural fluid. The positive cultural yield from pleural fluid has been given in collective reviews with 10 – 35 %, being ~ 25 % in the mean [14, 30]. In one of the largest series (n=100] the sensitivity of pleural fluid culture was 28 % [18, 55]. The use of radiometric or non-radiometric liquid culture systems (BACTEC, MB/BacT, MGIT) will markedly acceler‐ ate results and possibly lead to an enhanced yield (~ 50 %), when bedside instead of laboratory inoculation is used [56]. The yield of sputum cultures in tuberculous effusion is expectedly largely dependent on the extent and nature of pulmonary involvement and may mount up to ~ 50 %. In the non-expectorating patient the use of induced sputum is advised [57]. The positive yield is also believed to be higher in HIV-infected patients [53, 57]. In the complete absence of pulmonary lesions according to most sources the sensitivity will be no more than 4-7 % [30]. Only exceptionally a surprisingly high figure of 31 % for induced sputum has been reported

Immunological studies of pleural fluid in TB-pleurisy focus on the measurement and analysis of chemokins and interleukins that are characteristically associated with the tuberculous immune response. TNFα and IFNγ revealed at a cut-off 140 pg/ml a sensitivity of 94 % and a specificity of 85 % [58,60]. Similarly as for ADA the major confounders were bacterial empyema and parapneumonic effusion respectively. Interestingly TNFα did not attain enough discrim‐ inatory power to separate TB from various inflammatory conditions and is no more considered a valid option in the diagnosis of TB. More recent meta analysis-derived collective data from 22 studies resulted in an overall sensitivity of 89 % at a 97 % specificity [61]. Thus at present IFNγ-determination in pleural fluid – contrasting to systemic IGRA-application – would appear a useful diagnostic test with a sensitivity and discriminatory power comparable to that of ADA-determination if one was to accept the significantly higher costs and disregard more powerful diagnostic options as provided by subsequently discussed invasive biopsy techni‐

/l significantly higher yields are being reported amounting in

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 277

differential diagnoses should be considered.

*5.3.3. Microbiological studies*

with CD4 cell counts < 200 x 106

*5.3.4. Immunological and molecular studies*

[57].

ques.


Nevertheless, based on the most accepted cut-off level of 40 IU/l and provided its critical use in areas of at least intermediate TB-prevalence ADA determination must be regarded as a true diagnostic enrichment. An era of successful ADA-use has been recently summarized and confirmed by a large size metaanalysis (63 studies, 5297 tuberculous and non-tuberculous effusions) resulting in a sensitivity and specificity of 92 % and 90 % respectively [52].

#### *5.3.2. Cytological analysis*

Based on the immunological processes involved, a marked lymphocytosis is the predicted and characteristic feature of TB-pleurisy along with significantly increased total white cell counts as reflected in one representative study with a mean count of 2.309/mm3 (range 30 – 24.009 mm3 ) [32]. Usually 90 – 95 % of pleural fluid cells are T-lymphocytes, the remainder being Blymphocytes and (mostly) activated mesothelial cells. Only exceptionally (in ~ 5 %) lympho‐ cyte counts < 50 % may occur [27]. Thus when an 80 % lymphocyte reference line is chosen, pleuritis tuberculosa exudativa is by far the most frequent cause of pleural lymphocytosis [46]. Rarely, in particular in the early phase of inflammation fluid cytology may reveal neutrophil leucocyte (PMN) predominance. Expansion of the eosinophil compartment would be an extremely unusual finding. In the presence of significant numbers of eosinophils (> 5 %) differential diagnoses should be considered.
